Ludvig A Munthe

• Tjärnhage, Elias; Våtsveen, Thea Kristin; Raki, Melinda; Nemazee, David; Farhan, Hesso & Munthe, Ludvig Andre [Vis alle 7 forfattere av denne artikkelen] (2026). Repurposing ALK inhibitors as influenza and corona virus antivirals targeting lymphocyte tyrosine kinase (LTK). Virus Research. ISSN 0168-1702. 370. doi: 10.1016/j.virusres.2026.199759. Fulltekst i vitenarkiv
• Douvlataniotis, Dimitrios Karolos; Titov, Aleksei; Zeun, Julia; Bilici, Merve; Palashati, Heyilimu & Loh, Waywen [Vis alle 23 forfattere av denne artikkelen] (2026). TCR T cells targeting IgA- and IgG-expressing multiple myeloma. Blood. ISSN 0006-4971. doi: 10.1182/blood.2025031897. Fulltekst i vitenarkiv Vis sammendrag

  T cell-based therapies have shown remarkable efficacy in multiple myeloma (MM), yet the disease remains largely incurable. Here, we investigated the constant domains of the immunoglobulin heavy chain (IgH) as novel targets for therapeutic T cell receptors (TCRs), after confirming high and homogeneous IGH expression in >95% of MM patients. MM cells secrete excessive monoclonal immunoglobulins (M-proteins) that drive complications but are inaccessible to CAR T-cell or antibody targeting. Peptides from IgA and IgG constant regions were eluted from HLA-A*02:01, and reactive TCRs were isolated from healthy donors using allo-HLA-A*02:01 presentation to circumvent self-tolerance. T cells engineered with two TCRs specific for IgA or IgG passed a stringent multi-tier safety screen and selectively eliminated MM cells from 20 HLA-A*02:01+ patients secreting the relevant IgH in vitro. In vivo, IgA-TCR T cells eradicated IgA+HLA-A*02:01+ MM cells in xenograft models and reduced circulating IgA in humanized mice. These findings establish immunoglobulin constant domains as viable TCR targets in MM, potentially making ~40% of patients of European descent eligible for TCR T cell therapy, and extension to additional HLA alleles could further broaden eligibility. The approach may also be applicable to lymphoma and antibody-mediated autoimmune diseases.

• Gopalakrishnan, Ramakrishna Prabhu; Ward, Jerrold M.; Greiff, Victor; Braathen, Ranveig; Hu, Xian & Bajelan, Livia [Vis alle 10 forfattere av denne artikkelen] (2026). Idiotype-specific CD4+ T cells chronically stimulate autoreactive B cells to develop into B lymphomas in mice. Nature Communications. doi: 10.1038/s41467-026-69916-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Autoimmunity increases the risk of developing B lymphoma in humans; however, the molecular mechanism(s) underlying this link remain(s) unexplained. Here, we develop a mouse model to dissect the contribution of Id-driven T-B collaboration and show that chronic interaction between B cells and CD4 + T cells first leads to autoimmunity and later to the development of B (and T) cell lymphomas. We find that serum autoantibodies and lymphoma B cell receptor (BCR) are related and have the same specificity for ubiquitous self-antigens (histone and nucleosome) (Signal 1). Self-reactive B lymphoma cells are helped by CD4 + T cells that recognize a lymphoma neoantigen, an MHC class II-presented Idiotypic (Id) peptide (Signal 2). The mechanism, called Id-driven T-B collaboration, results in relentless mutual stimulation of B and T cells with germinal center markers, autoimmunity, and finally, malignant transformation of either B or T cells. Our results thus indicate Id-driven T-B collaboration as a potential mechanism linking autoimmunity and the development of lymphomas.

• Tsykunova, Galina; Holme, Pål Andre; Tran, Hoa Thi Tuyet; Frederiksen, Henrik; Tjønnfjord, Eirik & Munthe, Ludvig Andre [Vis alle 16 forfattere av denne artikkelen] (2025). Safety and Efficacy of Daratumumab in Immune Thrombocytopenia. Blood Advances. ISSN 2473-9529. 10(1), s. 143–154. doi: 10.1182/bloodadvances.2025017279. Fulltekst i vitenarkiv Vis sammendrag

  Resistance to B-cell targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38-positive long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase II study evaluated safety and efficacy of daratumumab in 21 previously treated ITP patients. Following a safety run-in, two dosing cohorts were included, receiving eight and ten subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary endpoints were safety and response (two consecutive platelet counts ≥50x109/L at week 12 for the safety run-in/Cohort 1, and at week 16 for Cohort 2). At baseline, median platelet count was 17x109/L, median number of prior therapies was four. Most treatment-emergent adverse events were transient grade 1-2, most commonly infections (38%).Two patients (4.7%) experienced grade 3 adverse events, one infusion-related reaction, and one SARS-CoV-2 infection with acute renal failure. Ten patients (48%) met the primary efficacy endpoint. Sustained response (two consecutive platelet counts ≥50x109/L at week 24) was achieved in eight patients (38%). Two patients relapsed after week 24. There was no difference in response or relapse rates between cohorts. Patient-reported quality of life measured by SF-36 improved in responding patients. Daratumumab decreased immunoglobulin levels in all patients, and substantially reduced CD38+ cells in peripheral blood and bone marrow. There was no significant difference in anti-platelet antibodies between responders and non-responders. This study confirms CD38 as an important target in ITP. NCT04703621; EudraCT 2019-004683-22.

• Podgorica, Mirjam; Drivet, Elsa Maria Caroline; Vestbøstad, Johanne Bonsaksen; Kvam, Ann Kristin; Wik, Hilde Skuterud & Munthe, Ludvig [Vis alle 7 forfattere av denne artikkelen] (2025). Azaindole 1, a selective Rock1/2 kinase inhibitor, induces G2/M arrest and cell death in B-cell acute lymphoblastic leukemia (B-ALL). Leukemia and Lymphoma. ISSN 1042-8194. 66(12), s. 2311–2315. doi: 10.1080/10428194.2025.2536125. Fulltekst i vitenarkiv
• Våtsveen, Thea Kristin; Giliberto, Mariaserena; Björnsdottir, Valgerdur; Centonze, Federica Grazia; Besse, Andrej & Frey, Yannick [Vis alle 19 forfattere av denne artikkelen] (2025). Targeting proteostasis in multiple myeloma through inhibition of LTK. Leukemia. ISSN 0887-6924. 39(9), s. 2237–2245. doi: 10.1038/s41375-025-02682-8. Fulltekst i vitenarkiv Vis sammendrag

  Multiple myeloma (MM) cells secrete high levels of immunoglobulin and are therefore addicted to mechanisms that maintain proteome homeostasis (proteostasis). While proteasome inhibitors that target the degradative aspect of proteostasis have proven effective, only limited attempts have been made to target protein secretion. Here we show that the receptor tyrosine kinase LTK is a regulatory node in the proteostasis network that responds to secretory load and helps cells maintain a high secretory output. LTK is a highly similar paralog to ALK and by repurposing existing ALK inhibitors, we demonstrate that targeting LTK causes immunoglobulin retention, ER stress and subsequent apoptosis of primary MM cells, even in patients refractory to proteasome inhibitors. Thus, LTK is a novel therapeutic target in the biosynthetic pathway of proteostasis, with significant potential for MM treatment.

• Viermyr, Hans-Kittil; Tonby, Kristian; Ponzi, Erica; Trouillet-Assant, Sophie; Poissy, Julien & Arribas, José R. [Vis alle 49 forfattere av denne artikkelen] (2024). Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial. EBioMedicine. 111. doi: 10.1016/j.ebiom.2024.105511. Fulltekst i vitenarkiv Vis sammendrag

  Background The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Methods Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Findings Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. Interpretation This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

• Podgorica, Mirjam; Drivet, Elsa Maria Caroline; Viken, Jonas Krag; Richman, Alyssa; Vestbøstad, Johanne Bonsaksen & Szodoray, Peter [Vis alle 12 forfattere av denne artikkelen] (2024). Transcriptome analysis of primary adult B-cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis. European Journal of Haematology. ISSN 0902-4441. 112(5), s. 731–742. doi: 10.1111/ejh.14164. Fulltekst i vitenarkiv Vis sammendrag

  Background B-cell acute lymphoblastic leukemia (B-ALL) is classified into subgroups based on known driver oncogenes and molecular lesions, including translocations and recurrent mutations. However, the current diagnostic tests do not identify subtypes or oncogenic lesions for all B-ALL samples, creating a heterogeneous B-ALL group of unknown subtypes. Methods We sorted primary adult B-ALL cells and performed transcriptome analysis by bulk RNA sequencing (RNA-seq). Results Transcriptomic analysis of an adult B-ALL cohort allowed the classification of four patient samples with subtypes that were not previously revealed by standard gene panels. The leukemia of two patients were of the DUX4 subtype and two were CRLF2+ Ph-like B-ALL. Furthermore, single nucleotide variant analysis detected the oncogenic NRAS-G12D, KRAS-G12D, and KRAS-G13D mutations in three of the patient samples, presenting targetable mutations. Additional oncogenic variants and gene fusions were uncovered, as well as multiple variants in the PDE4DIP gene across five of the patient samples. Conclusion We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.

• Wolf, Asia-Sophia Fumika Michaela; Hammersbøen, Kristin Reine; Ørbo, Hilde Sofie Sager; Bhandari, Sabin; Solum, Guri & Kjønstad, Ingrid Fadum [Vis alle 30 forfattere av denne artikkelen] (2024). T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study. EBioMedicine. 108. doi: 10.1016/j.ebiom.2024.105317. Fulltekst i vitenarkiv Vis sammendrag

  Background Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2–4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. Findings Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.

• Kared, Hassen; Jyssum, Ingrid; Alirezaylavasani, Amin; Egner, Ingrid Marie; Tran, Trung & Tietze, Lisa [Vis alle 17 forfattere av denne artikkelen] (2024). Dynamics of SARS-CoV-2 immunity after vaccination and breakthrough infection in rituximab-treated rheumatoid arthritis patients: a prospective cohort study. Frontiers in Immunology. 15:1296273, s. 1–12. doi: 10.3389/fimmu.2024.1296273. Fulltekst i vitenarkiv Vis sammendrag

  Background: SARS-CoV-2 vaccination in rheumatoid arthritis (RA) patients treated with B cell-depleting drugs induced limited seroconversion but robust cellular response. We aimed to document specific T and B cell immunity in response to vaccine booster doses and breakthrough infection (BTI). Methods: We included 76 RA patients treated with rituximab who received up to four SARS-CoV-2 vaccine doses or three doses plus BTI, in addition to vaccinated healthy donors (HD) and control patients treated with tumor necrosis factor inhibitor (TNFi). We quantified anti-SARS-CoV-2 receptor-binding domain (RBD) Spike IgG, anti-nucleocapsid (NC) IgG, 92 circulating inflammatory proteins, Spike-binding B cells, and Spike-specific T cells along with comprehensive high-dimensional phenotyping and functional assays. Findings: The time since the last rituximab infusion, persistent inflammation, and age were associated with the anti-SARS-CoV-2 RBD IgG seroconversion. The vaccine-elicited serological response was accompanied by an incomplete induction of peripheral Spike-specific memory B cells but occurred independently of T cell responses. Vaccine- and BTI-elicited cellular immunity was similar between RA and HD ex vivo in terms of frequency or phenotype of Spike-specific cytotoxic T cells and in vitro in terms of the functionality and differentiation profile of Spike-specific T cells. Interpretation: SARS-CoV-2 vaccination in RA can induce persistent effector T-cell responses that are reactivated by BTI. Paused rituximab medication allowed serological responses after a booster dose (D4), especially in RA with lower inflammation, enabling efficient humoral and cellular immunity after BTI, and contributed overall to the development of potential durable immunity.

• Imbery, John Franklin; Wiik, Celina Marie; Heinzelbecker, Julia; Jebsen, Jenny Karoline; Dobbing, Mia K. & Bottini, Nunzio [Vis alle 12 forfattere av denne artikkelen] (2024). CD38 regulates chronic lymphocytic leukemia proliferation via CD45 phosphatase activity. Molecular Therapy: Oncology. 32(3), s. 1–15. doi: 10.1016/j.omton.2024.200841. Fulltekst i vitenarkiv Vis sammendrag

  Chronic lymphocytic leukemia (CLL) growth is dependent on both B cell receptor (BCR) signaling and signals from microenvironmental T helper (Th) cells. We previously described a mechanism where Th cells enhance BCR signaling and proliferation through CD45 phosphatase activity regulation via galectin-1 and CD43. The CLL negative prognostic indicator CD38 is linked to BCR signaling and proliferation, with its expression induced by Th cells. Here, we explore a link between CD38 and CD45 phosphatase activity regulation using patient-derived material in a Th-CLL cell co-culture model. Results demonstrate CD43 and galectin-1 are co-expressed with CD38, defining proliferative CLL cells with augmented CD45 activity. CD38 enzymatic and receptor inhibition regulated CD43 and galectin-1 expression, CD45 activityhi populations, and CLL proliferation, while leaving Th cells largely unaffected. Mechanistically, CD38- or LGALS1 (galectin-1)-deficient malignant B cell lines further confirmed CD38-mediated regulation of CD45 activity and BCR signaling through CD43 expression and galectin-1 surface binding, while galectin-1 contributed to CD43/CD45 colocalization. Together, this highlights CD38 as an important regulator of CD45 activity via CD43 and galectin-1, in turn acting as a positive modulator of CLL proliferation. Ultimately, the CD38/CD45 molecular hub could be an important therapeutic target in CLL.

• Alirezaylavasani, Amin; Egner, Ingrid Marie; Dahl, Tuva Børresdatter; Chopra, Adity; Kasahara, Taissa de Matos & Goll, Guro Løvik [Vis alle 15 forfattere av denne artikkelen] (2024). Deficient SARS-CoV-2 hybrid immunity during inflammatory bowel disease. Clinical Immunology. ISSN 1521-6616. 271, s. 1–13. doi: 10.1016/j.clim.2024.110404. Fulltekst i vitenarkiv Vis sammendrag

  Patients with Inflammatory Bowel Disease (IBD) undergoing immunosuppressive therapies face heightened susceptibility to severe COVID-19. An in-depth understanding of systemic inflammation and cellular immune responses after SARS-CoV-2 vaccination and breakthrough infections (BTI) is required for optimizing vaccine strategies in this population. While the prevalence of high serological responders post- third COVID-19 vaccine dose was lower, and the antibody waning was higher in IBD patients than in healthy donors (HD), IBD patients showed an increase in anti-RBD Wild Type IgG levels and cross-reactive Spike -specific memory B cells following BTI. However, there was no significant enhancement in cellular immune responses against anti-SARS-CoV-2 post-BTI, with responses instead characterized by activation of SARS-CoV-2 specific and also bystander CD8 T cells. These results suggest a complex interaction between chronic inflammation in IBD and the generation of new immune responses, highlighting the need for tailored vaccine regimens and anti-inflammatory therapies to boost cellular immunity against SARS-CoV-2.

• Wüsthoff, Linda Elise Couëssurel; Lund-Johansen, Fridtjof; Henriksen, Kathleen; Wildendahl, Gull; Jacobsen, Jon-Aksel & Gomes, Leni [Vis alle 11 forfattere av denne artikkelen] (2024). Seroprevalence of SARS-CoV-2 and humoral immune responses to COVID-19 mRNA vaccines among people who use drugs - in the light of tailored mitigating strategies. Harm Reduction Journal. 21(1). doi: 10.1186/s12954-024-01023-9. Fulltekst i vitenarkiv Vis sammendrag

  Background During the initial wave of the COVID-19 pandemic, there was a surprisingly low incidence of SARS-CoV-2 among People Who Use Drugs (PWUD) in Oslo, Norway, despite their heightened vulnerability regarding risk of infection and severe courses of the disease.This study aims to investigate the seroprevalence of SARS-CoV-2 antibodies among PWUD, their antibody responses to relevant virus infections and COVID-19 mRNA vaccines, and their vaccination coverage compared to the general population. Methods Conducted as a prospective cohort study, data was collected from residents in six institutions for homeless PWUD and users of a low-threshold clinic for opioid agonist treatment. Ninety-seven participants were recruited for SARS-CoV-2 seroprevalence analysis. Additional two participants with known positive SARS-CoV-2 test results were recruited for further analyses. Twenty-five participants completed follow-up. Data included questionnaires, nasal swabs and blood samples. Data on vaccination coverage was obtained from the National Vaccine Register. Serologic methods included detection of antibodies to relevant virus proteins, neutralizing antibodies to SARS-CoV-2, antibodies to the full-length spike protein, and receptor-binding domain from SARS-CoV-2. Results Among PWUD, antibodies to SARS-CoV-2 were detected in 2 out of 97 samples before vaccines against SARS-CoV-2 were available, comparable to a 2.8% frequency in population-based screening. Levels of serum antibodies to seasonal coronaviruses and Epstein-Barr-Virus (EBV) in PWUD were similar to population-based levels. After the second vaccine dose, binding and neutralizing antibody levels to SARS-CoV-2 in PWUD were comparable to controls. Eighty-four of PWUD received at least one dose of COVID-19 mRNA vaccine, compared to 89% in the general population. Conclusion Results indicate that PWUD did not exhibit increased SARS-CoV-2 seroprevalence or elevated serum antibodies to seasonal coronaviruses and EBV. Moreover, vaccine responses in PWUD were comparable to controls, suggesting that vaccination is effective in conferring protection against SARS-CoV-2 also in this population.

• Heinzelbecker, Julia; Fauskanger, Marte; Jonson, Ida; Krengel, Ute; Løset, Geir Åge & Munthe, Ludvig Andre [Vis alle 7 forfattere av denne artikkelen] (2024). Chimeric antigen receptor T cells targeting the GM3(Neu5Gc) ganglioside. Frontiers in Immunology. 15:1331345, s. 1–12. doi: 10.3389/fimmu.2024.1331345. Fulltekst i vitenarkiv Vis sammendrag

  Chimeric antigen receptor (CAR) T cell technology has ushered in a new era of immunotherapy, enabling the targeting of a broad range of surface antigens, surpassing the limitations of traditional T cell epitopes. Despite the wide range of non-protein tumor-associated antigens, the advancement in crafting CAR T cells for these targets has been limited. Owing to an evolutionary defect in the CMP-Neu5Ac hydroxylase (CMAH) that abolishes the synthesis of CMP-Neu5Gc from CMP-Neu5Ac, Neu5Gc is generally absent in human tissues. Despite this, Neu5Gc-containing antigens, including the ganglioside GM3(Neu5Gc) have consistently been observed on tumor cells across a variety of human malignancies. This restricted expression makes GM3(Neu5Gc) an appealing and highly specific target for immunotherapy. In this study, we designed and evaluated 14F7-28z CAR T cells, with a targeting unit derived from the GM3(Neu5Gc)-specific murine antibody 14F7. These cells exhibited exceptional specificity, proficiently targeting GM3(Neu5Gc)-expressing murine tumor cells in syngeneic mouse models, ranging from B cell malignancies to epithelial tumors, without compromising safety. Notably, human tumor cells enhanced with murine Cmah were effectively targeted and eliminated by the 14F7 CAR T cells. Nonetheless, despite the detectable presence of GM3(Neu5Gc) in unmodified human tumor xenografts, the levels were insufficient to trigger a tumoricidal T-cell response with the current CAR T cell configuration. Overall, our findings highlight the potential of targeting the GM3(Neu5Gc) ganglioside using CAR T cells across a variety of cancers and set the stage for the optimization of 14F7-based therapies for future human clinical application.

• Alirezaylavasani, Amin; Skeie, Linda Gail; Egner, Ingrid Marie; Chopra, Adity; Dahl, Tuva Børresdatter & Prebensen, Christian Haugland [Vis alle 16 forfattere av denne artikkelen] (2024). Vaccine responses and hybrid immunity in people living with HIV after SARS-CoV-2 breakthrough infections. npj Vaccines. 9(1), s. 1–15. doi: 10.1038/s41541-024-00972-3. Fulltekst i vitenarkiv Vis sammendrag

  The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count <350 cells per mm3). Their diminished vaccine responses raised concerns about their vulnerability to SARS-CoV-2 breakthrough infections (BTI). Our in-depth study here revealed chronic inflammation in PLWH and a limited anti-Spike IgG response after vaccination in INR. Nevertheless, the imprinting of Spike-specific B cells by vaccination significantly enhanced the humoral responses after BTI. Notably, the magnitude of cellular CD4 response in all PLWH was comparable to that in healthy donors (HD). However, the polyfunctionality and phenotype of Spike-specific CD8 T cells in INR differed from controls. The findings highlight the need for additional boosters with variant vaccines, and for monitoring ART adherence and the durability of both humoral and cellular anti-SARS-CoV-2 immunity in INR.

• Ørbo, Hilde Sofie Sager; Kasahara, Taissa de Matos; Wolf, Asia-Sophia Fumika Michaela; Bjørlykke, Kristin Hammersbøen; Sexton, Joseph & Jyssum, Ingrid [Vis alle 24 forfattere av denne artikkelen] (2024). Humoral and cellular responses to a fifth bivalent SARS-CoV-2 vaccine dose in patients with immune-mediated inflammatory diseases on tumour necrosis factor inhibitors: a prospective cohort study. The Lancet Regional Health - Europe. 48. doi: 10.1016/j.lanepe.2024.101121. Fulltekst i vitenarkiv Vis sammendrag

  Background As most people now have established hybrid immunity, the need for regular, updated SARS-CoV-2 vaccine boosters in patients with immune-mediated inflammatory diseases (IMIDs) is unclear. The study aim was to assess humoral and cellular immunogenicity of a fifth bivalent vaccine dose in patients with IMID on tumour necrosis factor inhibitors (TNFi). Methods In the longitudinal, observational Nor-vaC study, we assessed anti-spike and neutralising antibodies against Wuhan, Omicron BA.1 and BA.4, as well as frequency and polyfunctionality of responding T cells, following a fourth monovalent and a fifth bivalent (BA.1 or BA.4/5) vaccine dose in patients with or without hybrid immunity using TNFi. Findings Between December 17, 2021, and June 20, 2023, 456 infection-naïve patients with IMIDs using TNFi received a fourth vaccine dose and were otherwise eligible for inclusion. A total of 373/456 (82%) received a fifth vaccine dose, of these 190/373 (51%) had hybrid immunity defined as having had COVID-19 between the fourth and fifth dose. In patients with hybrid immunity, the fifth dose did not induce improved humoral responses compared to infection, neither with BA.1 (median anti-spike antibody concentrations 23,244 IU/ml (IQR 15,138–45,233) vs 36,341 IU/ml (11,887–53,710), p = 0.52) nor BA.4/5 (31,693 IU/ml (15,176–54,186), p = 0.30). Comparison of neutralising antibodies yielded similar results. In infection-naïve patients, a fifth BA.4/5 vaccine, but not the BA.1, induced slightly higher humoral responses (18,890 IU/ml (6494–50,211)) compared to the fourth dose (7304 IU/ml (3245–17,260), p < 0.0001). CD8 T cell responses remained stable following a fourth dose (median frequency of spike-specific cells 0.039% (IQR 0.010–0.14)), infection (0.058% (0.026–0.17)) and a fifth dose (0.058% (0.013–0.20). Interpretation In patients on TNFi with hybrid immunity, there was no immunological benefit of an updated fifth SARS-CoV-2 booster dose. Stable CD8 cellular responses following four doses indicate established protective immunity. Patients whose only risk factor is TNFi may in future follow vaccine recommendations for the general population.

• Ørbo, Hilde Sofie Sager; Hammersbøen, Kristin Reine; Sexton, Joseph; Jyssum, Ingrid; Tveter, Anne Therese & Christensen, Ingrid Egeland [Vis alle 18 forfattere av denne artikkelen] (2024). Incidence and outcome of COVID-19 following vaccine and hybrid immunity in patients on immunosuppressive therapy: identification of protective post-immunisation anti-RBD antibody levels in a prospective cohort study. RMD Open. 10(2). doi: 10.1136/rmdopen-2023-003545. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication. Methods IMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2–5 weeks post-immunisation. Results Between 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels <6000 binding antibody units/mL were associated with an increased risk of COVID-19 following three (HR 1.37 (95% CI 1.08 to 1.74)) and four doses (HR 1.28 (95% CI 1.02 to 1.62)), and of COVID-19 re-infection (HR 4.47 (95% CI 1.87 to 10.67)). Conclusion Vaccinated patients with IMID have a low risk of severe COVID-19. Hybrid immunity lowers the risk of infection. High post-immunisation anti-RBD levels protect against COVID-19. These results suggest that knowledge on COVID-19 history, and assessment of antibody levels post-immunisation can help individualise vaccination programme series in high-risk individuals. Trial registration number NCT04798625.

• Ravussin, Anthony; Robertson, Anna Hayman; Wolf, Asia-Sophia Fumika Michaela; Blix, Kristine; Kjønstad, Ingrid Fadum & Solum, Guri [Vis alle 13 forfattere av denne artikkelen] (2023). Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study. The Lancet Healthy Longevity. 4(5), s. e188–e199. doi: 10.1016/S2666-7568(23)00055-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65–80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses. Methods 4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries. Findings Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04). Interpretation Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing.

• Malecka, Agnieszka Maria; Østlie, Ingunn; Trøen, Gunhild; Malecki, Jedrzej Mieczyslaw; Delabie, Jan & Tierens, Anne [Vis alle 9 forfattere av denne artikkelen] (2023). Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease. Clinical and Experimental Immunology. ISSN 0009-9104. 216(1), s. 45–54. doi: 10.1093/cei/uxad135. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.

• Federico, Lorenzo; Malone, Brandon; Tennøe, Simen; Chaban, Viktoriia; Osen, Julie Røkke & Gainullin, Murat [Vis alle 13 forfattere av denne artikkelen] (2023). Experimental validation of immunogenic SARS-CoV-2 T cell epitopes identified by artificial intelligence. Frontiers in Immunology. 14:1265044, s. 1–14. doi: 10.3389/fimmu.2023.1265044. Fulltekst i vitenarkiv Vis sammendrag

  During the COVID-19 pandemic we utilized an AI-driven T cell epitope prediction tool, the NEC Immune Profiler (NIP) to scrutinize and predict regions of T cell immunogenicity (hotspots) from the entire SARS-CoV-2 viral proteome. These immunogenic regions offer potential for the development of universally protective T cell vaccine candidates. Here, we validated and characterized T cell responses to a set of minimal epitopes from these AI-identified universal hotspots. Utilizing a flow cytometry-based T cell activation-induced marker (AIM) assay, we identified 59 validated screening hits, of which 56% (33 peptides) have not been previously reported. Notably, we found that most of these novel epitopes were derived from the non-spike regions of SARS-CoV-2 (Orf1ab, Orf3a, and E). In addition, ex vivo stimulation with NIP-predicted peptides from the spike protein elicited CD8 + T cell response in PBMC isolated from most vaccinated donors. Our data confirm the predictive accuracy of AI platforms modelling bona fide immunogenicity and provide a novel framework for the evaluation of vaccine-induced T cell responses.

• Kared, Hassen; Alirezaylavasani, Amin; Lund, Kathrine Persgård; Chopra, Adity; Tietze, Lisa & Kasahara, Taissa de Matos [Vis alle 17 forfattere av denne artikkelen] (2023). Hybrid and SARS-CoV-2-vaccine immunity in kidney transplant recipients. EBioMedicine. 97. doi: 10.1016/j.ebiom.2023.104833. Fulltekst i vitenarkiv Vis sammendrag

  Background Kidney transplant recipients (KTR) are at high risk for severe COVID-19 and have demonstrated poor response to vaccination, making it unclear whether successive vaccinations offer immunity and protection. Methods We conducted a serologically guided interventional study where KTR patients that failed to seroconvert were revaccinated and also monitored seroconversion of KTR following the Norwegian vaccination program. We analysed IgG anti-RBD Spike responses from dose 2 (n = 432) up to after the 6th (n = 37) mRNA vaccine dose. The frequency and phenotype of Spike-specific T and B cell responses were assessed in the interventional cohort after 3–4 vaccine doses (n = 30). Additionally, we evaluated the Specific T and B cell response to breakthrough infection (n = 32), measured inflammatory cytokines and broadly cross-neutralizing antibodies, and defined the incidence of COVID-19-related hospitalizations and deaths. The Norwegian KTR cohort has a male dominance (2323 males, 1297 females), PBMC were collected from 114 male and 78 female donors. Findings After vaccine dose 3, most KTR developed Spike-specific T cell responses but had significantly reduced Spike-binding B cells and few memory cells. The B cell response included a cross-reactive subset that could bind Omicron VOC, which expanded after breakthrough infection (BTI) and gave rise to a memory IgG+ B cell response. After BTI, KTR had increased Spike-specific T cells, emergent non-Spike T and B cell responses, and a systemic inflammatory signature. Late seroconversion occurred after doses 5–6, but 38% (14/37) of KTR had no detectable immunity even after multiple vaccine doses. Interpretation Boosting vaccination can induce Spike-specific immunity that may expand in breakthrough infections highlighting the benefit of vaccination to protect this vulnerable population.

• Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; König, Marton; Øverås, Mathias Herstad; Solum, Guri & Kjønstad, Ingrid Fadum [Vis alle 18 forfattere av denne artikkelen] (2023). T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis. JCI Insight. 8(12), s. 1–14. doi: 10.1172/jci.insight.165111. Fulltekst i vitenarkiv Vis sammendrag

  Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

• Jørgensen, Kristin Kaasen; Høivik, Marte Lie; Chopra, Adity; Benth, Jurate Saltyte; Ricanek, Petr & Moum, Bjørn Allan [Vis alle 18 forfattere av denne artikkelen] (2023). Humoral immune response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease on immunosuppressive medication: association to serum drug levels and disease type. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 58(8), s. 874–882. doi: 10.1080/00365521.2023.2177884. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterized. The aims of this study were to explore the serological response associated with IBD, and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. Materials and methods This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn’s disease (CD), and healthy controls. Antibodies to the receptor-binding domain of SARS-CoV-2 spike proteins, and serum concentrations of ongoing biologic and immunomodulatory medications were assessed prior to, and 2-5 weeks after the second vaccine dose. Serologic response was defined as anti-Spike antibodies ≥70 AU/ml. Results In 958 IBD patients (380 UC, 578 CD) and 323 healthy controls, the median (Q1; Q3) anti-Spike antibody level (AU/ml) was lower in patients (618 (192; 4370)) compared to controls (3355 (896; 7849)) (p < 0.001). The antibody levels were lower in CD (439 (174; 3304)) compared to UC (1088 (251; 5975)) (p < 0.001). No associations were demonstrated between antibody levels and serum drug concentrations for TNF inhibitor (TNFi), vedolizumab and ustekinumab. Patients receiving TNFi + thiopurines with a subtherapeutic 6-thioguanine nucleotide (6-TGN) level had higher response rate (93%) compared to patients with 6-TGN within the therapeutic range (53%) (p = 0.003). A diagnosis of UC, mRNA-1273 vaccine, and other treatments than TNFi + thiopurines were associated with humoral response. Conclusions Patients with CD had an attenuated humoral response to SARS-COV-2 vaccination as compared to patients with UC. The lack of association between serum levels of biologics and serologic response indicates vaccination regardless of proximity to drug administration.

• Gainullin, Murat; Federico, Lorenzo; Osen, Julie Røkke; Chaban, Viktoriia; Kared, Hassen & Alirezaylavasani, Amin [Vis alle 18 forfattere av denne artikkelen] (2023). People who use drugs show no increase in pre-existing T-cell cross-reactivity toward SARS-CoV-2 but develop a normal polyfunctional T-cell response after standard mRNA vaccination. Frontiers in Immunology. 14:1235210, s. 1–13. doi: 10.3389/fimmu.2023.1235210. Fulltekst i vitenarkiv Vis sammendrag

  People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4 + and CD8 + T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients.

• Hovd, Markus Herberg; Åsberg, Anders; Munthe, Ludvig Andre; Heldal, Kristian; Reisæter, Anna Varberg & Vaage, John T. [Vis alle 8 forfattere av denne artikkelen] (2023). Humoral vaccine response and breakthrough infections in kidney transplant recipients during the COVID-19 pandemic: a nationwide cohort study. EClinicalMedicine. 60. doi: 10.1016/j.eclinm.2023.102035. Fulltekst i vitenarkiv Vis sammendrag

  Background Kidney transplant recipients (KTRs) experienced reduced SARS-CoV-2 vaccine response and were at increased risk of severe COVID-19. It is unknown if level of vaccine induced anti-receptor binding domain IgG (anti-RBD IgG) correlates with protection from and survival following COVID-19. We aimed to evaluate the effect of vaccine response on risk of breakthrough infections (BTI) and COVID-19 death in KTRs. Methods We performed a nationwide study, examining the competing risk of SARS-CoV-2 infection, COVID-19 related/unrelated death, and vaccine efficacy as assessed by level of anti-RBD IgG response 4–10 weeks after each vaccination. The study included all KTR in Norway alive and with a functioning graft on February 20th, 2020, and events after November 11th, 2022 were right-censored. A pre-pandemic reference-cohort from January 1st 2019 to January 1st 2020 was included to evaluate excess mortality. The study was conducted at Oslo University Hospital, Rikshospitalet, Norway. Findings The study included 3607 KTRs (59 [48–70] years) with a functioning graft at February 20th, 2020, who received (median [IQR]) 4 [3–4] vaccines (range 2–6, 99% mRNA). Anti-RBD IgG was measured in 12 701 serum samples provided by 3213 KTRs. Vaccine response was assessed 41 [31–57] days after vaccination. A total of 1090 KTRs were infected with SARS-CoV-2, 1005 (92%) were BTI, and vaccine response did not protect against BTI. The hazard ratio for COVID-19 related death 40 days post-infection was 1.71 (95% CI: 1.14, 2.56) comparing vaccine response levels (≥5 vs. ≥5000 BAU/mL). No excess non-COVID-19 mortality was registered in KTRs surviving SARS-CoV-2 infection compared to a 2019 pre-pandemic reference. Interpretation Our findings suggested that SARS-CoV-2 mRNA vaccine response did not predict protection against infection, but prevention of fatal disease progression in KTRs and greater vaccine response further reduced the risk of COVID-19 death. No excess non-COVID-19 mortality was seen during the pandemic.

• Hermansen, Johanne Uthus; Yin, Yanping; Urban, Aleksandra; Myklebust, Camilla Victoria; Karlsen, Linda & Melvold, Katrine [Vis alle 11 forfattere av denne artikkelen] (2023). A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine. Cell death discovery. 9. doi: 10.1038/s41420-023-01426-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL that are used to test drug sensitivity must mimic the tumor microenvironment to reflect clinical responses. Ex vivo models have been developed that capture individual or multiple aspects of the CLL microenvironment, but they are not necessarily compatible with high-throughput drug screens. Here, we report on a model that has reasonable associated costs, can be handled in a regularly equipped cell lab, and is compatible with ex vivo functional assays including drug sensitivity screens. The CLL cells are cultured with fibroblasts that express the ligands APRIL, BAFF and CD40L for 24 h. The transient co-culture was shown to support survival of primary CLL cells for at least 13 days, and mimic in vivo drug resistance signals. Ex vivo sensitivity and resistance to the Bcl-2 antagonist venetoclax correlated with in vivo responses. The assay was used to identify treatment vulnerabilities and guide precision medicine for a patient with relapsed CLL. Taken together, the presented CLL microenvironment model enables clinical implementation of functional precision medicine in CLL.

• Federico, Lorenzo; Tvedt, Tor Henrik Anderson; Gainullin, Murat; Osen, Julie Røkke; Chaban, Viktoriia & Lund, Kathrine Persgård [Vis alle 19 forfattere av denne artikkelen] (2023). Robust spike-specific CD4⁺ and CD8⁺ T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1210899. Fulltekst i vitenarkiv Vis sammendrag

  Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna’s mRNA-1273 or Pfizer/BioNTech’s BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (&amp;gt;2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8 + and CD4 + T cells, respectively. The response rate increased to 90% for CD4 + T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4 + T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses.

• Bjørlykke, Kristin H.; Ørbo, Hilde Sofie Sager; Tveter, Anne Therese; Jyssum, Ingrid; Sexton, Joseph & Tran, Trung [Vis alle 21 forfattere av denne artikkelen] (2022). Four SARS-CoV-2 vaccine doses or hybrid immunity in patients on immunosuppressive therapies: a Norwegian cohort study. The Lancet Rheumatology. 5(1), s. e36–e46. doi: 10.1016/S2665-9913(22)00330-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. Methods This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2–4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625. Findings Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2–4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2–4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45–65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878–11 243]) than after the third dose (median 5087 BAU/ml [1250–9081]; p< 0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916–12 001]; p< 0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440–35 935]) than in the vaccine group (p<0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses. Interpretation Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group.

• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Vis alle 40 forfattere av denne artikkelen] (2022). Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants. npj Vaccines. 7(1). doi: 10.1038/s41541-022-00586-7. Fulltekst i vitenarkiv Vis sammendrag

  Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

• Imbery, John Franklin; Heinzelbecker, Julia; Jebsen, Jenny Karoline; McGowan, Marc Kevin; Myklebust, Camilla Victoria & Bottini, Nunzio [Vis alle 13 forfattere av denne artikkelen] (2022). T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation. British Journal of Haematology. ISSN 0007-1048. 198(3), s. 556–573. doi: 10.1111/bjh.18285. Fulltekst i vitenarkiv Vis sammendrag

  Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature-like B cells. Supportive to CLL cell survival is chronic B-cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T-helper (Th) cells in a CD40L-dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non-malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient-derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin-1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin-1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin-1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin-1 and CD43-mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL.

• Kared, Hassen; Wolf, Asia-Sophia Fumika Michaela; Alirezaylavasani, Amin; Ravussin, Anthony; Solum, Guri & Tran, Trung [Vis alle 17 forfattere av denne artikkelen] (2022). Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults. Nature Communications. 13(1). doi: 10.1038/s41467-022-31888-y. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (T FH ) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG + B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.

• Syversen, Silje Watterdal; Jyssum, Ingrid; Tveter, Anne Therese; Tran, Trung; Sexton, Joseph & Provan, Sella Aarrestad [Vis alle 22 forfattere av denne artikkelen] (2022). Immunogenicity and Safety of Standard and Third-Dose SARS-CoV-2 Vaccination in Patients Receiving Immunosuppressive Therapy. Arthritis & Rheumatology. ISSN 2326-5191. 74(8), s. 1321–1332. doi: 10.1002/art.42153. Fulltekst i vitenarkiv Vis sammendrag

  Objective Immunogenicity and safety following receipt of the standard SARS–CoV-2 vaccination regimen in patients with immune-mediated inflammatory diseases (IMIDs) are poorly characterized, and data after receipt of the third vaccine dose are lacking. The aim of the study was to evaluate serologic responses and adverse events following the standard 2-dose regimen and a third dose of SARS–CoV-2 vaccine in IMID patients receiving immunosuppressive therapy. Methods Adult patients receiving immunosuppressive therapy for rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis, as well as healthy adult controls, who received the standard 2-dose SARS–CoV-2 vaccination regimen were included in this prospective observational study. Analyses of antibodies to the receptor-binding domain (RBD) of the SARS–CoV-2 spike protein were performed prior to and 2–4 weeks after vaccination. Patients with a weak serologic response, defined as an IgG antibody titer of ≤100 arbitrary units per milliliter (AU/ml) against the receptor-binding domain of the full-length SARS–Cov-2 spike protein, were allotted a third vaccine dose. Results A total of 1,505 patients (91%) and 1,096 healthy controls (98%) had a serologic response to the standard regimen (P < 0.001). Anti-RBD antibody levels were lower in patients (median 619 AU/ml interquartile range [IQR] 192–4,191) than in controls (median 3,355 AU/ml [IQR 896–7,849]) (P < 0.001). The proportion of responders was lowest among patients receiving tumor necrosis factor inhibitor combination therapy, JAK inhibitors, or abatacept. Younger age and receipt of messenger RNA–1273 vaccine were predictors of serologic response. Of 153 patients who had a weak response to the standard regimen and received a third dose, 129 (84%) became responders. The vaccine safety profile among patients and controls was comparable. Conclusion IMID patients had an attenuated response to the standard vaccination regimen as compared to healthy controls. A third vaccine dose was safe and resulted in serologic response in most patients. These data facilitate identification of patient groups at risk of an attenuated vaccine response, and they support administering a third vaccine dose to IMID patients with a weak serologic response to the standard regimen.

• Sandvei, Marie Søfteland; Jacobsen, Geir Wenberg; Stien, Marianne Heldal; Ræder, Helge; Munthe, Ludvig Andre & Skogen, Vegard (2022). A national intercalated medical student research program –student perceptions, satisfaction, and factors associated with pursuing a PhD. Medical Education Online. 27:2122105(1), s. 1–8. doi: 10.1080/10872981.2022.2122105. Fulltekst i vitenarkiv Vis sammendrag

  Background To counteract a decreasing number of physician-scientists, a national intercalated Medical Student Research Programme (MSRP) was launched in Norway in 2002. We aimed to assess whether the students’ favourable perceptions and satisfaction with the program had prevailed since the inception in 2002 and until 2015, and to identify factors associated with pursuing a PhD. Methods The study was an incorporation of data from two previous national evaluations of the MSRP performed in 2007 and 2015. We used electronic questionnaires to explore demographic characteristics, area and type of research, student satisfaction, and future scientific goals. In 2007, questionnaires were sent to all 208 students, and 183 (88%) replied. In 2015, the corresponding numbers were 279, and 240 (86%). Categorical data were analysed using either Kruskal-Wallis or Pearson’s chi square test. Differences between sample means were assessed with Student`s t-test while logistic regression was used to test associations between selected covariates and the students’ ambitions to pursue a PhD degree. Results Overall, the student satisfaction was 79%. However, more students in 2015 received less regular and less supervision time and expressed a need for more of it. Seventy-seven per cent expressed an ambition to pursue a PhD. Students were more likely to have a PhD ambition if they were satisfied with the program, had a supervisor with high expectations for them, or had already published some of their results. At both time points, students (86% vs. 89%) responded that the MSRP had a positive impact on their regular curriculum achievements. Conclusions The high degree of satisfaction with the national MSRP among undergraduate students has prevailed since the inception in 2002. By far, the program has also met its goal to increase the number of aspiring physician-scientists. However, to maintain that goal over time, adequate and personal supervision is a prerequisite.

• Syversen, Silje Watterdal; Jyssum, Ingrid; Tveter, Anne Therese; Sexton, Joseph; Christensen, Ingrid Egeland & Tran, Trung [Vis alle 20 forfattere av denne artikkelen] (2022). Immunogenicity and safety of a three-dose SARS-CoV-2 vaccination strategy in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. RMD Open. 8(2). doi: 10.1136/rmdopen-2022-002417. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID. Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. Anti-Spike antibodies were assessed 2–4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2–4 weeks following three doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events. Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p<0.001. Adverse events were reported by 464 (47%) patients and by 196 (78%) controls. Disease flares were reported by 70 (7%) patients. Conclusions This study shows that additional vaccine doses to patients with IMID contribute to strong and sustained immune-responses comparable to healthy persons vaccinated twice, and supports repeated vaccination of patients with IMID. Trial registration number NCT04798625.

• Huse, Kanutte; Bai, Baoyan; Hilden, Vera Irene; Bollum, Lise Kristin; Våtsveen, Thea Kristin & Munthe, Ludvig Andre [Vis alle 10 forfattere av denne artikkelen] (2022). Mechanism of CD79A and CD79B support for IgM+ B cell fitness through B cell receptor surface expression. Journal of Immunology. ISSN 0022-1767. 209(10), s. 2042–2053. doi: 10.4049/jimmunol.2200144. Fulltekst i vitenarkiv Vis sammendrag

  he BCR consists of surface-bound Ig and a heterodimeric signaling unit comprised of CD79A and CD79B. Upon cognate Ag recognition, the receptor initiates important signals for B cell development and function. The receptor also conveys Ag-independent survival signals termed tonic signaling. Although the requirement of a CD79A/CD79B heterodimer for BCR complex assembly and surface expression is well established based on mice models, few studies have investigated this in human mature B cells. In this study, we found that human tonsillar B cells with high surface expression of IgM or IgG had potentiated BCR signaling compared with BCRlow cells, and high IgM expression in germinal center B cells was associated with reduced apoptosis. We explored the mechanism for IgM surface expression by CRISPR/Cas9-induced deletion of CD79A or CD79B in four B lymphoma cell lines. Deletion of either CD79 protein caused loss of surface IgM in all cell lines and reduced fitness in three. From two cell lines, we generated stable CD79A or CD79B knockout clones and demonstrated that loss of CD79A or CD79B caused a block in N-glycan maturation and accumulation of immature proteins, compatible with retention of BCR components in the endoplasmic reticulum. Rescue experiments with CD79B wild-type restored surface expression of CD79A and IgM with mature glycosylation, whereas a naturally occurring CD79B G137S mutant disrupting CD79A/CD79B heterodimerization did not. Our study highlights that CD79A and CD79B are required for surface IgM expression in human B cells and illuminates the importance of the IgM expression level for signaling and fitness.

• Skånland, Sigrid S; Inngjerdingen, Marit; Bendiksen, Henrik; York, Jamie Piers; Spetalen, Signe & Munthe, Ludvig Andre [Vis alle 7 forfattere av denne artikkelen] (2022). Functional testing of relapsed chronic lymphocytic leukemia guides precision medicine and maps response and resistance mechanisms. An index case. Haematologica. ISSN 0390-6078. 107(8), s. 1994–1998. doi: 10.3324/haematol.2021.280393. Fulltekst i vitenarkiv
• Minton, Annabel R.; Smith, Lindsay D.; Bryant, Dean J.; Strefford, Jonathan C.; Forconi, Francesco & Stevenson, Freda K. [Vis alle 12 forfattere av denne artikkelen] (2022). B-cell receptor dependent phagocytosis and presentation of particulate antigen by chronic lymphocytic leukemia cells. Exploration of Targeted Anti-tumor Therapy. ISSN 2692-3114. 3(1), s. 37–49. doi: 10.37349/etat.2022.00070. Fulltekst i vitenarkiv
• Christensen, Ingrid Egeland; Jyssum, Ingrid; Tveter, Anne Therese; Sexton, Joseph; Tran, Trung & Mjaaland, Siri [Vis alle 19 forfattere av denne artikkelen] (2022). The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls—a prospective cohort study. BMC Medicine. 20(1), s. 1–13. doi: 10.1186/s12916-022-02587-8. Fulltekst i vitenarkiv Vis sammendrag

  Background The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline. Methods IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6–48 days, second within 49–123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction. Results A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn’s disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15–24] and 97 days [87–105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018–6068] in patients and 6187 BAU/ml [4105–7496] in controls (p<0.001) at first assessment, and 608 BAU/ml [IQR 58–1053] in patients and 1520 BAU/ml [979–3766] in controls (p<0.001) at second assessment. At second assessment, low anti-RBD antibody levels (defined as <200 BAU/ml) were found in 449 (41%) patients, and 6 (5%) controls (p<0.001). The change was − 83% in patients and − 66% in controls (p<0.001). Patients had a greater estimated 30 days percent reduction in anti-RBD levels compared to controls − 4.9 (95% CI − 7.4 to − 2.4), (p<0.05). Among therapies, mono- or combination treatment with tumor necrosis factor inhibitors was associated with the greatest decline. Conclusions Within 4 months after vaccination, antibody levels declined considerably in both IMID patients and controls. Patients had lower initial antibody levels and a more pronounced decline compared to healthy controls and were therefore more likely to decline to low antibody levels. These results support that IMID patients need additional vaccine doses at an earlier stage than healthy individuals.

• Giliberto, Mariaserena; Raj, Deepak Balaji Thimiri Govinda; Cremaschi, Andrea; Skånland, Sigrid S; Gade, Alexandra & Tjønnfjord, Geir Erland [Vis alle 9 forfattere av denne artikkelen] (2022). Ex vivo drug sensitivity screening in multiple myeloma identifies drug combinations that act synergistically. Molecular Oncology. ISSN 1574-7891. 16(6), s. 1241–1258. doi: 10.1002/1878-0261.13191. Fulltekst i vitenarkiv Vis sammendrag

  The management of multiple myeloma (MM) is challenging: An assortment of available drug combinations adds complexity to treatment selection, and treatment resistance frequently develops. Given the heterogeneous nature of MM, personalized testing tools are required to identify drug sensitivities. To identify drug sensitivities in MM cells, we established a drug testing pipeline to examine ex vivo drug responses. MM cells from 44 patients were screened against 30 clinically relevant single agents and 44 double- and triple-drug combinations. We observed variability in responses across samples. The presence of gain(1q21) was associated with low sensitivity to venetoclax, and decreased ex vivo responses to dexamethasone reflected the drug resistance observed in patients. Less heterogeneity and higher efficacy was detected with many combinations compared to the corresponding single agents. We identified new synergistic effects of melflufen plus panobinostat using low concentrations (0.1–10 nm and 8 nm, respectively). In agreement with clinical studies, clinically approved combinations, such as triple combination of selinexor plus bortezomib plus dexamethasone, acted synergistically, and synergies required low drug concentrations (0.1 nm bortezomib, 10 nm selinexor and 4 nm dexamethasone). In summary, our drug screening provided results within a clinically actionable 5-day time frame and identified synergistic drug efficacies in patient-derived MM cells that may aid future therapy choices.

• Jyssum, Ingrid; Kared, Hassen; Tran, Trung; Tveter, Anne Therese; Provan, Sella Aarrestad & Sexton, Joseph [Vis alle 22 forfattere av denne artikkelen] (2021). Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study. The Lancet Rheumatology. 00. doi: 10.1016/S2665-9913(21)00394-5. Fulltekst i vitenarkiv Vis sammendrag

  Background In rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap. Methods This prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2–4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7–10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov, NCT04798625, and is ongoing. Findings Between Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222–324] in responders vs 107 days [80–152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4+ T-cell responses and 14 (74%) had CD8+ T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4+ and CD8+ T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths. Interpretation This study provides important insight into the divergent humoral and cellular responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis. A third vaccine dose given 6–9 months after a rituximab infusion might not induce a serological response, but could be considered to boost the cellular immune response.

• Szodoray, Peter; Andersen, Tor Kristian; Heinzelbecker, Julia; Imbery, John Franklin; Huszthy, Peter C. & Stanford, Stephanie M. [Vis alle 12 forfattere av denne artikkelen] (2021). Integration of T helper and BCR signals governs enhanced plasma cell differentiation of memory B cells by regulation of CD45 phosphatase activity. Cell reports. 36:109525(6), s. 1–24. doi: 10.1016/j.celrep.2021.109525. Fulltekst i vitenarkiv Vis sammendrag

  Humoral immunity relies on the efficient differentiation of memory B cells (MBCs) into antibody-secreting cells (ASCs). T helper (Th) signals upregulate B cell receptor (BCR) signaling by potentiating Src family kinases through increasing CD45 phosphatase activity (CD45 PA). In this study, we show that high CD45 PA in MBCs enhances BCR signaling and is essential for their effective ASC differentiation. Mechanistically, Th signals upregulate CD45 PA through intensifying the surface binding of a CD45 ligand, Galectin-1. CD45 PA works as a sensor of T cell help and defines high-affinity germinal center (GC) plasma cell (PC) precursors characterized by IRF4 expression in vivo. Increasing T cell help in vitro results in an incremental CD45 PA increase and enhances ASC differentiation by facilitating effective induction of the transcription factors IRF4 and BLIMP1. This study connects Th signals with BCR signaling through Galectin-1-dependent regulation of CD45 PA and provides a mechanism for efficient ASC differentiation of MBCs.

• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Vis alle 22 forfattere av denne artikkelen] (2021). Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. doi: 10.1136/jnnp-2021-327612. Fulltekst i vitenarkiv Vis sammendrag

  Introduction The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. Objective To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). Methods All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3–12 weeks after full vaccination, and compared with healthy subjects. Results 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. Conclusions Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

• Schultz, Nina Haagenrud; Sørvoll, Ingvild Hausberg; Michelsen, Annika; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Ahlen, Maria Therese [Vis alle 11 forfattere av denne artikkelen] (2021). Thrombosis and thrombocytopenia after CHADOX1 NCoV-19 vaccination. New England Journal of Medicine. ISSN 0028-4793. 384(22), s. 2124–2130. doi: 10.1056/NEJMoa2104882. Fulltekst i vitenarkiv Vis sammendrag

  We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

• Holm, Sverre; Kared, Hassen; Michelsen, Annika Elisabet; Kong, Xiang Yi; Dahl, Tuva Børresdatter & Schultz, Nina Haagenrud [Vis alle 21 forfattere av denne artikkelen] (2021). Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia. European Heart Journal. ISSN 0195-668X. 42(39), s. 4064–4072. doi: 10.1093/eurheartj/ehab506. Fulltekst i vitenarkiv Vis sammendrag

  Aims - We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients.<p> <p>Methods and results - We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.<p> <p>Conclusions - The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.

• Skånland, Sigrid Strand; Cremaschi, Andrea; Bendiksen, Henrik; Hermansen, Johanne Uthus; Raj, Deepak Balaji Thimiri Govinda & Munthe, Ludvig Andre [Vis alle 8 forfattere av denne artikkelen] (2019). An in vitro assay for biomarker discovery and dose prediction applied to ibrutinib plus venetoclax treatment of CLL. Leukemia. ISSN 0887-6924. doi: 10.1038/s41375-019-0569-7. Fulltekst i vitenarkiv
• Chellappa, Stalin; Kushekhar, Kushi; Munthe, Ludvig Andre; Tjønnfjord, Geir Erland; Aandahl, Einar Martin & Okkenhaug, Klaus [Vis alle 7 forfattere av denne artikkelen] (2019). The PI3K p110δ isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function. Journal of Immunology. ISSN 0022-1767. 202(5), s. 1397–1405. doi: 10.4049/jimmunol.1701703. Fulltekst i vitenarkiv
• Huszthy, Peter Csaba; Gopalakrishnan, Ramakrishna Prabhu; Jacobsen, Johanne Tracey; Haabeth, Ole Audun; Løset, Geir Åge & Braathen, Ranveig [Vis alle 10 forfattere av denne artikkelen] (2019). B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 116(51), s. 25850–25859. doi: 10.1073/pnas.1902836116. Fulltekst i vitenarkiv Vis sammendrag

  The B cell receptors (BCRs) for antigen express variable (V) regions that are enormously diverse, thus serving as markers on individual B cells. V region-derived idiotypic (Id) peptides can be displayed as pId:MHCII complexes on B cells for recognition by CD4+ T cells. It is not known if naive B cells spontaneously display pId:MHCII in vivo or if BCR ligation is required for expression, thereby enabling collaboration between Id+ B cells and Id-specific T cells. Here, using a mouse model, we show that naive B cells do not express readily detectable levels of pId:MHCII. However, BCR ligation by Ag dramatically increases physical display of pId:MHCII, leading to activation of Id-specific CD4+ T cells, extrafollicular T-B cell collaboration and some germinal center formation, and production of Id+ IgG. Besides having implications for immune regulation, the results may explain how persistent activation of self-reactive B cells induces the development of autoimmune diseases and B cell lymphomas.

• Hermansen, Johanne Uthus; Tjønnfjord, Geir Erland; Munthe, Ludvig Andre; Tasken, Kjetil & Skånland, Sigrid Strand (2018). Cryopreservation of primary B cells minimally influences their signaling responses. Scientific Reports. 8:17651, s. 1–7. doi: 10.1038/s41598-018-36121-9. Fulltekst i vitenarkiv Vis sammendrag

  Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreservation on signaling responses and the reproducibility of phospho flow measurements are however unknown in many cell systems. Here, B lymphocytes were isolated from healthy donors and patients with the B cell malignancy chronic lymphocytic leukemia and analyzed by phospho flow using phospho-specific antibodies targeting 20 different protein epitopes. Cells were analyzed both at basal conditions and after activation of cluster of differentiation 40 (CD40) or the B cell receptor. Pharmacodynamics of the novel pathway inhibitor ibrutinib was also assessed. At all conditions, fresh cells were compared to cryopreserved cells. Minimal variation between fresh and frozen samples was detected. Reproducibility was tested by running samples from the same donors in different experiments. The results demonstrate reproducibility across different phospho flow runs and support the use of cryopreserved samples in future phospho flow studies of B lymphocytes.

• Myhrvold, Ida Kristin; Cremaschi, Andrea; Hermansen, Johanne Uthus; Tjønnfjord, Geir Erland; Munthe, Ludvig Andre & Tasken, Kjetil [Vis alle 7 forfattere av denne artikkelen] (2018). Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia. OncoTarget. 9(10), s. 9273–9284. doi: 10.18632/oncotarget.23949. Fulltekst i vitenarkiv Vis sammendrag

  Chronic lymphocytic leukemia (CLL) has a high incidence and a steeply growing prevalence in the Western world. The heterogeneity of the disease necessitates individual mapping of biology and predicted drug response in each patient as basis for administration of tailored treatments. Cell signaling aberrations may serve as biological indicators for suitable therapy. By applying phospho-specific flow cytometry, we mapped basal and induced phosphorylation levels of 20 phospho-epitopes on proteins relevant to B-cell signaling in B cells from 22 CLL patients and 25 normal controls. The signaling response of the cytostatic drugs fludarabine, doxorubicin and vincristine was also investigated. CLL cells exerted similar or lower basal phosphorylation levels compared to normal B cells, with the exception of STAT3 (pY705) which was increased. Interestingly, STAT3 inhibitors normalized the STAT3 (pY705) level and reduced cell viability. Vincristine treatment significantly modulated phosphorylation levels in CLL cells, while no effect was observed in controls or after fludarabine or doxorubicin treatment. After BCR stimulation, CLL cells showed a tendency towards impaired phosphorylation levels, significant for several of the analyzed proteins. However, the level of Akt (pS473) was more potently induced in IgHV unmutated CLL (UM-CLL) patient samples and was significantly higher than in M-CLL samples. Importantly, the PI3Kδ inhibitor idelalisib potently reversed the effect of anti-IgM on Akt (pS473). Thus, signaling aberrations could be identified by phosphoflow cytometry and aberrant signaling could be normalized by small molecule drugs. This approach can identify relevant drug targets as well as drug effects in the individual patient.

• Traxel, Sabrina; Schadt, Linda; Eyer, Tatjana; Mordasini, Vanessa; Gysin, Claudine & Munthe, Ludvig Andre [Vis alle 9 forfattere av denne artikkelen] (2018). Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients. Oncogene. ISSN 0950-9232. doi: 10.1038/s41388-018-0594-4. Fulltekst i vitenarkiv
• Jacobsen, Geir Wenberg; Ræder, Helge; Stien, Marianne Heldal; Munthe, Ludvig Andre & Skogen, Vegard (2018). Springboard to an academic career - A national medical student research program. PLOS ONE. 13:e0195527(4), s. 1–8. doi: 10.1371/journal.pone.0195527. Fulltekst i vitenarkiv Vis sammendrag

  Over the last decades there has been a decline in the recruitment of medical students into academia in all medical fields. Concurrently, medical research has increasingly included other disciplines in multidisciplinary convergence, introducing an unmet recruitment gap and requirement for medical researchers. To counteract the trend and recruit students to academic medicine, a national intercalated Medical Student Research Program (MSRP) was established in Norway in 2002. A preliminary evaluation in 2009 suggested that the MSRP had resulted in recruitment, but could not conclude on a lasting effect beyond graduation in a study that did not include any controls. These results led us to hypothesize that the MSRP could increase the number of PhD degrees and attract medical students towards academic medicine. Adopting a case cohort design, we here report that the intercalated MSRP had a significant impact of the throughput of physician-scientists to PhD, by increasing the rate of PhD completion 10-fold (p<0.001). Moreover, almost twice as many MSRP physicians reported an academic aspiration (49% vs 22%, p<0.001). Results suggested that an MSRP-like approach could efficiently address the unmet recruitment gap and strengthen the medical disciplines in medical research.

• Wang, Dong; Fløisand, Yngvar; Myklebust, Camilla Victoria; Bürgler, Simone; Ribes, Anna Maria Parente & Hofgaard, Peter Olaf [Vis alle 13 forfattere av denne artikkelen] (2017). Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice. Leukemia. ISSN 0887-6924. 31(10), s. 2114–2121. doi: 10.1038/leu.2017.69. Fulltekst i vitenarkiv Vis sammendrag

  Multiple myeloma (MM) is a plasma cell malignancy where MM cell growth is supported by the bone marrow (BM) microenvironment with poorly defined cellular and molecular mechanisms. MM cells express CD40, a receptor known to activate autocrine secretion of cytokines and elicit proliferation. Activated T helper (Th) cells express CD40 ligand (CD40L) and BM Th cells are significantly increased in MM patients. We hypothesized that activated BM Th cells could support MM cell growth. We here found that activated autologous BM Th cells supported MM cell growth in a contact- and CD40L-dependent manner in vitro. MM cells had retained the ability to activate Th cells that reciprocated and stimulated MM cell proliferation. Autologous BM Th cells supported MM cell growth in xenografted mice and were found in close contact with MM cells. MM cells secreted chemokines that attracted Th cells, secretion was augmented by CD40-stimulation. Within 14 days of culture of whole BM aspirates in autologous serum, MM cells and Th cells mutually stimulated each other, and MM cells required Th cells for further expansion in vitro and in mice. The results suggest that Th cells may support the expansion of MM cells in patients.

• Szodoray, Peter; Stanford, Stephanie M.; Molberg, Øyvind; Munthe, Ludvig Andre; Bottini, Nunzio & Nakken, Britt (2016). T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 138(3), s. 839–851.e8. doi: 10.1016/j.jaci.2016.01.035. Fulltekst i vitenarkiv
• Aas-Hanssen, Kristin; Thompson, Keith M; Bogen, Bjarne & Munthe, Ludvig Andre (2015). Systemic lupus erythematosus: Molecular mimicry between anti-dsDNA CDR3 idiotype, microbial and self peptides-as antigens for Th cells. Frontiers in Immunology. 6:00382. doi: 10.3389/fimmu.2015.00382. Fulltekst i vitenarkiv Vis sammendrag

  Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell-dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A feature of SLE is the finding of IgG autoantibodies specific for dsDNA. The specificity of the Th cells that drive the expansion of anti-dsDNA B cells is unresolved. However, anti-microbial, anti-histone, and anti-idiotype Th cell responses have been hypothesized to play a role. It has been entirely unclear if these seemingly disparate Th cell responses and hypotheses could be related or unified. Here, we describe that H chain CDR3 idiotypes from IgG+ B cells of lupus mice have sequence similarities with both microbial and self peptides. Matched sequences were more frequent within the mutated CDR3 repertoire and when sequences were derived from lupus mice with expanded anti-dsDNA B cells. Analyses of histone sequences showed that particular histone peptides were similar to VDJ junctions. Moreover, lupus mice had Th cell responses toward histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cells in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.

• Bürgler, Simone; Vives, Aleix Gimeno; Ribes, Anna Maria Parente; Wang, Dong; Os, Audun & Devereux, Stephen [Vis alle 10 forfattere av denne artikkelen] (2015). Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-γ by a T-bet-dependent mechanism. Journal of Immunology. ISSN 0022-1767. 194(2), s. 827–835. doi: 10.4049/jimmunol.1401350. Fulltekst i vitenarkiv
• Almåsbak, Hilde Kjersti; Walseng, Even; Kristian, Alexandr; Myhre, Marit Renee; Suso, Else Marit Inderberg & Munthe, Ludvig Andre [Vis alle 11 forfattere av denne artikkelen] (2015). Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model. Gene Therapy. ISSN 0969-7128. 22(5), s. 391–403. doi: 10.1038/gt.2015.4. Fulltekst i vitenarkiv
• Haabeth, Ole Audun; Tveita, Anders; Fauskanger, Marte Hotvedt; Schjesvold, Fredrik Hellem; Lorvik, Kristina Berg & Hofgaard, Peter Olaf [Vis alle 11 forfattere av denne artikkelen] (2014). How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules? Frontiers in Immunology. 5:174. doi: 10.3389/fimmu.2014.00174. Fulltekst i vitenarkiv Vis sammendrag

  CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

• Etokebe, Godfrey; Bulat-Kardum, Ljiljana; Munthe, Ludvig Andre; Balen, Sanja & Dembic, Zlatko (2014). Association of variable number of tandem repeats in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with susceptibility to tuberculosis. PLOS ONE. 9(3). doi: 10.1371/journal.pone.0091385. Fulltekst i vitenarkiv Vis sammendrag

  We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease.

• Jacobsen, Johanne Tracey; Haabeth, Ole Audun; Tveita, Anders; Schjetne, Karoline W; Munthe, Ludvig Andre & Bogen, Bjarne (2014). Naive idiotope-specific B and T cells collaborate efficiently in the absence of dendritic cells. Journal of Immunology. ISSN 0022-1767. 192(9), s. 4174–4183. doi: 10.4049/jimmunol.1302359. Fulltekst i vitenarkiv
• Aas-Hanssen, Kristin; Funderud, Ane; Thompson, Keith M; Bogen, Bjarne & Munthe, Ludvig Andre (2014). Idiotype-specific Th cells support oligoclonal expansion of Anti-dsDNA B cells in mice with lupus. Journal of Immunology. ISSN 0022-1767. 193(6), s. 2691–2698. doi: 10.4049/jimmunol.1400640. Fulltekst i vitenarkiv
• Ruffini, Pier Adelchi; Os, Audun; Dolcetti, Riccardo; Tjønnfjord, Geir Erland; Munthe, Ludvig Andre & Bogen, Bjarne (2014). Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice. Journal of Translational Medicine. 12(1). doi: 10.1186/1479-5876-12-207. Fulltekst i vitenarkiv Vis sammendrag

  Background Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine. Methods Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells. Results DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments. Conclusions These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs.

• Os, Audun; Bürgler, Simone; Ribes, Anna Maria Parente; Funderud, Ane; Wang, Dong & Thompson, Keith M [Vis alle 9 forfattere av denne artikkelen] (2013). Chronic Lymphocytic Leukemia Cells Are Activated and Proliferate in Response to Specific T Helper Cells. Cell reports. 4(3), s. 566–577. doi: 10.1016/j.celrep.2013.07.011. Fulltekst i vitenarkiv
• Kielland, Anders; Camassa, Laura Maria Azzurra; Døhlen, Gaute; Munthe, Ludvig Andre; Blomhoff, Rune & Amiry-Moghaddam, Mahmood [Vis alle 7 forfattere av denne artikkelen] (2012). Activity in Perinatal Brain During Infectious and Hypoxic-Ischemic Insults revealed by a Reporter Mouse. Brain Pathology. ISSN 1015-6305. 22(4), s. 499–510. doi: 10.1111/j.1750-3639.2011.00548.x. Fulltekst i vitenarkiv
• Kielland, Anders; Camassa, Laura Maria Azzurra; Døhlen, Gaute; Munthe, Ludvig Andre; Blomhoff, Rune & Amiry-Moghaddam, Mahmood [Vis alle 7 forfattere av denne artikkelen] (2012). NF-kappa B Activity in Perinatal Brain During Infectious and Hypoxic-Ischemic Insults Revealed by a Reporter Mouse. Brain Pathology. ISSN 1015-6305. 22(4), s. 499–510. doi: 10.1111/j.1750-3639.2011.00548.x. Fulltekst i vitenarkiv
• Selmer, Kaja Kristine; Gilfillan, Gregor Duncan; Strømme, Petter; Lyle, Robert; Hughes, Timothy & Hjorthaug, Hanne Sagsveen [Vis alle 13 forfattere av denne artikkelen] (2012). A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions. European Journal of Human Genetics. ISSN 1018-4813. 20(1), s. 58–63. doi: 10.1038/ejhg.2011.126. Fulltekst i vitenarkiv
• Nakken, Britt; Munthe, Ludvig Andre; Konttinen, Yrjo T.; Sandberg, Anna Klokk; Szekanecz, Zoltan & Alex, Philip [Vis alle 7 forfattere av denne artikkelen] (2011). B-cells and their targeting in rheumatoid arthritis — Current concepts and future perspectives. Autoimmunity Reviews. ISSN 1568-9972. 11(1), s. 28–34. doi: 10.1016/j.autrev.2011.06.010. Fulltekst i vitenarkiv
• Jacobsen, Johanne Tracey; Lunde, Elin; Gjerstad, Vibeke Sundvold; Munthe, Ludvig Andre & Bogen, Bjarne (2010). The cellular mechanism by which complementary Id(+) and anti-Id antibodies communicate: T cells integrated into idiotypic regulation. Immunology and Cell Biology. ISSN 0818-9641. 88(5), s. 515–522. doi: 10.1038/icb.2009.118. Fulltekst i vitenarkiv
• Holmøy, Trygve; Vartdal, Frode; Hestvik, Anne Lise Karlsgot; Munthe, Ludvig Andre & Bogen, Bjarne (2010). The idiotype connection: linking infection and multiple sclerosis. Trends in immunology. ISSN 1471-4906. 31(2), s. 56–62. doi: 10.1016/j.it.2009.11.001. Fulltekst i vitenarkiv
• Funderud, Ane; Aas-Hanssen, Kristin; Aksaas, Anne Kristin; Hafte, Tolesa Tilahun; Corthay, Alexandre & Munthe, Ludvig Andre [Vis alle 8 forfattere av denne artikkelen] (2009). Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA). Cellular Signalling. ISSN 0898-6568. 21(2), s. 274–281. doi: 10.1016/j.cellsig.2008.10.013. Fulltekst i vitenarkiv
• Zangani, Michael Mehrdad; Carlsen, Harald; Kielland, Anders; Os, Audun; Hauglin, Harald & Blomhoff, Rune [Vis alle 8 forfattere av denne artikkelen] (2009). Tracking Early Autoimmune Disease by Bioluminescent Imaging of NF-kappa B Activation Reveals Pathology in Multiple Organ Systems. American Journal of Pathology. ISSN 0002-9440. 174(4), s. 1358–1367. doi: 10.2353/ajpath.2009.080700. Fulltekst i vitenarkiv
• Zangani, Michael M; Frøyland, Marianne; Gao, Yue Qiu; Meza, Zepeda Leonardo; Kutok, JL & Thompson, Keith M [Vis alle 8 forfattere av denne artikkelen] (2007). Lymphomas can develop from B cells chronically helped by idiotype-specific T cells. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 204. doi: 10.1084/jem.20061220. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre; Corthay, Alexandre; Os, Audun; Zangani, Michael M & Bogen, Bjarne (2005). Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from immunoglobulin V region-specific T cells. Journal of Immunology. ISSN 0022-1767. 175, s. 2391–2400. Fulltekst i vitenarkiv
• Corthay, Alexandre; Lundin, Katrin; Munthe, Ludvig Andre; Frøyland, Marianne; Gedde-Dahl, Thobias & Dembic, Zlatko [Vis alle 7 forfattere av denne artikkelen] (2004). Immunotherapy in multiple myeloma: Id-specific strategies suggested by studies in animal models. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 53, s. 759–769. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre; Os, A; Zangani, Michael M & Bogen, Bjarne (2004). MHC-Restricted Ig V region-driven T-B lymphocyte collaboration: B cell receptor ligation facilitates switch to IgG production. Journal of Immunology. ISSN 0022-1767. 172(12), s. 7476–7484. Fulltekst i vitenarkiv
• Lundin, Knut E. A.; Hofgaard, Peter Olaf; Omholt, Hilde; Munthe, Ludvig Andre; Corthay, Alexandre & Bogen, Bjarne (2003). Therapeutic effect of anti-idiotype-specific CD4+ T cells against B-cell lymphoma in the absence of anti-idiotypic antibodies. Blood. ISSN 0006-4971. 102, s. 605–612. Fulltekst i vitenarkiv

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• Drivet, Elsa Maria Caroline; Tsykunova, Galina; Egner, Ingrid Marie; Lund, Katrine Persgård; Goll, Guro Løvik & Tran, Hoa Thi Thyuet [Vis alle 11 forfattere av denne artikkelen] (2026). Interleukin-17-associated inflammation in non-responders and B-cell remodeling after daratumumab in refractory immune thrombocytopenia. Haematologica. ISSN 0390-6078. doi: 10.3324/haematol.2026.301032. Fulltekst i vitenarkiv Vis sammendrag

  Not available.

• König, Marton; Holmøy, Trygve; Nygaard, Gro Owren; Riise, Jon; Midtvedt, Karsten & Goll, Guro Løvik [Vis alle 11 forfattere av denne artikkelen] (2026). Vaccination of immunosuppressed patients. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.25.0555. Fulltekst i vitenarkiv
• Kongsrud, Karoline; Tvedt, Charlotte Hop; Christensen, Thea Josefine; Caulier, Benjamin William; Spasevska, Ivana & Hilden, Vera Irene [Vis alle 14 forfattere av denne artikkelen] (2025). B-cell Lymphoma Patient-Derived Xenograft Models for improved preclinical in vivo testing. Fulltekst i vitenarkiv Vis sammendrag

  The treatment landscape for B-cell non-Hodgkin lymphoma (B-NHL) has expanded dramatically in recent years, including advanced immunotherapies and targeted drugs. Yet, early relapse is still associated with an adverse prognosis, highlighting the need for new treatment options. For identification of potent new treatment strategies and combinatorial approaches, better preclinical models are needed that can facilitate testing at larger scale. Patient-derived xenograft (PDX) models are in vivo models established by engrafting tumor fragments from cancer patients into immunodeficient mice. The PDX tumors can retain the molecular features including clonal heterogeneity of the original tumor. Our aim is to establish relevant PDX models from B-cell lymphoma tumors for in vivo and ex vivo testing of drugs and immunotherapy. We have successfully established PDX models from diffuse large B-cell lymphoma (DLBCL, n= 3) and mantle cell lymphoma (MCL, n= 2). For phenotypical characterization, we have developed a 32-marker spectral flow cytometry panel to identify key B cell features (CD10, CD19, CD20, CD22, CD37, CD79B, and Ig heavy and Ig light chains) and other immune cells including T cell subsets and myeloid cells. In addition, targeted sequencing will be used to determine if the mutational composition is stable over time, across different PDX generations. These results will facilitate selection of the best models for future studies. As proof-of -concept, we have used one of the MCL PDX models to test the efficacy of kinase inhibitors and the efficacy of CD19 CAR T cells. These models might support the development of personalized treatment strategies.

• Våtsveen, Thea Kristin & Munthe, Ludvig Andre (2025). Targeting Proteostasis in Multiple Myeloma through Inhibition of Leukocyte Tyrosine Kinase (LTK). Fulltekst i vitenarkiv
• Kared, Hassen; Huse, Kanutte; Spasevska, Ivana; Myklebust, June Helen & Munthe, Ludvig Andre (2025). Mapping T Cell subsets and TME types in Prostate Cancer. Fulltekst i vitenarkiv
• Christensen, Thea Josefine; Spasevska, Ivana; Huse, Kanutte; Eide, Marianne Brodtkorb; Munthe, Ludvig Andre & Myklebust, June Helen [Vis alle 7 forfattere av denne artikkelen] (2024). Development of ex-vivo 3D culture assay to facilitate preclinical testing of B-cell non-Hodgkin´s lymphoma. Fulltekst i vitenarkiv
• Christensen, Thea Josefine; Spasevska, Ivana; Huse, Kanutte; Eide, Marianne Brodtkorb; Munthe, Ludvig Andre & Myklebust, June Helen [Vis alle 7 forfattere av denne artikkelen] (2024). Development of ex-vivo 3D culture assay to facilitate preclinical testing of B-cell non-Hodgkin´s lymphoma. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre (2024). Immune infiltrates and characterizing ongoing immunity in prostate cancer. Fulltekst i vitenarkiv
• Federico, Lorenzo; Malone, Brandon; Tennøe, Simen; Chaban, Viktoriia; Osen, Julie Røkke & Gainullin, Murat [Vis alle 13 forfattere av denne artikkelen] (2024). Corrigendum: Experimental validation of immunogenic SARS-CoV-2 T cell epitopes identified by artificial intelligence (Frontiers in Immunology, (2023), 14, (1265044), 10.3389/fimmu.2023.1265044). Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1377041. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre (2024). Session Chair and Introduction to Keynote lecture by Poly Matzinger. Fulltekst i vitenarkiv
• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Vis alle 40 forfattere av denne artikkelen] (2023). Author Correction: Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants (npj Vaccines, (2022), 7, 1, (174), 10.1038/s41541-022-00586-7). npj Vaccines. 8(1). doi: 10.1038/s41541-023-00600-6. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre (2023). ITP research in Norway - scope and premliminary findings. Fulltekst i vitenarkiv
• Rasmussen, Tilde; König, Marton; Lorentzen, Åslaug Rudjord; Schikora-Rustad, Stine; Berge, Tone & Holmøy, Trygve [Vis alle 17 forfattere av denne artikkelen] (2022). Safety of a third SARS CoV 2 mRNA vaccine dose in people with multiple sclerosis. Fulltekst i vitenarkiv
• König, Marton; Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; Chopra, Adity; Tran, Trung & Torgauten, Hilde Marie [Vis alle 28 forfattere av denne artikkelen] (2022). Immunogenicity and efficacy of mRNA-COVID-19 vaccines in people with multiple sclerosis. Fulltekst i vitenarkiv
• Midtvedt, Karsten; Vaage, John T.; Heldal, Kristian; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Åsberg, Anders (2022). Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response. American Journal of Transplantation. ISSN 1600-6135. doi: 10.1111/ajt.17091. Fulltekst i vitenarkiv
• Grødeland, Gunnveig; Fossum, Even & Munthe, Ludvig Andre (2022). Vaksinasjon av immunsupprimerte. [Radio]. Vaksinepodden. Fulltekst i vitenarkiv
• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, The Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Vis alle 22 forfattere av denne artikkelen] (2021). Humoral Immunity to SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis using High-Efficacy Disease Modifying Therapies. Fulltekst i vitenarkiv
• Ribes, Anna Maria Parente; Skånland, Sigrid Strand; Bürgler, Simone; Os, Audun; Wang, Dong & Bogen, Bjarne [Vis alle 9 forfattere av denne artikkelen] (2016). Spleen tyrosine kinase inhibitors reduce CD40l-induced proliferation of chronic lymphocytic leukemia cells but not normal B cells. Haematologica. ISSN 0390-6078. 101(2), s. e59–e62. doi: 10.3324/haematol.2015.135590. Fulltekst i vitenarkiv
• Jacobsen, Johanne Tracey; Schjetne, Karoline W; Munthe, Ludvig Andre & Bogen, Bjarne (2012). Naive anti-Id B cells and Id-specific CD4(+) T cells collaborate efficiently to non infectious antigens in the absence of dendritic cells. Journal of Immunology. ISSN 0022-1767. 188. Fulltekst i vitenarkiv
• Nakken, Britt; Alex, Philip; Munthe, Ludvig Andre; Szekanecz, Zoltan & Szodoray, Peter (2012). Immune-Regulatory Mechanisms in Systemic Autoimmune and Rheumatic Diseases. Clinical & Developmental Immunology. ISSN 1740-2522. doi: 10.1155/2012/957151. Fulltekst i vitenarkiv
• Nakken, Britt; Munthe, Ludvig Andre & Szodoray, Peter (2011). B Cells in Rheumatoid Arthritis (RA). Scandinavian Journal of Immunology. ISSN 0300-9475. 73(4), s. 377–377. Fulltekst i vitenarkiv
• Os, Audun; Bürgler, Simone; Ribes, Anna Maria Parente; Funderud, Ane; Thompson, Keith M & Tjønnfjord, Geir Erland [Vis alle 8 forfattere av denne artikkelen] (2011). CLL Cells can Collaborate with Antigen-Specific T Helper Cells and Receive Help to Proliferate. Scandinavian Journal of Immunology. ISSN 0300-9475. 73(4), s. 383–383. Fulltekst i vitenarkiv
• Jacobsen, Johanne Tracey; Schjetne, Karoline W; Munthe, Ludvig Andre & Bogen, Bjarne (2011). New Immunoglobulin Knock-in Mice for Idiotype (Id)-Driven T-B Collaboration. Scandinavian Journal of Immunology. ISSN 0300-9475. 73(4), s. 388–388. Fulltekst i vitenarkiv
• Munthe, Ludvig Andre; Corthay, Alexandre; Os, Audun & Bogen, Bjarne (2002). B cells that present Ig V regions on MHC class II molecules are stimulated by V region-specific CD4+ T cells to proliferate and secrete autoantibodies in vivo. A novel murine model of lupus-like and inflammatory bowel disease. Fulltekst i vitenarkiv
• Strand, Thomter, Helena; Federico, Lorenzo; Munthe, Ludvig Andre & Straume, Daniel (2026). A pipeline for adoptive cell therapy of tumor infiltrating lymphocytes (TIL) for metastatic sarcoma. Norges miljø- og biovitenskapelige universitet (NMBU). Fulltekst i vitenarkiv Vis sammendrag

  Metastatic sarcoma represents one of the most therapeutically challenging malignancies in oncology. Despite decades of anthracycline-based chemotherapy, prognosis for patients with advanced or treatment-resistant disease remains poor, with a median survival of one to two years following metastasis. Sarcomas are characteristically regarded as immunologically cold tumors, with low tumor mutational burden, sparse T cell infiltration, and a suppressive tumor microenvironment that limits the efficacy of conventional immunotherapeutic approaches including immune checkpoint blockade. The recent FDA approval of lifileucel, a tumor-infiltrating lymphocyte (TIL)-based adoptive cell therapy for metastatic melanoma, has renewed interest in extending this approach to other solid tumors. However, the immunological properties of sarcoma present distinct obstacles to successful TIL expansion and therapeutic application that have not been systematically addressed. This thesis aimed to establish a robust pre-rapid expansion protocol (pre-REP) pipeline for the ex vivo expansion of TILs from resected metastatic sarcoma samples, with the goal of generating viable, T cell-enriched, and tumor-reactive cell products. Building on prior work in non-small cell lung cancer demonstrating that enhanced co-stimulation substantially improves TIL yield compared to IL-2 alone, we evaluated a novel protocol that was compared to the conventional IL-2-only protocol across metastatic sarcoma samples representing several histological subtypes, including gastrointestinal stromal tumor (GIST), synovial sarcoma, and osteosarcoma. The expanded products were assessed for live cell yield, immunophenotype by flow cytometry, and tumor-reactive function. A comparison with an intermediate protocol across the pre-REP and REP phases of TIL manufacturing was also undertaken. This work investigates whether the novel pre-REP protocol can overcome the immunological barriers imposed by the cold sarcoma microenvironment to generate viable, phenotypically desirable, and functionally tumor-reactive TIL products, providing a proof-of-concept foundation for further development of TIL-based adoptive cell therapy in sarcoma.

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