Project title: Mechanisms of immune regulation by regulatory T cells in liver transplantation.
Regulatory T (Treg) cells are subset of suppressive CD4+ T helper cells important for the maintenance of self-tolerance, suppression of allergic responses, and prevention of rejection reactions after organ transplantation. They are also involved in the suppressive microenvironment of tumours, and promote growth and metastasis. The Tasken/Aandahl group has extensively studied Treg molecular mechanisms of intercellular communication and immune-regulation. There are performed approximately 100 liver transplantations annually at Rikshospitalet and sampling will be done prior to transplantation and 3, 6 and 12 months post transplantation. I will study patients transplanted for primary sclerosing cholangitis (PSC), and patients transplanted due to un-resectable hepatocellular carcinoma (HCC). I want to understand the precise immunosuppressive mechanism of Tregs and explore their functional activity in transplant recipients with respect to disease severity, effects of immunosuppressive medication and the significance of Tregs in rejection reactions 2/10 and graft function. In a second sub-project I will do a comparative studies of liver transplant recipients (PSC vs. HCC), which gives us the opportunity to do comparative studies of Treg function in an autoimmune disease versus a malignancy.
I will investigate the dual role of Tregs in controlling autoimmunity (PSC) versus a malignancy (HCC) and their role in the complex immunological interactions that take place after liver transplantation.
The specific objectives of this project are to:
1. Map signalling pathways inside effector T cells that convey the inhibitory signal from the Tregs.
2. Characterise the immune status in PSC and HCC patients prior to and after liver transplantation.
3. Correlations of immune status prior to transplantation and early post transplantation rejection reactions.
4. Study the effects of immune suppression on Treg function and the T cell repertoire.
Nijland M, Veenstra RN, Visser L, Xu C, Kushekhar K, van Imhoff GW, Kluin PM, van den Berg A, Diepstra A. HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy?. Oncoimmunology. 2017 Mar 3;6(4):e1295202
Kushekhar Kushi, Paczesny Sophie, JAK polymorphisms: jack of all cytokines, masters GVHD?. Leukemia & Lymphoma 58(2):255-256. 2016.
Yu Jeffrey, Storer Barry E, Kushekhar Kushi, Zaid Mohammad Abu, Zhang Qing, Gafken Philip R, Ogata Yuko, Martin Paul J, Flowers Mary E, Hansen John A, Biomarker Panel for Chronic Graft-Versus-Host Disease. Journal of Clinical Oncology 34(22):2583-9. 2016.
Liu Xiaowen, Yue Zongliang, Yu Jeffrey, Daguindau Etienne, Kushekhar Kushi, Zhang Qing, Ogata Yuko, Gafken Philip R, Inamoto Yoshihiro, Gracon Adam, Proteomic characterization reveals that MMP‐3 correlates with Bronchiolitis Obliterans Syndrome following allogeneic hematopoietic cell and lung transplantation. American Journal of Transplantation 16(8):2342-51, 2016.
Kushekhar Kushi, Human Leukocyte antigen and classical Hodgkin lymphoma: genetic predisposition and susceptibility mechanisms, 2015. ISBN: 978-90-367-7548-9.
Kushekhar Kushi, van den Berg Anke, Nolte Ilja, Hepkema Bouke, Visser Lydia, Diepstra Arjan, Genetic associations in classical Hodgkin lymphoma: a systematic review and insights into susceptibility mechanisms. Cancer Epidemiology Biomarkers & Prevention 23 (12):2737-2747, 2014.
Diepstra A, Xin H, Kushekhar Kushi, Nolte I, Visser L, Bouwman I, Kouprie N, Veenstra R, van Imhoff G, Poppema S, HLA Associations in EBV Status Defined Subgroups of Classical Hodgkin Lymphoma. Klinische Pädiatrie 226 (02) P_03, 2014.
Kushekhar Kushi, Nolte Ilja, Veenstra Rianne, van Imhoff Gustaaf, Poppema Sibrand, Visser Lydia, Hepkema Bouke, Diepstra Arjan, van den Berg Anke, HLA associations in classical Hodgkin lymphoma: age matters. Tissue Antigens 81 (5), 298-299, 2013.
Kushekhar Kushi*, Huang Xin*, Nolte Ilja, Kooistra Wierd, Visser Lydia, Bouwman Ilby, Kouprie Niels, Veenstra Rianne, van Imhoff Gustaaf, Olver Bianca, HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS One 7 (7):e39986, 2012.
Huang Xin, Hepkema Bouke, Nolte Ilja, Kushekhar Kushi, Jongsma Theo, Veenstra Rianne, Poppema Sibrand, Gao Zifen, Visser Lydia, Diepstra Arjan, HLA-A* 02: 07 is a protective allele for EBV negative and a susceptibility allele for EBV positive classical Hodgkin lymphoma in China, PLoS One 7(2):e31865, 2012.
Huang Xin*, Kushekhar Kushi*, Nolte Ilja, Kooistra Wierd, Visser Lydia, Bouwman Ilby, Kouprie Niels, Veenstra Rianne, van Imhoff Gustaaf, Olver Bianca, Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups. Blood 118 (19):5211-5217, 2011.
Kushekhar Kushi, Veenstra Rianne, Gualco Gabriela, Domeney Pollyanna, Hepkema Bouke, Visser Lydia, Bacchi Carlos E, Diepstra Arjan, Van Den Berg Anke. EBV and HLA associations in Classical Hodgkin Lymphoma Patients From Brazil. Blood 118 (21):4858-4858, 2011.