Digital Public Defence: Anub Mathew Thomas

MD Anub Mathew Thomas at Institute of Clinical Medicine will be defending the thesis “Complement in Sterile Inflammation and Methodological Challenges” for the degree of PhD (Philosophiae Doctor).

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Photo: Amalie Hovland, UiO

The public defence will be held as a video conference over Zoom.

The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

Click here to participate in the public defence

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Digital Trial Lecture – time and place

See Digital Trial Lecture.

Adjudication committee

  • First opponent: Professor Seppo Meri, University of Helsinki, Finland
  • Second opponent: Researcher Lubka Roumenina, INSERM, France
  • Third member and chair of the evaluation committee: Associate Professor Marius Trøseid, Faculty of Medicine, University of Oslo

Chair of the Defence

Professor II Tor Inge Tønnessen, Faculty of Medicine, University of Oslo

Principal Supervisor

Researcher Andreas Barratt-Due, Faculty of Medicine, University of Oslo

Summary

The complement system and the Toll-like receptors (TLRs) are two essential components of the innate immunity and play a crucial role in sterile inflammation. The aim of this thesis was to explore whether inhibition of complement (C5) or the accessory TLR-molecule CD14, or the combination thereof attenuated sterile inflammation induced by meconium or cell-free heme. Furthermore, the thesis focuses on methodological challenges when assessing complement activation.

In an in vivo piglet model of meconium aspiration syndrome, intratracheal meconium instillation induced a severe persistent lung injury to all animals and a vast systemic inflammatory response. Dual inhibition of complement and CD14 did not improve lung function but attenuated systemic release of inflammatory mediators, IL-1b and IL-6, and myeloperoxidase activity in the bronchoalveolar fluid. In the second paper, we demonstrated that C5-inhibition attenuated heme-induced release of proinflammatory cytokines, LTB-4, MMP-8, MMP-9, IL-1Ra, reduced upregulation of CD11b on granulocytes and monocytes and attenuated monocytic tissue factor expression. Prothrombin fragment F1+2-release was additionally attenuated when targeting both complement and CD14. Importantly, the findings corroborated with the clinic of two sickle-cell disease patients included in the study thus suggesting that targeting complement has the potential to reduce thromboinflammation in sickle-cell disease crisis patients.

In the methodological studies, we showed that a neoepitope in the C5a-moiety of C5 was exposed in eculizumab-C5 complexes implying false positive detection of C5a in patients treated with eculizumab. Secondly, we demonstrated that complement activation products are sensitive markers of complement activation and not inferior when compared to the ratio of the activation product and its parent protein. This is of clinical importance when deciding which assays to be used to detect complement activation both with high sensitivity and specificity.

Additional information

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Published Nov. 13, 2020 10:52 AM - Last modified Nov. 30, 2020 9:49 AM