Characterizing immunomodulatory properties of a novel therapeutic approach for multiple sclerosis - Inhibition of Bruton's tyrosine kinase

by Sarah Dybowski
Doctoral thesis
Date of Examination:2024-03-27
Date of issue:2024-05-06
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Persistent Address: http://dx.doi.org/10.53846/goediss-10477

 

 

Files in this item

Name:Dissertation_Dybowski.pdf
Size:6.31Mb
Format:PDF
Description:Dissertation

This file will be freely accessible after 2025-01-30.

Abstract

English

Multiple Sclerosis is a complex and challenging chronic disease of the central nervous system (CNS), characterized by inflammation, demyelination, and neurodegeneration. The depletion of B cells using anti-CD20 antibodies as therapeutic strategy, has proven to be highly effective. However, in the long-term, a complete absence of B cells does not come without adverse side effects, and in addition, B cell subpopulations appear to be capable of providing regulatory properties. Consequently, there is an increasing emphasis on modulating B cell functions rather than entirely eliminating these immune cells. Among the emerging strategies, Bruton's tyrosine kinase (BTK) inhibitors such as evobrutinib, have gained attention for their pleiotropic immunomodulatory effects. Here, we evaluated the impact of one prominent BTK inhibitor, evobrutinib in various animal models of MS, each representing distinct aspects of human CNS autoimmunity. The results obtained demonstrated that evobrutinib treatment effectively reduced the development of spontaneous CNS autoimmune disease by inhibiting the pro-inflammatory activation of B cells and myeloid cells. Notably, long-term evobrutinib treatment maintained Ig levels and accordingly preserved the overall humoral immune response – in contrast to continuous anti-CD20 treatment. After the discontinuation of anti-CD20 therapy, evobrutinib treatment facilitated the restoration of Ig levels while impeding the redevelopment of pathogenic B cells and favoring the development of B cell with regulatory properties. These results highlight that BTK inhibition may serve as ideal maintenance therapy after eradication of established pathogenic B cells via anti-CD20. Besides these B cell properties, this study revealed that evobrutinib treatment also limited the pro-inflammatory activity of myeloid cells independently of B cells. Evobrutinib inhibited antigen presentation of myeloid cells while promoting phagocytosis in vitro. These findings highlight the potential of evobrutinib as an effective therapeutic approach for MS, offering insights into its mechanisms of action across multiple immune cell types involved in CNS autoimmunity.
Keywords: Multiple sclerosis; Bruton's tyrosine kinase
Schlagwörter: MS; BTK; EAE; evobrutinib; anti-CD20; Bregs; B cells; myeloid cells