Immune regulation at the CNS barriers and in the CNS: role of immune cell trafficking

B01

Infiltration of immune cells into the central nervous system (CNS) is one major hallmark of multiple sclerosis (MS) pathology. Natalizumab is a therapeutic integrin for to treat MS that inhibits the very late antigen (VLA)-4. In rare cases, therapy is accompanied by a progressive multiple leukencephalopathy, a rare but potentially fatal brain infection. By extending the dosing interval of natalizumab, the PML incidence in MS patients can be reduced by 90%, whereas efficacy seems preserved. We hypothesize that a cellular subtype preferentially benefits from extended natalizumab interval dosing and resumes CNS immune surveillance in patients receiving extended interval dosing. We will investigate the relationship between therapeutic integrin engagement and selectin expression for lymphocyte surveillance function with implications for virus control. Furthermore, we will analyze the antigen specificity of MCAM+ and CCR5high CNS-infiltrating T cells to decipher their exact roles in CNS immune surveillance versus inflammation. Lastly, we will transfer the generated molecular and cellular concepts of adaptive CNS immunity to the coagulation system. There we will analyze the contribution of leukocyteplatelet aggregates to adaptive CNS immunity in the context of MS. In other words, we will tackle these questions:

      1. What is the role of CNS-patrolling CD4 vs CNS-resident CD8 lymphocytes in CNS immune surveillance, MS pathology and viral control with decreasing VLA-4 inhibition?
      2. Why do certain immune cells specifically infiltrate the CNS?
      3. Could immune cells performing (excessive) CNS immune surveillance contribute to MS pathology or even pathogenesis?
      4. Is there a direct mechanistic link between integrin-β1 engagement by natalizumab, T-cell activation and L-selectin shedding?
      5. What is the tole of Role of platelet-leukocyte-aggregates in MS pathology and progression?

      Herich et al., Brain 2019

      Herich et al., Brain 2019

       

Principal Investigators

Univ.-Prof. Dr. rer. nat. Nicholas Schwab
Klinik für Neurologie mit Institut für Translationale Neurologie
Münster
nicholas.schwab@ukmuenster.de

Prof. Dr. med. Alexander Zarbock
Klinik für Anästhesiologie und Intensivmedizin
Münster
zarbock@uni-muenster.de

News

Thu, 15/09/2022
Photo gallery: Inflammation & Imaging Symposium in the MIC building
Muenster. From September 12th to 14th scientists from Muenster University and their international guests discussed the latest developments in research on inflammation and the imaging of the immune system at the 2nd Inflammation & Imaging Symposium. The annual event is jointly organised by several research networks from Münster, among them the CRC/TRR 128 “Multiple Sclerosis”. […]...more
Tue, 28/06/2022
CRC Retreat in Münster
Muenster. After a long pause, more than 90 participants of the CRC joined in Muenster Factory Hotel to update on the latest developments. We heard the most recent on a selection of the CRC projects and there was also plenty of time for fruitful discussion and socializing in the evening....more
Mon, 23/05/2022
EU Research Council awards Lydia Sorokin Advanced Grant
Münster – The biochemist and Principal investigator of the CRC 128 Prof. Dr. Lydia Sorokin has received the coveted “Advanced Grant” awarded by the European Research Council (ERC). The funding of ca. 2.3 million euros enables the realisation of outstanding research projects. Lydia Sorokin heads the Institute for Physiological Chemistry and Pathobiochemistry at Muenster University. […]...more