Co-inhibitory signaling in autoimmune inflammatory diseases of the central nervous system

• Applicant: Professor Dr. Veit Rothhammer
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401772351

Multiple Sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which affects young individuals during the most productive phases of their lives. The different subtypes of MS are caused by the infiltration of innate and adaptive immune cells into the CNS. These immune cells get reactivated in the interaction with CNS resident cells, such as astrocytes and microglia, and elicit inflammatory responses that lead to lesion formation, demyelination, and neuronal loss. In this pathogenetic cascade, the interaction of CNS infiltrating with CNS resident cells is crucial for the initiation of the immune response and promotes both acute and chronic stages of MS. In addition to the secretion of soluble mediators, astrocytes and microglia express membrane-bound receptors to directly influence CNS infiltrating immune cells. However, the relevance of these interactions is not well characterized.Programmed death ligand 1 and 2 (PD-L1 and PD-L2) are members of the B7 family of ligands with co-inhibitory functions on immune cell activation and are expressed on astrocytes and microglia. The engagement of PD-L1 and PD-L2 with its receptor PD-1 on infiltrating immune cells inhibits proliferation and inflammatory mediator production, while it induces anergy and apoptosis of pathogenic T cells and inflammatory monocytes, which are important for acute and chronic stages of MS. However, the molecular mechanisms in control of PD-L1 / PD-1 interactions within the CNS are not well characterized. Given the anti-inflammatory and down-modulatory effects of PD-1/PD-L1 interactions, enhancing this pathway may represent a novel therapeutic strategy for relapsing-remitting and secondary progressive stages of MS.In this project, we will study the relevance of co-inhibitory PD-1 / PD-L1 interactions in the CNS between astrocytes, microglia and CNS infiltrating immune cells during acute and chronic stages of autoimmune inflammation. We will explore mechanisms to enhance this interaction in an animal model of MS by nasal application of therapeutics, such as IFN-β and ligands to the aryl hydrocarbon receptor. In a translational approach, we will evaluate the relevance of soluble PD-L1 and its regulating factors as biomarkers for MS. These studies have implications for autoimmune diseases, but may lead to novel therapeutic strategies for neoplastic and infectious disorders of the CNS.

• DFG Programme: Research Grants