Investigating the role of the ATP-P2X7 axis in the development and progression of T cell-driven cerebral vasculitis

• Applicant: Dr. Bjoern Rissiek
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533586492

Cerebral vasculitis refers to inflammation of brain blood vessels causing serious dysfunction or damage to the brain. Cerebral vasculitis can affect brain blood vessels of all sizes and is usually the consequence of an autoimmune disease. Primary angiitis of the central nervous system (PACNS) is rare autoimmune disease affecting small to medium-sized cerebral blood vessels. PACNS is difficult to diagnose and many details of the immunopathology of PACNS are still unknown. Disease symptoms are ranging from diffuse neurological symptoms over headache to stroke, but patients can also suffer from seizures, cranial nerve palsies or myelopathies. Indeed, the limited number of patients makes it difficult to conduct larger clinical studies with significant outcome, limiting progress in gain of knowledge and therapy options to case reports and studies on samples from patient’s biopsy banks. In order to better understand immunological processes occurring at the inflamed blood brain barrier, we developed a new mouse model: the “BrEndO” mouse. In BrEndO mice brain (Br) endothelial (Endo) cells can be forced to express chicken ovalbumin (O), thereby making them a target for ovalbumin-specific CD8 T cells. This results in a T cell driven cerebral vasculitis. In the proposed project we aim at investigate the role of the ATP-gated P2X7 ion channel in the development and progression of cerebral vasculitis with the long-term goal to evaluate P2X7 as new drug target for treating PACNS patients. P2X7 is mostly known for its role in inflammasome formation in innate immune cells such as macrophages. However, recent studies demonstrate that P2X7 is also crucial for the development and maintenance of memory cells, especially with tissues. Theses tissue-resident memory cells (Trm) form after e.g. viral infections in order to prevent rapid re-infection. However, Trm are also suspected to be detrimental factors in autoimmunity. It is our hypothesis that P2X7 modulates cerebral vasculitis at different stages including the T cell priming phase, the T cell-driven acute phase in the brain, and the development of tissue-resident memory CD8 T cells. In particular, we hypothesize that established Trm can be eliminated by “starvation” via long-term P2X7 blockade. Therefore, we aim at elucidating the role of P2X7 in the development of a CD8+ T cell response against antigens in endothelial cells by using P2X7-deficient and P2X7-overexpressing mice. We further plan to visualize and quantify the amount of the P2X7 ligand ATP in the brain during the acute and chronic phase of cerebral vasculitis. We plan to analyze the function of P2X7 on brain infiltrating immune cells during the acute phase of cerebral vasculitis by using P2X7-blocking nanobodies and we will explore if intracerebrally produced P2X7-blocking nanobodies can prevent formation of tissue-resident memory T cells (Trm) or remove already established ovalbumin-specific Trm in the chronic phase of cerebral vasculitis.

• DFG Programme: Research Grants