Studying T cell-driven vasculitis of the central nervous system in the BrEndO mouse model
SCHÄDLICH I. 1, NGUYEN D. 1, JIANG J. 1, WIRTH D. 2, MITTRÜCKER H. 1, MAGNUS T. 1, RISSIEK B. 1
1 University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2 Helmholtz Center for Infection Research, Braunschweig, Germany
Brain blood vessels can be the target of an autoimmune response e.g. in patients with primary angiitis of the central nervous system (PACNS). With 2.4 cases per 1 million person-years, PACNS is a rare disease and the underlying immunopathological mechanisms are not yet understood. As patient samples are rare and our current knowledge is largely based on small cohort descriptive studies and case reports, new preclinical animal models could help to extend our knowledge towards immunopathological processes occurring during cerebral vasculitis. Along this line, we generated the “BrEndO mouse”, which can be used to study T cell-driven inflammation of cerebral blood vesssels. In BrEndO mice, brain (Br) endothelial cells (Endo) express ovalbumin (O) after injection of tamoxifen, making them a target for adoptively transferred OT-I CD8 T cells. Six days after OT-I transfer, tamoxifen treated BrEndO mice show (1) massive CD8 T cell infiltration into the brain, co-localizing with blood vessels, (2) blood-brain-barrier dysfunction, (3) micro-bleedings and (4) neurological deficits. Further, in the absence of transferred OT-I T cells, we observed an “endogenous” anti-OVA CD8 T cell response resulting in brain infiltration of SIINFEKL-specific CD8 T cells at day 9 after tamoxifen treatment. This endogenous anti-OVA CD8 T cell response did not trigger severe disease symptoms as observed after OT-I transfer, but could be enhanced to a similar level by co-infection with OVA-transgenic Listeria monocytogenes.
In summary, the BrEndo mouse model can be used to investigate T cell-driven cerebral blood vessel inflammation, paving the way for studies on immunological mechanisms and the evaluation of new immunomodulatory therapeutic approaches to treat cerebral vasculitis.