MHC-mismatched mixed chimerism augments thymic regulatory T cell production and prevents relapse of EAE (THER7P.960)

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune inflammatory disease in central nervous system with demyelination, axon damage, and paralysis. There is no yet curative therapy. Induction of MHC-mismatched mixed chimerism is proposed to be a potential cure for autoimmune diseases, but this has not yet been tested in animal models of MS, experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2b) donor in SJL/J (H-2s) EAE recipients eliminates symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity and elimination of infiltration of T, B and macrophage cells in the spinal cord, as judged by HE, immunofluorescent staining and flow cytometry analysis. We also see regeneration of myelin as judged by fast-blue staining and prevention of axon damage as judged by electronic microcopy. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4+ T cells and significant increase of Foxp3+ regulatory T percentage among host-type CD4+ T cells in the spleen and lymph nodes. We have also found a marked increase of Foxp3+ regulatory T percentage among host-type CD4+ and CD4+CD8+ thymocytes in the thymus. Thymectomy leads to loss of prevention of EAE relapse by the mixed chimerism. These results indicate that induction of MHC-mismatched mixed chimerism can augment thymic production of Foxp3+ regulatory T cells and cure EAE.