1036-LBO: BATF plays a crucial role in induction of autoimmunity and BOS development following administration of antibodies to MHC

Abstract

Development of antibodies to donor specific antigen following transplantation is an increased risk factor for development of chronic rejection. We have previously demonstrated that administration of anti-MHC antibodies (ABs) results in the induction of immune responses against self antigens (K α 1 tubulin (KAT) and collagen V (Col V) leading to development of OAD mediated by IL-17. The overall objective of the study was to define the molecular mechanisms that contribute to OAD development . Basic leucine zipper transcription factor, ATF-like (BATF) is an upstream signaling mediator that controls development of TH17 responses and induction of autoimmunity. BATF−/− mice and wild type mice were administered anti-MHC ABs endobronchially and analyzed for the development of OAD on day 30. Humoral and cellular immune responses against the self antigens (KAT and Col V) were analyzed by ELISA and ELISPOT respectively. B cell infiltration in the lungs were analyzed by flow cytometry and IL-6expression was analyze by qRT-PCR. Histopathological analysis of lungs from BATF−/− demonstrated no significant development of OAD following administration anti-MHC ABs. BATF−/− resulted in a eight fold reduction in cellular infiltration ( p < 0.05), 12 fold reduction in epithelial metaplasia and 10.4 fold reduction in fibrosis compared to controls. We observed a 93% reduction in the B cell infiltration and 3.8 fold reduction in the expression of IL-6 in the BATF deficient animals compared to controls. Moreover we observed a complete abrogation of humoral immune responses against the self antigen and 4.2 fold reduction in the IL-17 secreting cells against the self antigens in BATF−/− mice. Based on these results, we conclude that BATF play an important role in induction of immune responses to self antigens and immunopathogenesis of OAD following administration of anti-MHC. Therefore, strategies to block BATF signaling should be considered for preventing the development of chronic rejection.