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Aim: De novo autoantibodies (autoAbs) against lung restricted autoantigens, namely k-alpha 1 tubulin (KAT) and collagen type V (colV), develop following transplant but their role in allograft rejection remains unclear. Using the murine model of lung transplant we investigated whether these autoAbs can abrogate immunosuppression mediated tolerance of lung allografts and induce rejection of syngeneic grafts. Methods: Abs to KAT, ColV and isotype control (n =5/group) were administered in Bl/6 murine recipients of MHC-mismatched Balb/c single left lung allografts that were tolerized using costimulatory blockade (MR1 and CTLA4-Ig). ELISPOT was used to analyze antigen specific T cells. Graft rejection was characterized using histochemistry. Syngeneic single left lung transplants were performed in B/6 mice following which Abs to KAT, ColV and isotype control were injected. Results: Lung allografts showed no rejection following co-stimulatory blockade. Administration of either KAT or colV autoAbs, but not isotype control, led to allograft rejection (but not native lungs) by day 45. This correlated with infiltration of IFN and IL-17 secreting Tcells specific to the lung-restricted autoantigens (but not Collagen II) as well as donor MHC antigens (but not against third party MHC antigens). Either KAT or colV autoAbs alone induced immunity against the other lung restricted autoantigen as well but not against non-lung antigen Collagen II. Administration of either colV or KAT autoAbs led to the rejection of syngeneic left lung grafts (but not native lungs) that was associated with infiltration of autoantigen specific IFN and IL-17 secreting T cells. Conclusions: De novo autoAbs can abrogate immunosuppression mediated lung allograft tolerance. Autoabs can lead to graft rejection in the absence of alloimmunity as evident by rejection of syngeneic grafts. AutoAbs also lead to epitope spreading and development of additional autoimmune responses against target tissue-restricted as well as donor MHC antigens. [ABSTRACT FROM AUTHOR]