Autoreactivity to self H‐2K b peptides in TAP1 –/– mice. Intravenous administration of H‐2K b class I‐derived peptides induces long‐term survival of grafts from C57BL/6 donors

Summary We and others have previously shown that TAP1 –/– mice (H‐2 b ) reject grafts from donors without major histocompatibility complex (MHC) disparity that express wild‐type levels of H‐2 b class I molecules (C57BL/6, TAP1 +/+ mice). In this same model, we also showed that subcutaneous priming of TAP1 –/– mice with synthetic peptides derived from the H‐2K b molecule accelerated graft rejection and that in vivo depletion of CD4 + T cells induced a significant prolongation of graft survival, suggesting an important role for CD4 T cells. We hypothesize that, in this model, rejection is triggered by the recognition of class I molecules or derived peptides, in an inflammatory microenvironment, by a functionally altered autoreactive T‐cell repertoire that escapes the control of peripheral regulatory mechanisms. In the present study, we analysed the cellular autoreactivity induced by synthetic peptides derived from the H‐2K b sequence in naive and TAP1 –/– mice transplanted with C57BL/6 grafts, and investigated whether intravenous modulation of autoreactivity to these peptides induced transplantation tolerance. We showed that TAP1 –/– mice have peripheral autoreactive T cells that recognize H‐2K b peptides. A significant amplification of proliferation against these peptides was detected in TAP1 –/– mice that rejected grafts, indicating that the inflammatory context of transplantation induced peripheral expansion of these autoreactive T cells. Furthermore, intravenous injection of H‐2K b ‐derived peptides significantly prolonged graft survival in some animals. In these mice (> 100 days graft survival), we observed intragraft inhibition of interferon‐γ and interleukin‐10 expression, suggesting that these cytokines have an active role during the rejection. In conclusion, our present data indicate that inflammatory autoreactive T cells directed against H‐2K b peptides can be inhibited in the periphery to prolong graft survival in TAP1 –/– mice.