Autoantibody Responses to a Heart Allograft Augment Allograft Vasculopathy By Amplifying Conventional Cellular and Humoral Alloimmune Effector Mechanisms.

Abstract

Introduction: Although transplant-related autoantibody responses are reported increasingly, their contribution to graft failure remains poorly understood. We used a MHC-mismatched murine heart transplant model in which passenger donor CD4 T cells trigger recipient autoantibody to examine the hypothesis that humoral autoimmunity contributes to allograft vasculopathy (AV) by amplifying conventional alloimmune responses. Methods: A new donor strain (bm12.Kd.IE) was created, to incorporate additional MHC class I (H-2Kd) and class II (I-E) target alloantigens. IgG allo- and autoantibody responses were measured weekly. Indirect-pathway CD4 T cell responses were assessed by transfer of CFSE-labelled TCR75 T cells, CD8 cytotoxic responses were measured by ELISPOT. Donor CD4 T cell were depleted with anti-CD4 antibody (YTS 191.1) AV was assessed morphometrically. Results: Heart allografts from unmodified donors provoked long-lasting indirect-pathway CD4 T cell responses and strong, class-switched alloantibody responses against the mismatched Kd class I alloantigen. Moderate CD8 T cellular cytotoxicity was also observed. These were associated with development of progressive allograft vasculopathy and eventual graft failure. In contrast, alloimmune responses were barely above background following grafting with CD4 T cell-depleted hearts that did not trigger autoimmunity, with only minimal vasculopathy development and indefinite graft survival. The contribution of donor CD4 T cells to graft rejection was not due to a direct effect on the graft, because they are killed within days after transplantation, but instead to the humoral immunity that they trigger; in the absence of recipient B cells, donor T cell responses remained vigorous, but host CD4 T cell alloimmunity was diminished and no longer influenced by the presence of donor CD4 T cells. Conclusions: Concurrent humoral autoimmunity contributes to allograft rejection by augmenting conventional alloimmunity, and is triggered by even transient donor T cell survival.