Evidence Against the Role of Th1 in the Development of Chronic Cardiac Allograft Rejection

Abstract

384 Transient depletion of CD4+ T cells in mouse vascularized cardiac allograft recipients prolongs allograft survival, however grafts exhibit signs of chronic rejection characterized by collagen deposition and neointima development. It has been suggested that chronic rejection is associated with persistent low-level immune responses directed against the graft. While it is well established that Th1 cells promote acute allograft rejection, the role of these cells in chronic rejection remains unclear. The present study was designed to determine whether IFNγ producing Th1 cells contribute to the development of chronic cardiac allograft rejection. To this end, splenocytes obtained from C57BL/6 (B6) recipients bearing Balb/c hearts with signs of chronic rejection were adoptively transferred into B6 SCID cardiac allograft recipients. Transfer of these cells resulted in accelerated and exacerbated chronic allograft rejection in the majority of SCID recipients. Hence, this transfer system allowed us to explore the underlying mechanisms involved in chronic cardiac allograft rejection and the participation of Th1 in this process. Characterization of splenocytes prior to adoptive transfer into B6 SCID allograft recipients revealed a hyporesponsiveness in Th1 function. However, splenocyte proliferative responses to mitogens or alloantigens and precursor CTL and IL-2 producing T lymphocyte frequencies were comparable to naive splenocytes. Further, transferred splenocytes recovered from SCID allograft recipients with advanced signs of chronic rejection remained deficient in Th1 function, suggesting that Th1 are not involved in this disease process. Two additional observations indicated that Th1 are not associated with chronic rejection: 1) chronic cardiac rejection developed in allografts of IL-12 knockout recipients treated transiently with anti-CD4 mAb, and 2) transfection of grafts with TGFβ1 ablated Th1 responses, but resulted in accelerated chronic rejection. Finally, when splenocytes used for adoptive transfer retained Th1 function, transfer of these cells resulted in acute allograft rejection in SCID recipients. Hence, the absence rather than the presence of Th1 was associated with chronic rejection. These data suggest that Th1-independent effector mechanisms are responsible for chronic rejection in this model. Ongoing studies employing this transfer system are aimed at identifying the cellular and cytokine mediators in this disease process.