Cytokine regulation of chronic cardiac allograft rejection

Transient depletion of CD4⁺ T cells in mouse cardiac allograft recipients results in chronic graft rejection. To determine the underlying mechanisms involved in this process, 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 into SCID recipients resulted in accelerated and exacerbated chronic rejection in the majority of mice. Characterization of splenocytes prior to adoptive transfer revealed a hyporesponsiveness in Th1 function. However, splenocyte proliferative responses to mitogens or alloantigens, and precursor CTL and IL-2 producing T cell frequencies were comparable to naive splenocytes. Further, transferred splenocytes recovered from SCID allograft recipients remained deficient in Th1 function. Hence, Th1 are not critically involved in chronic rejection in this model. The development of chronic rejection in IL-12 knockout allograft recipients further supports this possibility. Interestingly, when splenocytes used for adoptive transfer retained Th1 function, transfer of these cells resulted in acute allograft rejection in SCID recipients. Using this transfer system, ongoing studies are designed to elucidate the role of specific cellular mediators involved in the pathogenesis of chronic cardiac allograft rejection.