A Critical Role for Transforming Growth Factor- b in Donor Transfusion-induced Allograft Tolerance

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in humans and animals but the immunological mechanisms of this effect remain unclear. We have analyzed the expression and the role of endogenous TGFb 1 in a model of heart allograft tolerance, induced by pregraft DST in adult rats. We reported previously that this tolerance occurs despite a strong infiltration of leukocytes into the graft that are unable to produce both Th1and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGFb 1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGFb 1. TGFb 1–producing cells are virtually absent among early infiltrating cells in rejected grafts but are found at a later time point. The induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti–TGFb mAb. Moreover, overexpression of active TGFb 1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGFb as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGFb –producing regulatory cells are also involved in allograft tolerance. ( J. Clin. Invest. 1998. 102:1920–1926.)