A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in hum ans and animals but the immunological mechanisms of this effect remain uncl ear. We have analyzed the expression and the role of endogenous TGF-beta 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 in filtration of leukocytes into the graft that are unable eo produce both Th1 - and Th2-related cytokines in vivo, Allografts from DST-treated rats expre ss high levels of TGF-beta 1 mRNA and active protein. This phenomenon is co rrelated with the rapid infiltration of leukocytes producing high amounts o f TGF-beta 1, TGF-beta 1-producing cells are virtually absent among early i nfiltrating cells in rejected grafts but are found at a later time point. T he induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti-TGF-beta mAb. Moreover, overexpression of active TGF-b eta 1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results ident ify TGF-beta as a critical cytokine involved in the suppression of allograf t rejection induced by DST and suggest that TGP-beta-producing regulatory c ells are also involved in allograft tolerance.