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

Abstract

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 TGF-␤ 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 Th1-and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGF-␤ 1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGF-␤ 1. TGF-␤ 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-TGF-␤ mAb. Moreover, overexpression of active TGF-␤ 1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGF-␤ as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGF-␤ -producing regulatory cells are also involved in allograft tolerance. ( J. Clin. Invest. 1998.

Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats

“…1,2 In certain tolerance protocols, such as the one induced by donor blood transfusion, expression of both Th1 and Th2 cytokines is inhibited in tolerated grafts as compared with levels observed in rejected ones. 3 In this and in other models of tolerance, expression of TGF-␤1 has been clearly implicated in the establishment of tolerance. 3,4 Furthermore, IFN-␥ and TGF-␤1 seem reciprocally to regulate pro-and compared with Addl324-treated (9.3 ± 3.3 days) or untreated groups (7.8 ± 1.5 days).…”

“…3 In this and in other models of tolerance, expression of TGF-␤1 has been clearly implicated in the establishment of tolerance. 3,4 Furthermore, IFN-␥ and TGF-␤1 seem reciprocally to regulate pro-and compared with Addl324-treated (9.3 ± 3.3 days) or untreated groups (7.8 ± 1.5 days). Immunohistochemical analysis of allografts after gene transfer of IL-10 showed that leukocyte infiltration was quantitatively equivalent to that seen in control groups but with a strong tendency towards lower levels of CD8 + cells.…”

“…Similarly, although TGF␤1 increases during heart allograft rejection in this strain combination and reaches maximal levels between days 5 and 7, earlier expression of TGF␤1 within the graft after adenovirus-mediated gene transfer prolonged allograft survival. 3 In our study, transduction of transplanted hearts with 10 9 p.f.u. of AdIL-4 did not produce a significant change in allograft survival as compared with controls.…”

“…We have already shown successful prolongation of cardiac allograft survival with this same gene transfer protocol, using an adenovirus coding for TGF-␤1. 3 Furthermore, expression of these immunosuppressive molecules by adenoviruses may also blunt the anti-adenovirus immune response and prolong transgene expression.…”

“…Increased expression of TGF-␤1 has been shown to play a key role in the development of allograft tolerance by donor-specific blood transfusion and overexpression of TGF-␤1 by adenovirus-mediated gene transfer prolongs allograft survival. 3 Furthermore, Qin et al 43 found that plasmid-mediated gene transfer of TGF-␤1 prolonged murine allograft survival in a model of neonatal cardiac transplantation.…”