Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates

Abstract

Anergic T cells generated ex vivo are reported to have immunosuppressive effects in vitro and in vivo. Here, we tested this concept in nonhuman primates. Alloreactive T cells were rendered anergic ex vivo by coculture with donor alloantigen in the presence of anti-CD80/CD86 mAbs before adoptive transfer via renal allograft to rhesus monkey recipients. The recipients were briefly treated with cyclophosphamide and cyclosporine A during the preparation of the anergic cells. Thirteen days after renal transplantation, the anergic T cells were transferred to the recipient, after which no further immunosuppressive agents were administered. Rejectionfree survival was prolonged in all treated recipients, and 3 of 6 animals survived long term (410-880 days at study's end). In the long-surviving recipients, proliferative responses against alloantigen were inhibited in a donor-specific manner, and donor-type, but not third-party, skin allografts were also accepted, which demonstrated that antigen-specific tolerance had been induced. We conclude that anergic T cells generated ex vivo by blocking CD28/B7 costimulation can suppress renal allograft rejection after adoptive transfer in nonhuman primates. This strategy may be applicable to the design of safe clinical trials in humans.

Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells

“…In fact, CsA has been implicated in the induction of transplantation tolerance by sparing of CD4 ϩ suppressor cells and when used in combination with costimulation blocking agents. 12,[30][31][32][33][34] Further research on the in vivo role of CD27 ϩ T REG s and CD27 Ϫ T REG s may elucidate how the effect of rapamycin and CsA on the skewing of T REG subsets may differentially affect the induction of allograft tolerance.…”

Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin

“…However, depletion of CD4 ϩ CD25 ϩ T cells had no impact on direct pathway antidonor responses (25). In contrast, it was reported recently that infusion of ex vivo generated Tregs promoted long-term survival of renal allografts in nonhuman primates (NHP) by a mechanism that involves donor Ag-specific suppression of direct pathway reactivity (26).…”

Clinical Transplantation Tolerance

“…In a more complex trial that used costimulatory blockade ex vivo, Bashuda et al reported successful induction of renal allograft tolerance in three of six monkey recipients who received adoptive transfer of anergized T cells, induced by co-culture with donor alloantigen in the presence of anti-CD80/CD86 antibody [103]. Although induction of allograft tolerance was not consistent, this study represents the first report of renal allograft tolerance induction by adoptive transfer of anergized cells in NHP.…”