Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates
Hisashi Bashuda, … , Satoshi Teraoka, Ko Okumura
Hisashi Bashuda, … , Satoshi Teraoka, Ko Okumura
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1896-1902. https://doi.org/10.1172/JCI23743.
View: Text | PDF
Research Article Transplantation

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. Rejection-free 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.

Authors

Hisashi Bashuda, Masaaki Kimikawa, Kenichiro Seino, Yojiro Kato, Fumiko Ono, Akira Shimizu, Hideo Yagita, Satoshi Teraoka, Ko Okumura

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Effect of anti-human CD80/CD86 mAbs on MLR in rhesus monkeys and functio...
Effect of anti-human CD80/CD86 mAbs on MLR in rhesus monkeys and functional activities of the cultured cells. (A) Freshly isolated CD4+ T cells (fresh cells) from peripheral blood of rhesus monkeys were cocultured with irradiated allogeneic PBMCs (stimulator) in the presence or absence of anti-human CD80/CD86 mAbs (10 μg/ml each) for 5 days. (B) Peripheral blood CD4+ T cells (fresh cells, white bars) or the cultured cells (black bars) were stimulated with donor or third-party splenocytes (gray bars). After 3 days culture or 5 days (for fresh cells), the responder cells were evaluated for their proliferation. (C and D) Dose-dependent suppression of the alloresponses of peripheral blood CD4+ T cells to donor-type stimulator cells by the cultured anergic cells. Cultures were set up with recipient CD4+ T cells (105 cells/well) and donor (C) or third-party (D) stimulators (105 cells/well) for 7 days. Cultured donor splenocytes (105) or different numbers of the cultured cells were also added in some wells. In all assays, cells were incubated for 6 days and then pulsed with 10 μCi of [3H]thymidine for the last 18 hours and counted. The bars represent the mean of triplicate values and the brackets indicate the SD. rIL-2, recombinant IL-2.