Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates.
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.
Bashuda
Hisashi
H
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan. bashuda@med.juntendo.ac.jp
Kimikawa
Masaaki
M
Seino
Kenichiro
K
Kato
Yojiro
Y
Ono
Fumiko
F
Shimizu
Akira
A
Yagita
Hideo
H
Teraoka
Satoshi
S
Okumura
Ko
K
D019264:Adoptive Transfer; D000818:Animals; D017635:Clonal Anergy; D003404:Creatinine / Q000097:blood; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000637:transplantation*; D013997:Time Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003520:Cyclophosphamide; D003404:Creatinine