Prevention of allogeneic cardiac graft rejection by transfer of ex vivo expanded antigen-specific regulatory T-cells.
The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan ; Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan ; Japan Science and Technology Agency, CREST, Tokyo, Japan.
Fumika
F
Takasato
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan ; Japan Science and Technology Agency, CREST, Tokyo, Japan.
Rimpei
R
Morita
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan ; Japan Science and Technology Agency, CREST, Tokyo, Japan.
Takashi
T
Schichita
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan ; Japan Science and Technology Agency, CREST, Tokyo, Japan.
Takashi
T
Sekiya
Department of Pediatric Surgery, International University Medical Welfare Hospital, Nasushiobara, Tochigi, Japan.
Yasuhide
Y
Morikawa
Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan.
Tatsuo
T
Kuroda
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
Masanori
M
Niimi
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan ; Japan Science and Technology Agency, CREST, Tokyo, Japan.
Akihiko
A
Yoshimura
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014184:Transplantation, Homologous