Induced regulatory T cells in allograft tolerance via transient mixed chimerism
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S. Allan, Joren C. Madsen, Gilles Benichou, Rex-Neal Smith, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi, Tatsuo Kawai
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S. Allan, Joren C. Madsen, Gilles Benichou, Rex-Neal Smith, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi, Tatsuo Kawai
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Research Article Immunology Transplantation

Induced regulatory T cells in allograft tolerance via transient mixed chimerism

Abstract

Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+ T cell responses in tolerant (TOL) recipients, while marked CD4+ T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+ cells were FOXP3+ in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+ cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.

Authors

Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S. Allan, Joren C. Madsen, Gilles Benichou, Rex-Neal Smith, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi, Tatsuo Kawai

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Figure 4

Loss of anti-donor CD8+ T cell responses despite substantial anti-donor CD4+ T cell responses in tolerant recipients.

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Loss of anti-donor CD8+ T cell responses despite substantial anti-donor ...
The CD3+ cells isolated from tolerant (TOL), acutely rejected (AR), and naive nonhuman primates (NHPs) were labeled with CFSE and were cultured with irradiated self or donor peripheral blood lymphocytes (PBLs) for 5 days. Naive T cells were cultured with irradiated MHC-mismatched PBLs. Cultured cells were then stained for CD4 and CD8. Representative flow cytometric data (A, CD8; C, CD4) and mean of % proliferation relative to the response to the self (B, CD8; D, CD4) are shown. Anti-donor CD8+ T cell hyporesponsiveness was observed in the TOL recipients, which was significantly lower than those observed in the AR recipients (A and B). However, substantial anti-donor CD4+ T cell proliferation was observed in TOL, which was comparable to that observed in the AR and naive NHPs (C and D). Proliferated cells (%) = proliferated cells (%) with donor antigens – proliferated cells (%) with the self. These assays were performed at 520 ± 86 days in the TOL recipients and 175 ± 37 days in the AR recipients after bone marrow transplantation. Data are presented as the mean ± SEM. *P < 0.05, ANOVA and the Bonferroni multiple-comparison method was used to test for significant differences among 3 groups; n = 8 per group.