Induced Regulatory T Cells in Allograft Tolerance Via Transient Mixed Chimerism

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2016 Jul 23

PMID 27446989

Citations 25

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

Affiliations

Soon will be listed here.

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, CD4FOXP3 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.

Citing Articles

Analysis of T-cell alloantigen response a direct pathway in kidney transplant recipients with donor-specific antibodies.

Iwahara N, Hotta K, Iwami D, Tanabe T, Tanaka Y, Ito Y Front Immunol. 2023; 14:1164794.

PMID: 37207202 PMC: 10189043. DOI: 10.3389/fimmu.2023.1164794.

Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates.

Sasaki H, Hirose T, Oura T, Otsuka R, Rosales I, Ma D Sci Transl Med. 2023; 15(690):eadd5318.

PMID: 37018417 PMC: 11022838. DOI: 10.1126/scitranslmed.add5318.

IL-10 modified mRNA monotherapy prolongs survival after composite facial allografting through the induction of mixed chimerism.

Avina A, De Paz D, Huang S, Chen K, Chang Y, Lee C Mol Ther Nucleic Acids. 2023; 31:610-627.

PMID: 36910717 PMC: 9996371. DOI: 10.1016/j.omtn.2023.02.016.

Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings.

Hu M, Rogers N, Li J, Zhang G, Wang Y, Shaw K Front Immunol. 2021; 12:717594.

PMID: 34512640 PMC: 8428972. DOI: 10.3389/fimmu.2021.717594.

Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency.

Trevelin S, Zampetaki A, Sawyer G, Ivetic A, Brewer A, Smyth L JCI Insight. 2021; 6(18).

PMID: 34375309 PMC: 8492330. DOI: 10.1172/jci.insight.149301.

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