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Am J Transplant. 2014 Jan;14(1):27-38. doi: 10.1111/ajt.12509. Epub 2013 Nov 13.

Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.

Author information

1
Department of Surgery, University of California, San Francisco, San Francisco, CA; Department of Biochemistry and Molecular Biology, Korea University, Seoul, Republic of Korea.

Abstract

Regulatory T cells (Tregs) are essential for the establishment and maintenance of immune tolerance, suggesting a potential therapeutic role for Tregs in transplantation. However, Treg administration alone is insufficient in inducing long-term allograft survival in normal hosts, likely due to the high frequency of alloreactive T cells. We hypothesized that a targeted reduction of alloreactive T effector cells would allow a therapeutic window for Treg efficacy. Here we show that preconditioning recipient mice with donor-specific transfusion followed by cyclophosphamide treatment deleted 70-80% donor-reactive T cells, but failed to prolong islet allograft survival. However, infusion of either 5 × 10(6) Tregs with direct donor reactivity or 25 × 10(6) polyclonal Tregs led to indefinite survival of BALB/c islets in more than 70% of preconditioned C57BL/6 recipients. Notably, protection of C3H islets in autoimmune nonobese diabetic mice required islet autoantigen-specific Tregs together with polyclonal Tregs. Treg therapy led to significant reduction of CD8(+) T cells and concomitant increase in endogenous Tregs among graft-infiltrating cells early after transplantation. Together, these results demonstrate that reduction of the donor-reactive T cells will be an important component of Treg-based therapies in transplantation.

KEYWORDS:

CD8+ T cell; T cell deletion; Treg therapy; diabetes

Comment in

PMID:
24354870
PMCID:
PMC5262439
DOI:
10.1111/ajt.12509
[Indexed for MEDLINE]
Free PMC Article
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