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

K. Lee, V. Nguyen, K. M. Lee, S. M. Kang, Q. Tang

Research output: Contribution to journalArticle

62 Citations (Scopus)

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 × 106 Tregs with direct donor reactivity or 25 × 106 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. This study demonstrates that donor-reactive regulatory T cells are more potent than polyclonal regulatory T cells in preventing rejection; however, both types require depletion of donor-reactive T effector cells for optimal efficacy. See editorial by Bradley on page 5.

Original languageEnglish
Pages (from-to)27-38
Number of pages12
JournalAmerican Journal of Transplantation
Volume14
Issue number1
DOIs
Publication statusPublished - 2014 Jan

Keywords

  • CD8 T cell
  • T cell deletion
  • Treg therapy
  • diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy'. Together they form a unique fingerprint.

  • Cite this