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 language | English |
---|---|
Pages (from-to) | 27-38 |
Number of pages | 12 |
Journal | American Journal of Transplantation |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2014 Jan |
Bibliographical note
Copyright:Copyright 2014 Elsevier B.V., All rights reserved.
Keywords
- CD8 T cell
- T cell deletion
- Treg therapy
- diabetes
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)