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Attenuation of Donor‐Reactive T Cells Allows Effective Control of Allograft Rejection Using Regulatory T Cell Therapy
Author(s) -
Lee K.,
Nguyen V.,
Lee K.M.,
Kang S.M.,
Tang Q.
Publication year - 2014
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12509
Subject(s) - medicine , immunology , transplantation , cd8 , islet , immunosuppression , cyclophosphamide , immune tolerance , cytotoxic t cell , immune system , regulatory t cell , cell therapy , t cell , cancer research , il 2 receptor , stem cell , biology , insulin , chemotherapy , microbiology and biotechnology , in vitro , biochemistry
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.