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J Surg Res. 2011 Jul;169(1):e69-75. doi: 10.1016/j.jss.2011.03.021. Epub 2011 Apr 5.

Requirements for prolongation of allograft survival with regulatory T cell infusion in lymphosufficient hosts.

Author information

1
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. todd.brennan@duke.edu

Abstract

BACKGROUND:

For the clinical applicability of regulatory T cells (Tregs) in transplantation, it is critical to determine if donor antigen specificity is required for their immunosuppressive function. We developed an allospecific CD4(+) T cell receptor transgenic (TCR-tg) mouse as a source for large numbers of Tregs with defined allospecificity and tested whether they are more effective than polyclonal Tregs at suppressing allograft rejection.

MATERIALS AND METHODS:

CD4(+)CD25(+)CD62L(hi) T cells were sorted from the spleen and peripheral lymph nodes of wild-type (WT-Tregs) and TCR-tg (Allo-Tregs) mice, and expanded using IL-2 and anti-CD3/anti-CD28 conjugated magnetic beads. Tregs were tested for their ability to suppress the proliferation and cytokine production of alloreactive CD4(+)CD25(-) T cells in mixed leukocyte assays. Syngeneic WT hosts were adoptively transferred 5 × 10(6) Tregs and transplanted with allogeneic hearts.

RESULTS:

Using anti-CD3/anti-CD28 conjugated beads, Tregs were expanded in vitro 100-fold and maintained their suppressor phenotype and function. Allo-Tregs were 6-8 times more potent on a cell-for-cell basis than WT-Tregs in suppressing allospecific proliferation in vitro. Allo-Tregs were unable to suppress in the absence of allo-antigen. Adoptive transfer of expanded Allo-Tregs into WT recipients prolonged the graft survival in a F1 heart transplant model compared with WT-Treg or no treatment [20.0 ± 4.4 d (n = 6) versus 10.4 ± 1.2 (n = 8) and 9.7 ± 1.6 d (n = 6)].

CONCLUSIONS:

Unlike polyclonal Tregs, allospecific Tregs are able to prolong allograft survival. However, large numbers of Allo-Tregs were unable to induce tolerance, suggesting that Treg therapy in immunocompetent recipients will require conditioning and/or additional immunomodulation for the induction of tolerance.

PMID:
21571317
PMCID:
PMC3114634
DOI:
10.1016/j.jss.2011.03.021
[Indexed for MEDLINE]
Free PMC Article
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