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Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation
Author(s) -
Guinan E. C.,
Cole G. A.,
Wylie W. H.,
Kelner R. H.,
Janec K. J.,
Yuan H.,
Oppatt J.,
Brennan L. L.,
Turka L. A.,
Markmann J.
Publication year - 2016
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.13725
Subject(s) - medicine , belatacept , immunosuppression , foxp3 , transplantation , il 2 receptor , kidney transplantation , immunology , kidney , calcineurin , t cell , immune system , kidney transplant
Short‐term outcomes of kidney transplantation have improved dramatically, but chronic rejection and regimen‐related toxicity continue to compromise overall patient outcomes. Development of regulatory T cells (Tregs) as a means to decrease alloresponsiveness and limit the need for pharmacologic immunosuppression is an active area of preclinical and clinical investigation. Nevertheless, the immunomodulatory effects of end‐stage renal disease on the efficacy of various strategies to generate and expand recipient Tregs for kidney transplantation are incompletely characterized. In this study, we show that Tregs can be successfully generated from either freshly isolated or previously cryopreserved uremic recipient (responder) and healthy donor (stimulator) peripheral blood mononuclear cells using the strategy of ex vivo costimulatory blockade with belatacept during mixed lymphocyte culture. Moreover, these Tregs maintain a CD 3 + CD 4 + CD 25 + CD 127 lo surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP 3 Treg‐specific demethylation region on allorestimulation with donor stimulator cells. These data support evaluation of this simple, brief Treg production strategy in clinical trials of mismatched kidney transplantation.