title: Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation.
abstract: 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 CD3(+) CD4(+) CD25(+) CD127(lo) surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP3 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.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: E C
authors.identifier: 0000-0003-3874-0007
authors.initials: EC
authors.lastname: Guinan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: G A
authors.initials: GA
authors.lastname: Cole
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: W H
authors.initials: WH
authors.lastname: Wylie
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: R H
authors.initials: RH
authors.lastname: Kelner
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Janec
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Epiontis GmbH, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Oppatt
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: L L
authors.initials: LL
authors.lastname: Brennan
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Markmann
mesh_terms: D000069594:Abatacept / Q000276:immunology; D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000276:immunology; D005919:Glomerular Filtration Rate; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D057832:Watchful Waiting
chemical_list: D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D000069594:Abatacept
keywords: basic (laboratory) research/science; cellular transplantation (non-islet); kidney transplantation/nephrology; kidney transplantation: living donor; organ transplantation in general; tolerance: costimulation blockade; tolerance: experimental; translational research/science