title: CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.
abstract: Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.|Department of Surgery, Duke University, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Espinosa
authors.affiliation: INSERM UMR1014, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Herr
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: G
authors.initials: G
authors.lastname: Tharp
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: S
authors.initials: S
authors.lastname: Bosinger
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.
authors.forename: R
authors.initials: R
authors.lastname: George
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.|Department of Surgery, Duke University, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Cheeseman
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.|Department of Surgery, Duke University, Durham, NC.
authors.forename: L
authors.initials: L
authors.lastname: Stempora
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: R
authors.initials: R
authors.lastname: Townsend
authors.affiliation: INSERM UMR1014, Villejuif, France.|Department of Nephrology, IFRNT, University of Kremlin Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: A
authors.initials: A
authors.lastname: Durrbach
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA.|Department of Surgery, Duke University, Durham, NC.
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000328:Adult; D064591:Allografts; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018959:CD57 Antigens / Q000378:metabolism*; D004351:Drug Resistance; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012307:Risk Factors
chemical_list: D018959:CD57 Antigens; D007166:Immunosuppressive Agents; D000069594:Abatacept