title: Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.
abstract: Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naïve cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: K P
authors.initials: KP
authors.lastname: Samy
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Guasch
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: S I
authors.initials: SI
authors.lastname: Mead
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Ghali
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: L
authors.initials: L
authors.lastname: Stempora
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.|Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007519:Isoantigens / Q000276:immunology; D007676:Kidney Failure, Chronic / Q000276:immunology* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011379:Prognosis; D012307:Risk Factors; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D066027:Transplant Recipients; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D007519:Isoantigens; D000069594:Abatacept; D020123:Sirolimus
keywords: basic (laboratory) research / science; clinical research / practice; fusion proteins and monoclonal antibodies: alemtuzumab; fusion proteins and monoclonal antibodies: belatacept; immune regulation; immunobiology; immunosuppressant; immunosuppression / immune modulation; kidney transplantation / nephrology; lymphocyte biology: differentiation / maturation; mechanistic target of rapamycin (mTOR)