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Author Notes:

Corresponding author: He Xu, M.D., Mailing Address: Department of Surgery, Duke University School of Medicine, HAFS Building, 7th Floor, Suite 7690, Durham, NC 27710, Telephone: (919) 681-4853, Fax Number: (919) 681-2779, Email: he.xu@duke.edu

The authors would like to thank US/FDA, the Georgia Research Alliance, the National Institutes of Health, and Roche ROTRF for research funding, and Emory Transplant Center Biorepository for sample collection and storage.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Subjects:

Research Funding:

This work was funded in part by grants from the US Food and Drug Administration (1R01 FD003539-01, ADK), the National Institutes of Health (R01 AI097423, ADK), the Georgia Research Alliance (ADK), and the Roche Organ Transplant Research Foundation grant (346678023, HX).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Surgery
  • Transplantation
  • clinical research
  • practice
  • basic (laboratory) research
  • science
  • immunosuppression
  • immune modulation
  • kidney transplantation
  • nephrology
  • immunobiology
  • immunosuppressant
  • fusion proteins and monoclonal antibodies: belatacept
  • fusion proteins and monoclonal antibodies: alemtuzumab
  • mechanistic target of rapamycin (mTOR)
  • immune regulation
  • lymphocyte biology: differentiation
  • maturation
  • REGULATORY T-CELLS
  • RENAL-ALLOGRAFT SURVIVAL
  • BLOOD B-CELLS
  • COSTIMULATION BLOCKADE
  • TOLERANCE
  • REJECTION
  • IMMUNITY
  • CYCLOSPORINE
  • ALEMTUZUMAB
  • DEPLETION

Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients

Tools:

Journal Title:

American Journal of Transplantation

Volume:

Volume 16, Number 2

Publisher:

, Pages 550-564

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

Copyright © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

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