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

Am J Transplant. 2016 Feb;16(2):550-64. doi: 10.1111/ajt.13469. Epub 2015 Oct 5.


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.

Trial registration: NCT00565773.

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept / therapeutic use*
  • Adult
  • Aged
  • CD28 Antigens / metabolism
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Graft Rejection / drug therapy
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Graft Survival
  • Humans
  • Immunologic Memory / drug effects
  • Immunologic Memory / immunology*
  • Immunosuppressive Agents / therapeutic use
  • Isoantigens / immunology
  • Kidney Failure, Chronic / immunology*
  • Kidney Failure, Chronic / surgery
  • Kidney Function Tests
  • Kidney Transplantation*
  • Lymphocyte Depletion
  • Male
  • Middle Aged
  • Pilot Projects
  • Prognosis
  • Risk Factors
  • Sirolimus / therapeutic use*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Transplant Recipients
  • Young Adult


  • CD28 Antigens
  • Immunosuppressive Agents
  • Isoantigens
  • Abatacept
  • Sirolimus

Associated data