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

Xu et al., Am J Transplant. (2015) - PMID: 26436448

Product(s) used in this publication: PepMix™ Peptide Pools

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00565773.

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

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)

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