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

He Xu*, K. P. Samy, A. Guasch, S. I. Mead, A. Ghali, A. Mehta, L. Stempora, A. D. Kirk

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)550-564
Number of pages15
JournalAmerican Journal of Transplantation
Volume16
Issue number2
DOIs
StatePublished - 1 Feb 2016
Externally publishedYes

Keywords

  • basic (laboratory) research / science
  • clinical research / practice
  • fusion proteins and monoclonal antibodies: alemtuzumab
  • fusion proteins and monoclonal antibodies: belatacept
  • immune regulation
  • immunobiology
  • immunosuppressant
  • immunosuppressant
  • immunosuppressant
  • immunosuppression / immune modulation
  • kidney transplantation / nephrology
  • lymphocyte biology: differentiation / maturation
  • mechanistic target of rapamycin (mTOR)

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