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

作者：Xu H^*; Samy K P; Guasch A; Mead S I; Ghali A; Mehta A; Stempora L; Kirk A D

来源：American Journal of Transplantation, 2016, 16(2): 550-564.

DOI：10.1111/ajt.13469

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

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(+) naive 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 subsetschanges 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.

• 出版日期2016-2