Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 16, Issue 2, Pages 550-564Publisher
WILEY
DOI: 10.1111/ajt.13469
Keywords
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
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Funding
- US Food and Drug Administration [1R01 FD003539-01]
- National Institutes of Health [R01 AI097423]
- Georgia Research Alliance
- Roche Organ Transplant Research Foundation [346678023]
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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.
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