B cell reconstitution following alemtuzumab induction under a belatacept-based maintenance regimen.

Lymphocyte depletion has been shown to control costimulation blockade-resistant rejection but, in some settings, to exacerbate antibody-mediated rejection (AMR). We have used alemtuzumab, which depletes T and B cells, combined with belatacept and rapamycin and previously reported control of both costimulation blockade-resistant rejection and AMR. To evaluate this regimen's effect on B cell signatures, we investigated 40 patients undergoing this therapy. B cell counts and phenotypes were interrogated using flow cytometry, and serum was analyzed for total IgG, IgM, and donor-specific alloantibody (DSA). Alemtuzumab induction produced pan-lymphocyte depletion; B cells repopulated faster and more completely than T cells. Reconstituting B cells were predominantly naïve, and memory B cells were significantly reduced (P = .001) post repopulation. Two B cell populations with potential immunomodulatory effects-regulatory (CD38hi CD24hi IgMhi CD20hi ) and transitional B cells (CD19+ CD27- IgD+ CD38hi )-were enriched posttransplant (P = .001). Total serum IgG decreased from baseline (P = .016) while IgM levels remained stable. Five patients developed DSAs within 36 months posttransplant, but none developed AMR. Baseline IgG levels in these patients were significantly higher than those in patients without DSAs. These findings suggest that belatacept and rapamycin together limit homeostatic B cell activation following B cell depletion and may lessen the risk of AMR. This regimen warrants prospective, comparative study. ClinicalTrials.gov NCT00565773.

Kidney transplantation using alemtuzumab, belatacept, and sirolimus: Five-year follow-up.

Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients.