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

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. We have reported control of costimulation-resistant rejection when belatacept is combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin (ABR). To assess the means by which the ABR regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients, characterizing peripheral lymphocyte phenotype and functional responses to donor, third-party, and viral antigens using flow cytometry, intracellular cytokine staining, and CFSE-based lymphocyte proliferation. Compared to 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, 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. ABR regimen uniquely alters 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 is permissive for control of rejection with belatacept monotherapy. TRIAL REGISTRATION ClinicalTrials.gov - NCT00565773

IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade–resistant rejection

“…As previously reported, profound lymphocyte depletion was achieved immediately following alemtuzumab therapy followed by slow CD4 + and CD8 + cell reconstitution and a relatively rapid B cell repopulation (10–11) . Alemtuzumab induction and belatacept/sirolimus-based immunosuppression effectively prevented T cell-mediated allograft rejection within 36 months post-transplantation.…”

“…Alemtuzumab induction and belatacept/sirolimus-based immunosuppression effectively prevented T cell-mediated allograft rejection within 36 months post-transplantation. All patients demonstrated excellent renal allograft function with sustained and improving estimated GFR (10) and intact T cell-mediated anti-cytomegalovirus and EBV responses (11) post-transplantation. No T cell depletion was seen in the non-depleted, conventionally treated patients.…”

“…Indeed, depletional induction and belatacept/sirolimus-based regimens without CNIs or steroids uniquely alters the T cell immune profile by inducing a repertoire enriched for CD2 low CD28 + cells, which are permissive for costimulation blockade–mediated control of allospecific T cell activation (10–11) . Furthermore, alemtuzumab-treated patients demonstrate increased numbers of regulatory T and B cells that may prevent alloimmune responses (10–11) .…”

Crosstalk Between T and B Cells in the Germinal Center After Transplantation

“…This review however acknowledges that the evidence so far has not fully evaluated the role of belatacept in transplantation, particularly with respect to costimulation blockade resistant rejection. Of pertinent interest, in a recent paper based on an alemtuzumab, belatacept, rapamycin based regimen in human kidney transplantation, it has been shown that, following depletional induction, the rapidly repopulating B cell phenotype is predominantly naïve and regulatory in nature 47 .…”

Memory T cells in organ transplantation: progress and challenges

“…In general, depletion might present a unique opportunity to shape the immune cell repertoire. Studies of alemtuzumab-mediated depletion in combination with belatacept and sirolimus (which inhibits IL-2 production) have shown that the burst of homeostatic activation is countered by a corresponding burst of T REG and B REG cell generation, and that this phenomenon is associated with exceptionally low rates of rejection 78 . This approach might offer an opportunity to specifically target the nutritional requirements of memory T cells in order to shape the immune-cell repertoire and aid in the elimination of allospecific effector memory T cells.…”