mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells

Abstract

Background De novo alloantibodies (DSA) contribute to antibody-mediated rejection and poor long-term graft survival. Since the development of DSA is associated with early graft loss of cell transplants and reduced long-term survival of solid organ transplants, we hypothesized that conventional immunosuppressives, calcineurin inhibitors (CNi) and mammalian target of rapamycin inhibitors (mTORi), may not be as effective for suppression of humoral alloimmunity as for cell-mediated immunity. Methods Wild-type or CD8-depleted mice were transplanted with allogeneic hepatocytes. Recipients were treated with mTORi and/or CNi and serially monitored for alloantibody and graft survival. The direct effect of mTORi and CNi on alloprimed B cell function was investigated in Rag1-/- mice adoptively transferred with alloprimed IgG1+ B cells. The efficacy of mTORi and/or CNi to suppress CD8-mediated cytotoxicity of IgG1+ B cells was evaluated in in vitro and in vivo cytotoxicity assays. Results mTORi, but not CNi, reduced alloantibody production in transplant recipients, directly suppressed alloantibody production by alloprimed IgG1+ B cells and delayed graft rejection in both low and high alloantibody-producers. Combination treatment with mTORi and CNi resulted in loss of the inhibitory effect observed for mTORi monotherapy in part due to CNi-suppression of CD8+ T cells which downregulate alloantibody production (CD8+ TAb-supp cells). Conclusions Our data supports that mTORi is a potent inhibitor of humoral immunity through suppression of alloprimed B cells and preservation of CD8+ TAb-supp cells. In contrast, alloantibody is readily detected in CNi-treated recipients because CNi does not suppress alloprimed B cells and interferes with downregulatory CD8+ TAb-supp cells.

Efficacy and Safety of Everolimus for Maintenance Immunosuppression of Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials

“…It is part of a distinguished group of immunosuppressive drugs that have a divergent mode of action to that of CNIs even though they bind to the identical intracellular immunophilin as tacrolimus, namely, FKBP12. The mTORi/FKBP12 complex binds to and hinders the TORC1 complex, preventing proliferation of numerous cell types, such as T-lymphocytes, alloprimed B cells, and CD8 TAb-supp cells [10, 11]. The side effect profile of EVR is different from that of CNI and includes impaired wound healing, mouth ulcers, stomatitis, arthralgia, hyperlipidemia, and anemia [12–15].…”

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

“…Antibody‐producing allospecific B cells play a central role in antibody‐mediated allograft rejection, particularly chronic renal allograft nephropathy . A recent report suggests that mTOR inhibition suppresses not only alloprimed B cells but also antibody‐suppressing CD8 + cells . However, mTOR inhibitor, when use as monotherapy following alemtuzumab induction, does not prevent de novo DSAs and antibody‐mediated rejection .…”

“…[45][46][47] A recent report suggests that mTOR inhibition suppresses not only alloprimed B cells but also antibody-suppressing CD8 + cells. 26 However, mTOR inhibitor, when use as monotherapy following alemtuzumab induction, does not prevent de novo DSAs and antibody-mediated rejection. 11 In contrast, this cohort study demonstrates that B7 costimulation blockade effectively inhibits de novo DSAs.…”

“…[20][21][22] In general, conventional immunosuppressive regimens, including those using polyclonal lymphocyte depletional induction, leave B cells relatively unaltered. 23 The ABR regimen, in contrast, leads to profound B cell depletion 10,13 and is designed to block costimulation signals between T and B cells in the germinal center 24,25 and suppress B cell proliferation by mammalian target of rapamycin (mTOR) inhibition, 26,27 resulting in promotion of B cell population skewing toward naïve subsets and subsets with potential immunoregulatory function.…”

mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now?

“… showed that knockdown of either mTORC1 and mTORC2 blocked endothelial cell proliferation induced by HLA Class I. In a murine model where mice were transplanted with allogeneic hepatocytes, administration of mTOR inhibitors suppressed alloantibody production by alloprimed IgG1 B cells, an effect that was not observed after calcineurin inhibitor (CNI) administration .…”