In Kidney Transplant Patients, Alemtuzumab but Not Basiliximab/Low-Dose Rabbit Anti-Thymocyte Globulin Induces B Cell Depletion and Regeneration, Which Associates with a High Incidence of De Novo Donor-Specific Anti-HLA Antibody Development

Abstract

In this single-center matched-cohort study, we evaluated the phenotype of repopulating B cells and its correlation with donor-specific anti-HLA Ab development and long-term graft function in 16 renal transplant recipients and 32 age- and gender-matched controls induced with alemtuzumab or basiliximab (Bas)/low-dose rabbit anti-thymocyte globulin (rATG), respectively. Alemtuzumab, but not Bas/rATG, profoundly depleted peripheral B cells in the first 2 mo posttransplantation. Early posttransplant, naive B cells were significantly depleted, whereas Ag-experienced and memory B cells were partially spared. Transitional B cells transiently increased 2 mo posttransplant. At month 6 posttransplant, pregerminal center B cells emerged, a process promoted by increased BAFF serum levels. Thereafter, B cell counts increased progressively, mainly due to expansion of naive B cells. Conversely, Bas/rATG did not modify the B cell phenotype throughout the follow-up period. Alemtuzumab was associated with a higher incidence of de novo DSA compared with Bas/rATG. DSA development was predicted by changes in the B cell compartment and correlated with worse long-term graft function. Thus, alemtuzumab-induced B cell depletion/reconstitution may promote chronic humoral responses against the graft.

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…45 However, although this hypothesis is interesting, it has been challenged by recent conflicting reports from two independent groups showing that alemtuzumab-induced B cell depletion/reconstitution is associated with a higher incidence of AMR compared with induction with ATG. 46,47 Basiliximab is a chimeric mousehuman nondepleting mAb targeting the a-chain (CD25) of the IL-2 receptor (Figure 1). Basiliximab was developed for induction therapy on the basis of the concept that it would block IL-2 binding, thereby inhibiting T cell proliferation.…”

“…Their mechanism of action is diverse and includes interference with intracellular transcription factors and signaling pathways of several surface receptors, including the T cell antigen receptor 52 and downstream kinases. 53 High doses of corticosteroids (.1 mg/kg), used for induction therapy in transplantation, also induce lymphocyte apoptosis (including B cells) 46,54 and can prevent in vitro differentiation of B cells into plasma cells. 55 High concentrations of corticosteroids are also likely to interfere with Fc g-receptor signaling, including the inhibitory Fc g-RIIb, which acts as a key negative modulator of B cell function and controls bone marrow plasma cell apoptosis.…”

Antithymocyte Globulin is Associated With a Lower Incidence of De Novo Donor-Specific Antibodies in Moderately Sensitized Renal Transplant Recipients

“…A recent study by Ayasoufi noted that administration of ATG a week prior to transplant was substantially superior in inhibiting anti-donor T cell responses than at the time of transplant, suggesting that ATG has the ability to target preexisting donor-reactive memory T cells (14). Importantly, ATG induces Tregs following immune reconstitution, indicating that rATG therapy may also suppress B cells and DSA generation via activation of Tregs (16)(17)(18). Further in vitro and clinical studies are needed to investigate these specific mechanisms.…”

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“…Recently, different investigators reported efficacy of alemtuzumab treatment in expansion of transitional B cells and regulatory B cells during kidney transplants. 35,36 The proper mechanism of such repopulation of Breg and Treg cells after depletion of alloreactive cells is not clear and subject to in- Single-center retrospective study involving Higher incidence of antibody-mediated rejection (AMR), and kidney transplant patients between similar incidence of acute cellular rejection, 1-year graft survival, Transplant Proc. Table 2.…”