Elevated Pretransplantation Soluble BAFF Is Associated With an Increased Risk of Acute Antibody-Mediated Rejection

Banham, Gemma D.; Prezzi, Davide; Harford, Sarah K.; Taylor, Craig; Hamer, Rizwan; Higgins, Rob; Bradley, J. Andrew; Clatworthy, Menna R.

doi:10.1097/tp.0b013e318298dd65

Cited by 67 publications

(50 citation statements)

References 30 publications

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“…Previous studies have demonstrated that an increased BAFF level directly correlates with the risk of alloantibody-mediated acute rejection in patients who received alemtuzumab induction and rapamycin monotherapy (50) as well as the patients who underwent antibody incompatible renal transplantation without depletional induction (51) . However, we demonstrate that an elevated BAFF level with a rapid repopulation of naïve but not memory B cells in the context of belatacept therapy supports this agent’s effectiveness in abrogating the production of donor specific antibodies.…”

Section: Discussionmentioning

confidence: 99%

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

Samy

Guasch

et al. 2016

American Journal of Transplantation

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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. 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

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Section: Discussionmentioning

confidence: 99%

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

Samy

Guasch

et al. 2016

American Journal of Transplantation

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“…Thus, BAFF may promote naïve and transitional B cell maturation, possibly explaining the increase in AMR . Simultaneously, a high BAFF or BAFFR level is associated with a higher risk of Ab production in stable patients, Ab‐mediated rejection, and graft dysfunction . In humans, BAFF blockade using belimumab, a human monoclonal Ab against BAFF, has been shown to be effective in the treatment of systemic lupus erythematosus .…”

Section: Regulatory Functions Of B Cells In Transplantationmentioning

confidence: 99%

Regulatory B cells and advances in transplantation

Luo

Wang

et al. 2018

Journal of Leukocyte Biology

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The effects of B cell subsets with regulatory activity on the immune response to an allograft have evoked increasing interest. Here, we summarize the function and signaling of regulatory B cells (Bregs) and their potential effects on transplantation. These cells are able to suppress the immune system directly via ligand–receptor interactions and indirectly by secretion of immunosuppressive cytokines, particularly IL‐10. In experimental animal models, the extensively studied IL‐10‐producing B cells have shown unique therapeutic advantages in the transplant field. In addition, adoptive transfer of B cell subsets with regulatory activity may reveal a new approach to prolonging allograft survival. Recent clinical observations on currently available therapies targeting B cells have revealed that Bregs play an important role in immune tolerance and that these cells are expected to become a new target of immunotherapy for transplant‐related diseases.

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“…Disappointing results from clinical trials suggest that, on its own, BAFF antagonism is ineffective to durably reduce HLA antibody levels (82). However, given that higher BAFF levels are associated with greater sensitization to HLA (83,84) and AMR (85), it remains an intriguing therapeutic target in the quest for suppressors of HLA antibody production. Another BAFF antagonist, atacicept, reduced dnDSA production in a nonhuman primate model of renal transplantation (86), and belimumab, which showed efficacy in systemic lupus erythematosus (87), is being investigated to reduce pretransplant HLA allosensitization (NCT02500251, ClinicalTrials.gov).…”

Section: Complement Depositionmentioning

confidence: 99%

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

Valenzuela¹,

Reed²

2017

Journal of Clinical Investigation

172

147

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Elevated Pretransplantation Soluble BAFF Is Associated With an Increased Risk of Acute Antibody-Mediated Rejection

Cited by 67 publications

References 30 publications

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

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

Regulatory B cells and advances in transplantation

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

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