Abstract
Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3+ iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4+ Foxp3+ iTreg following transplantation, treatment with anti-CD40 or Cd40 deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3+ iTreg and found that blockade of CD11b in Cd40−/− recipients resulted in increased donor-reactive Foxp3+ iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1β from CD11b+ and CD11c+ dendritic cells, and blockade of IL-1β synergized with CD40 deficiency to promote Foxp3+ iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1β-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3+ iTreg during transplantation.
Keywords
Abbreviations:
APC (antigen-presenting cell), cM7 (C-EQLKKSKTL-C), DC (dendritic cell), dLN (draining lymph node), DST (donor-specific transfusion), Foxp3+ (forkhead box P3+), IL (interleukin), iTreg (induced regulatory T cell), LN (lymph node), M7 (EQLKKSKTL), mAb (monoclonal antibody), MACS (macrophages), MFI (median fluorescence intensity), MHC (major histocompatibility complex), MLR (mixed lymphocyte reaction assay), NHP (non-human primate), No Rx (no treatment), PBS (phosphate-buffered saline), RANTES (regulated upon activation, normal T cell-expressed and secreted protein), sc (scrambled control), sCD154 (soluble CD154), WT (wild-type)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: March 27, 2024
Accepted: March 22, 2024
Received in revised form: March 21, 2024
Received: July 14, 2023
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2024 Published by Elsevier Inc. on behalf of American Society of Transplantation & American Society of Transplant Surgeons.
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