CD3 antibody therapy, successfully used to treat patients with recent onset type 1 diabetes, can restore self-tolerance to autoantigens. We extented these tolerogenic properties to the field of transplantation by demonstrating that short-term, low-dose course with CD3-specific antibodies at the time of effector T cell priming to the alloantigens induced tolerance to fully mismatched allografts. CD3 antibodies primarily targeted antigen-activated T cells while sparing Tregs which can transfer donor-specific tolerance. Of potential clinical relevance, we recently found that humanized CD3 antibodies also promote permanent islet graft acceptance when applied in mice transgenic for the human CD3epsilon chain. The aim of the present study was to further elucidate the immune mechanisms driving CD3 antibody-mediated tolerance. C57Bl/6 mice, rendered diabetic after an injection with streptozotocin, were grafted with fully MHC-mismatched BALB/c pancreatic islets and treated with CD3-specific antibodies at day 7 after transplantation, which induced allograft tolerance. Although after treatment, the percentage of Foxp3+ Tregs increased in secondary lymphoid organs and in the graft itself, Foxp3+ Tregs were not mandatory for tolerance induction. Furthermore, de novo generation of Foxp3+ Tregs was not evidenced in our model. However, tolerance induction relied on in situ PD-1 and TGF-beta signaling in T cells. In the allograft but not in secondary lymphoid organs, CD3 antibody treatment induced strong expression of the inhibitory receptor PD-1, particularly on CD8+ T cells that also acquire the capacity to produce high amounts of TGF-beta as shown by single cell PCR. Blocking these signaling pathways by neutralizing antibodies abrogated tolerance induction. In conclusion, CD3 antibody therapy establishes an intragraft tolerogenic environment via signaling through the inhibitory PD-1 pathway and local production of TGF-beta by both CD4+ and CD8+ T cells.
To cite this abstract in AMA style:Baas M, Besançon A, Kuhn C, Mangez C, Valette F, Goncalves T, Chatenoud L, You S. CD3 Antibody-Induced Transplant Tolerance Relies on In Situ TGF-Beta and PD-1 Signaling in T Cells [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/cd3-antibody-induced-transplant-tolerance-relies-on-in-situ-tgf-beta-and-pd-1-signaling-in-t-cells/. Accessed August 15, 2020.
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