The Emerging Era of Organ Transplantation and Anti-CD154mAb

In 1999, Kirk et al. published a manuscript demonstrating the surprising efficacy of anti-CD154mAb monotherapy in preventing renal allograft rejection in nonhuman primate (NHP) model ( 1 Kirk A.D. Burkly L.C. Batty D.S. Baumgartner R.E. Berning J.D. Buchanan K. et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med. 1999; 5: 686-693 Crossref PubMed Scopus (760) Google Scholar ). During the 1990s, two costimulation blockers, CTLA4-Ig and anti-CD154mAb, were heavily investigated in the setting of organ transplantation, typically in combination ( 2 Larsen C.P. Elwood E.T. Alexander D.Z. Ritchie S.C. Hendrix R. Tucker-Burden C. et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature. 1996; 381: 434-438 Crossref PubMed Scopus (1292) Google Scholar , 3 Kirk A.D. Harlan D.M. Armstrong N.N. Davis T.A. Dong Y. Gray G.S. et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A. 1997; 94: 8789-8794 Crossref PubMed Scopus (849) Google Scholar ). While the combination demonstrated promising efficacy in both murine and large animal models, targeting the CD40-CD40L signaling pathway yielded better outcomes than targeting the CD28-CD80/86 signaling pathway. The mechanisms underlying CD154mAb's superiority are still being exposed. Unfortunately, the clinical development of anti-CD154mAb was halted due to concern for thromboembolic complications in early clinical trials, which had not been prospectively revealed in murine models and minimally in NHP models. In the meantime, a modified version of CTLA4-Ig (belatacept, Bristol Myers Squibb) was approved for the prophylaxis of kidney transplant rejection in 2011. Differential induction of donor-reactive forkhead box P3+ regulatory T cell via blockade of CD154 vs CD40American Journal of TransplantationPreviewRecently 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. Full-Text PDF