Inhibition of CD154:CD11b interactions using a novel nanotherapeutic improves allograft survival

It is now appreciated that CD154 and CD40 may be differentially effective as therapeutic targets in transplantation owing to the ability of CD154 to bind to a second receptor, CD11b. We previously reported that the combination of anti-CD40 and a specific CD154:CD11b blocker enhanced allograft survival compared to anti-CD40 alone. In the current study, we have utilized a novel nanoparticle-based approach to more effectively deliver CD154:CD11b blockade during transplantation. Recipients of allogeneic skin grafts were treated with either CTLA-4Ig (CD80/ CD86 blocker) or the combination of CTLA-4Ig plus a hyaluronic acid nanoparticle-conjugated CD154:CD11b peptide inhibitor (iPepHANP). Results indicated that iPepHANP synergized with CTLA-4Ig in prolonging allograft survival and inhibiting donor-reactive CD4⁺ and CD8⁺ T cell responses. Specifically, frequencies of donor-reactive CD4⁺ and CD8⁺ T cells in the spleen were significantly reduced in iPepHANP + CTLA-4Ig-treated animals as compared to CTLA-4Ig alone. Moreover, iPepHANP + CTLA-4Ig administration significantly reduced donor-reactive CD4⁺ T cell and activated CD8⁺ T cell infiltration into skin allografts compared to CTLA-4Ig alone. Notably, mice treated for 100 days with the CD154:CD11b-blocking nanoparticle demonstrated sustained transplantation tolerance following secondary graft rechallenge in the absence of any further immunosuppression. Taken together, these data highlight the potential of CD154:CD11b-blocking nanoparticles as a therapeutic strategy in transplantation.