Nanotechnology Targeting Novel CD154:CD11b Interactions for Transplant Tolerance

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Abstract/ Summary Blockade of CD40-CD154 interactions is known to be a highly effective means of inhibiting alloreactive T cell responses and under some conditions inducing transplantation tolerance in both murine and non-human primate models. However, the potential of this therapeutic strategy to have a transformative impact on transplantation outcomes has yet to be realized. CD154 blockers were associated with adverse hypercoagulability in early clinical trials, instigating the therapeutic targeting of CD40 as an alternative therapy. However, CD40 blockers have failed in recent clinical trials due to insufficient efficacy. We therefore sought to determine if there is a biological explanation underlying the observed inferiority of blocking CD40 as compared to blocking CD154, in order to then devise ways to overcome it. In a 2020 study, we reported that CD11b is a second receptor for CD154 during alloimmunity, signaling through which is blocked by anti-CD154 reagents but not anti-CD40 reagents. We showed that CD154:CD11b interactions function locally within the allograft to enhance donor-reactive CD8+ T cell infiltration and accelerate allograft rejection. In addition, new preliminary data show that CD154 but not CD40 blockade results in the generation of graft-specific Foxp3+ iTreg, suggesting that the addition of CD154:CD11b blockade may boost iTreg generation in the context of anti-CD40. In this proposal, we will translate these findings into an NHP allogeneic renal transplant model to elucidate the role of CD154:CD11b blockade in transplantation tolerance, and to test a novel nanotherapeutic strategy to better target CD154:CD11b interactions and synergize with anti-CD40 in promoting transplantation tolerance in vivo. In the first Aim, we will elucidate the mechanisms by which CD154:CD11b blockade contributes to the inhibition of alloimmunity and the induction of Foxp3+ Treg, using novel techniques to identify and track alloreactive effector and regulatory T cells in NHP, and will use MIBI-TOF and transcriptomic approaches to interrogate the effects of blocking CD154:CD11b interactions on the immune architecture and transcriptomic profile of T cells, DC, and macrophage/monocytes within allografts. In the second Aim, we have developed a novel nanoparticle that is coated with a specific peptide inhibitor that prevents CD154:CD11b binding. Utilizing cutting edge nanotechnology to block this interaction, instead of a monoclonal antibody, offers the distinct advantage of the ability to bioengineer the nanoparticle with a separate immunomodulatory “payload” to further promote tolerance. Given the demonstrated ability of CD154 blockade to induce long-term, durable tolerance in NHP, our overall hypothesis is that combining the novel CD154:CD11b blocking nanoparticle with anti-CD40 will result in the establishment of transplantation tolerance.