Inhibition of TLR4 minimizes islet damage due to sterile inflammation and improves islet transplant outcomes.
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Chang, Charles A., 1991-
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Islet transplantation has emerged as an important treatment option for brittle type 1 diabetes and as an adjunct procedure after total pancreatectomy to prevent brittle diabetes. The efficacy and long-term function of islet transplantation have significantly improved over the last two decades. However, transplant outcomes are still largely compromised due to inflammation mediated prior to and after transplantation which results in the loss of as much as 50% of the islet graft. Toll-like receptor 4 (TLR4) has been identified as a major pro-inflammatory mediator of sterile inflammation by sensing damage-associated molecular patterns (DAMPs) and compromising graft function, making it a putative therapeutic target. Here, we study the effects of TLR4 blockade during the peri-transplant period on islet transplant outcomes using TAK-242, a small molecule inhibitor of TLR4, and a combination of basic biological assays as well as in vivo transplant models in mice. The results of early TLR4 blockade during islet isolation demonstrate a markedly reduced inflammatory profile in islets post-isolation which translated to reduced islet damage post-transplant and overall improved transplant outcomes with a cure rate of 75% for treated islets and 29% for untreated islets. Next, we developed a TLR4-antagonist prodrug and a chemical conjugation method to link the prodrug to the surface of islets which is slowly released, creating drug-eluting islets. Transplantation of a marginal dose of 100 modified islets into the kidney subcapsular space resulted in a cure rate of 100% compared to 0% for unmodified islets. In conclusion, we demonstrate that TLR4 is a major mediator of islet graft loss during the peri-transplant period. Therapies directed to inhibit this receptor, before and after transplant, are a promising avenue for improving islet transplant outcomes. The addition of TAK-242 to media during the isolation process is a rapidly translatable approach to clinical use, while the surface modification technique opens a broad range of possible transplant applications.