D299 - Resatorvid, a Small Molecule Inhibitor of Toll-Like Receptor 4 Prolongs the Survival and Function of Allogeneic Islet Transplants in a Mouse Transplant Model

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Author Block: J. Kuncha¹, C. Darden², J. Kirkland², R. R. Kane³, J. S. Danobeitia⁴, M. Lawrence⁵, B. Naziruddin², ¹Islet Cell Transplantation and Immunology Research, Baylor Scott and White Research Institute, Dallas, TX, ²Baylor University Medical Center, Dallas, TX, ³Baylor University, Waco, TX, ⁴Baylor University Medical Center at Dallas, Dallas, TX, ⁵Baylor Scott and White Research Institute, Dallas, TX
*Purpose: Transplantation of allogenic pancreatic or stem cell-derived islets has been shown to be effective in restoration of normoglycemia in type 1 diabetics. Development of innate and adaptive immune responses against the islet graft present significant challenge to improve the efficacy of this treatment. Our previous reports have shown that resatorvid (TAK-242), a small molecule inhibitor of toll-like receptor 4, is effective in controlling inflammatory and CD8-positive T cell responses. We now tested TAK-242 in prolonging the allogenic islet allograft survival using a mouse model.
*Methods: Islets (n=300) from BALB/c mice were transplanted into the kidney capsule of STZ-induced diabetic C57BL/6 mice. Groups of recipient mice were treated with TAK-242 or MAP84 a structural analog of TAK-242, FK506 or a combination of TAK-242 plus FK506. Graft function was monitored based on reversal of diabetes (<250 mg/dL) of blood glucose. Post-transplant levels of inflammatory cytokines in blood of the recipients were measured using BD cytometric bead assay. Statistical analysis of graft survival was performed using the log-rank test and one-way ANOVA followed by Tukey’s multiple comparisons test.
*Results: Analysis of graft survival demonstrated that diabetic mice treated daily with 5 mg/kg TAK-242 maintained normoglycemia for an average of 14 days when compared to 9 days by islets only (Fig. A). The combination of TAK-242 and 1 mg/kg FK506 daily treatment exhibited the longest survival with an average of 22 days (p<0.06) reaching close to statistical significance. Post-transplant levels of proinflammatory cytokines (IL-6, IL-4, IFN-g, IL-2, IL-17A) in serum were significantly decreased (p=0.0001) in TAK-242, FK506 and TAK-242+FK506 group (Fig. B) while no difference was observed IL-10 and MCP-1.
*Conclusions: Results from this in vivo analysis clearly indicate that blocking of TLR-4 controls the development of proinflammatory and T cell response which prolongs the survival of allogenic islets in diabetic mice. Adjunct administration of resatorvid along with reduced dose of FK506 will lessen the beta cell toxicity and prolong graft function.