Introduction: An instant blood-mediated inflammatory response (IBMIR) causes acute loss of pancreatic islets. Interferon gamma-induced protein 10 (IP-10) is a key proinflammatory chemokine that may contribute to the impairment of islet graft function. However, the effect of blocking IP-10 on IBMIR remains unclear. In this study, we determined effects of neutralizing IP-10 mAb on cytokine production in islets in vitro and compared efficacy of islet pretreatment with IP-10 mAb vs systemic injection of IP-10 mAb in the improvement of islet graft function.

Methods: We used a syngeneic C57BL/6 mouse islet transplant model to examine effects of IP-10 mAb on islet inflammation in vivo. Isolated islets were incubated with IP-10 mAb then subsequently infused into the portal vein (local treatment group) or IP-10 mAb was intraperitoneally injected to mice (systemic treatment group). Non-fasting blood glucose levels, IPGTT, and cytokine plasma levels were measured. Macrophage infiltration was analyzed by immunofluorescent staining. In vitro inflammatory assays were used to determine effects of IP-10 on inflammatory cytokine production. Isolated islets and macrophages were incubated with IP-10 recombinant protein in the presence of blood to measure cytokine production by QPCR and Luminex multiplex protein assays.

Results: Neutralizing IP-10 mAb improved blood glucose profiles and reduced plasma cytokine protein levels compared to control mAb group. Local treatment of islets with IP-10 mAb showed increased efficacy over the systemic IP-10 mAb treatment group. IP-10 mAb treatment significantly reduced IL-6, KC, IP-10, and MCP-1 plasma levels in recipients and suppressed macrophage infiltration in islet grafts. IL-6, IL-1β, and IFN-γ was induced in macrophages exposed to IP-10 in a concentration-dependent manner. IP-10 promoted the effect of IBMIR on islets incubated with blood by increasing IL-6 secretion.

Conclusion: IP-10 induced macrophage infiltration and production of inflammatory chemokines and cytokines in islets. Treatment with IP-10 mAb blocked inflammatory components of IBMIR both in vitro and in vivo and improved glucose control in mouse islet recipients. Local treatment of islets with IP-10 mAb prior to infusion was most effective in suppressing early inflammatory loss of islet grafts.

CITATION INFORMATION: Yoshimatsu G, Chang C, Darden C, Saravanan P, Naziruddin B, Lawrence M. IP-10 Monoclonal Antibody Treatment Suppresses Inflammatory Components of IBMIR and Improves Pancreatic Islet Graft Function. Am J Transplant. 2017;17 (suppl 3).

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