These findings demonstrate that anti-IL-6R antibody prevented the early loss of intrahepatic islet grafts with inhibiting HMGB1-induced immune activation after islet transplantation.

Adenosine suppresses the NKT cell-mediated IFN-gamma production of neutrophils in the liver of mice receiving islets, thus leading to prevention of early loss of transplanted syngenic and allogenic islets. The findings indicate that adenosine may improve efficiency of clinical islet transplantation.

These findings clearly demonstrate that successful islet transplantation from one donor to two recipients is feasible by targeting pro-inflammatory cytokines in mice, thus suggesting a potential application in clinical islet transplantation if similar mechanisms of islet graft loss could be mediated in humans.

Islets from the same donor were transplanted to each pair and for each pair, one rat was treated with C5a inhibitory peptide (bolus: 4 mg/kg, continuous infusion: 0.42 mg/kg/hr for 3 days) in addition to a continuous intravenous infusion of gabexate mesilate (2 mg/kg/hr) 30 minutes prior to islet infusion and up to 1 hour after the infusion. The other recipient was injected with equivalent amount of saline and served as a control. Two rats were treated with the same dose of gabexate mesilate. The curative rate, the duration to normoglycemia, insulin amount in the liver of the recipients, and in vivo glucose tolerance tests were evaluated. Results: The curative rate was remarkably improved (100% vs. 33.3%, p=0.005) and the duration to normoglycemia in cured animals was signifi cantly shortened in treated group (12.2 }1.4 vs. 25.0 }0.0, p=0.039). Two rats only received the gabexate mesilate did not restore normoglycemia during the whole study period. No difference was observed between the groups in terms of glucose tolerance (AUC:p=0.85, Kg:p=0.35). However, insulin amount in the liver was considerably higher in treated group than that in control group (18.0 }3.2 vs. 12.0 }1.0 ng/IEQs p=0.14). Notably, the increase of body weight in the recipients was not affected by treatment (the increase rate of body weight: 128.6 }1.2% vs. 127.7 }3.3%, p=0.80), suggesting that C5a inhibitory peptide combined with the gabexate mesilate is considered to be free from the side effect. Conclusions: These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate, without side effects, to control the detrimental innate immune responses induced in clinical islet transplantation.

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