OBJECTIVE: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti–IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS: Although treatment with either anti–IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti–IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti–IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti–IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell–mediated dominant protective effect against autoimmunity. CONCLUSIONS: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

Liver transplantation is an important treatment option for selected patients with nonresectable hepatocellular carcinoma (HCC). Several reports have suggested a lower risk of posttransplant tumor recurrence with the use of sirolimus and a higher one with calcineurin inhibitors, but the selection of an ideal immunosuppression protocol is still a matter of debate. The aim of this study was to define the immunosuppression associated with the best survival after liver transplantation for HCC. It was based on the Scientific Registry of Transplant Recipients and included 2,491 adult recipients of isolated liver transplantation for HCC and 12,167 for non-HCC diagnoses between March 2002 and March 2009. All patients remained on stable maintenance immunosuppression protocols for at least 6 months posttransplant. In a multivariate analysis, only anti-CD25 antibody induction and sirolimus-based maintenance therapy were associated with improved survivals after transplantation for HCC (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.45–0.9, P ≤ 0.01; HR 0.53, 95% CI: 0.31–0.92, P ≤ 0.05, respectively). The other studied drugs, including calcineurin inhibitors, did not demonstrate a significant impact. In an effort to understand whether the observed effects were due to a direct impact of the drug on tumor or more on liver transplant in general, we conducted a similar analysis on non-HCC patients. Although anti-CD25 induction was again associated with a trend toward improved survival, sirolimus showed a trend toward lower rates of survival in non-HCC recipients, confirming the specificity of its beneficial impact to cancer patients. Conclusion: According to these data, sirolimus-based immunosuppression has unique posttransplant effects on HCC patients that lead to improved survival. (HEPATOLOGY 2010.)

Background: Since the first report of successful pancreatic islet transplantation to reverse hyperglycaemia in diabetic rodents, there has been great interest in determining the optimal site for implantation. Although the portal vein remains the most frequently used site clinically, it is not ideal. About half of the islets introduced into the liver die during or shortly after transplantation. Although many patients achieve insulin independence after portal vein infusion of islets, in the long term most resume insulin injections. Methods: This review considers possible sites and techniques of islet transplantation in small and large animal models, and in humans. Metabolic, immunological and technical aspects are discussed. Results and conclusion: Many groups have sought an alternative site that might offer improved engraftment and long-term survival, together with reduced procedure-related complications. The spleen, pancreas, kidney capsule, peritoneum and omental pouch have been explored. The advantages and disadvantages of various sites are discussed in order to define the most suitable for clinical use and to direct future research.

DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343, 230–238] reported seven consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.