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.

Transplantation of donor-derived islets into the liver is a successful cellular replacement therapy for individuals with diabetes. However, the hepatic vasculature is not an optimal transplant site for several reasons, including graft attrition and the inability to retrieve or image the islets. Here we describe islet transplantation into a prevascularized, subcutaneous site created by temporary placement of a medically approved vascular access catheter. In mice with streptozotocin (STZ)-induced diabetes, transplantation of ∼500 syngeneic islets into the resulting 'device-less' space reversed diabetes in 91% of mice and maintained normoglycemia for >100 days. The approach was also effective in mice with pre-existing diabetes, in another mouse strain that mounts a more vigorous inflammatory response, and across an allogeneic barrier. These results demonstrate that transient priming of a subcutaneous site supports diabetes-reversing islet transplantation in mouse models without the need for a permanent cell-encapsulation device.

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.

IMPORTANCE Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.OBJECTIVE To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). DESIGN, SETTING, AND PARTICIPANTSThis multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. INTERVENTIONS Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. MAIN OUTCOMES AND MEASURESThe primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant. RESULTSOf 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.CONCLUSIONS AND RELEVANCE This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.

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.