Combined Therapy With Interleukin-4 and Interleukin-10 Inhibits Autoimmune Diabetes Recurrence in Syngeneic Islet-Transplanted Nonobese Diabetic Mice Analysis of Cytokine Mrna Expression in the Graft

Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice

“…Endogenous IL-10 inhibited spontaneous diabetes development in BDC2.5/NOD transgenic mice, whereas anti-IL-10 receptor treatment triggers disease onset (34). Elevated IL-10 levels have been correlated with islet graft survival in autoimmune diabetes models (18,19). On the basis of these results, IL-10 seems to represent an attractive candidate for immunotherapy to prevent autoimmune diabetes development and recurrence.…”

“…Systemic delivery of IL-10 thus far has consistently conferred protection to pancreatic islets as well as islet transplants (9,12,18), whereas local introduction of IL-10 into islets has seemed to be detrimental rather than helpful (13)(14)(15)(16). However, given the relatively short half-life of this cytokine, the extension of recombinant IL-10 treatment to clinical application is limited because of the need for repeated administration.…”

“…However, the success rate and long-term survival of islet grafts in human subjects has historically been very low (i.e., Ͻ8%) because of autoimmune/allogeneic immune rejection and cytotoxic effects of general immunosuppressants (17). Th1 cells have been shown to be correlated with the recurrence of diabetes after islet transplantation (18,19). Studies involving the syngeneic transplant of islet cells placed under the renal capsule of diabetic NOD mice have provided a suitable model for evaluating the therapeutic value of candidate agents for preventing autoimmune rejection of grafts.…”

Gene therapy in transplantation

“…IL-4 treatment of rats prolonged the survival of allogeneic neonatal hearts, 76 and similar prolongation of graft survival was seen in mice transplanted heterotopically with an allogeneic heart from a mouse transgenic for IL-4. 77 Combined treatment of IL-10 and IL-4 of non-obese diabetic (NOD) mice (a strain that develops autoimmune diabetes) prevents the recurrence of diabetes following syngeneic islet transplantation 78 whereas adenoviral gene transfer of IL-4 and IL-10 to NOD syngeneic islets fails to protect them from autoimmune destruction. 79 These results, obtained from experiments using cytokines with immunosuppressive characteristics, although promising, indicate that neither cytokine is able to prolong allogeneic organ survival as effectively or as long as treatments aimed at blockade of co-stimulation or adhesion.…”

IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice

“…In the inbred NOD mouse, a commonly used experimental model for IDDM, allogeneic transplanted pancreatic islets are reported to be rapidly destroyed by disease recurrence in contrast to allogeneic transplanted pituitary glands [2]. Several molecular/cellular mechanisms for this graft damage have been suggested, including involvement of the proinflammatory cytokines IL-1 and interferon-gamma (IFN-g) [4][5][6]. In the present study, the role of IL-1 in this process was investigated by using an IL-1 receptor antagonist (IL-1Ra) as a potential inhibitor of the diabetogenic process, after syngeneic pancreatic transplantation, in NOD mice.…”