Goal: Interleukin-13 (IL-13) is a multifunctional cytokine known to exert anti-inflammatory effects in type 1 diabetes (T1D). However, its therapeutic role in islet transplantation has not been explored. Our goal was to determine if IL-13 could improve the efficacy of minimal-dose islet transplantation across murine syngeneic, allogeneic, and xenogeneic transplantation models.

Methods: 8-10 weeks old female C57BL/6 mice were rendered diabetic by a single injection of Streptozotocin (200mg/kg body weight) and used as transplant recipients. Mice were divided into three groups: a test group that received islets accompanied by IL-13 treatment, a control group that received islets with saline, and a third control group that received IL-13 alone with no islet transplant. 50 C57BL/6 islets, 400 BALB/c islets, or 3000 human islet equivalents were transplanted under the kidney capsule of diabetic mice for minimal dose syngeneic (n=10/grp), allogeneic (n=12/grp), and xenogeneic (n=5/grp) transplantation, respectively. For the syngeneic test group, islets were preincubated with 10ng IL-13/ml media for 3 hrs before transplantation. For the allogeneic test group, 30ng IL-13/100ul saline was administered to islet recipients via IP injection five times every 48 hours post-transplant on Days 2, 4, 6, 8, and10, while for the xenogeneic test group, recipients received 50ng IL-13/100ul saline five times post-transplant on Days 4, 6, 8, 10 and 12. Tail vein blood glucose was measured daily, and diabetes defined as blood glucose (BG) >300 mg/dl on 2 consecutive days.

Results: 80% of diabetic recipient mice receiving syngeneic islets pretreated with IL-13 returned to normoglycemia within 16 days, and by day 20, 100% were rescued. On Day 33, the last day of the observation period, the BG for IL-13 treated mice was 148.4±27.3 mg/dL, while in contrast, BG was361±70.9 mg/dL for 55% of saline-treated control mice that remained diabetic. Following minimal dose islet allotransplantation, all control group mice became diabetic on Day 12±8 post-transplantation whereas all mice receiving islets with IL-13 remained non-diabetic post-transplantation until Day 90, the period of observation. Diabetic recipients receiving xenogeneic islets with IL-13 regained permanent normoglycemia by Day 25±1 with BG 225.2±49.5 mg/dL and remained cured until Day 45, the period of observation, with BG 215.6±60.1mg/dL, whereas mice in the control group remained diabetic. Diabetic mice receiving IL-13 alone with no islet transplantation did not return to normoglycemia.

Conclusions: This groundbreaking study identifies IL-13 as an immunomodulatory agent that significantly enhances islet graft survival and function across transplantation models. By facilitating normoglycemia with reduced islet numbers and shorter recovery time, IL-13 holds transformative clinical potential for optimizing islet transplantation outcomes and addressing donor scarcity.