Therapeutic principles established in non-human transplant models have value for clinical application despite cost related limitations on sample size. We have tested new therapies in marginal sized (3,000-5,000IEQ/kg) allogeneic islet transplants in NHPs. We transplanted allogeneic islets, into recipients treated with anti-CD40mAb (2C10R4) D-0,14,28,60,90,120, RPM D-0-120) +/- alpha 1-antitrypsin (AAT) D-1,3,7,10). In the second set of experiments we cultured islets in AAT overnight and transplanted marginally sized islets (2,000-5,000IEQ/kg) into MHC mismatched recipients treated with anti-CD40mAb+RPM+IL-2 (at day 160 post-Tx). Using state-of-the-art techniques for CyTOF and SOMAscan we are now able to individualize treatment for each animal. Results: AAT given as an adjunct to anti-CD40mAb+RPM is effective and safe in NHP recipients of islet transplants. Results in terms of transplant function are far superior to that obtained anti-CD40mAb+RPM alone. In 5 NHPs transplanted without AAT, graft survival was 169-217 days despite cessation of treatment at day 120 post-transplant. In 5 NHP recipients of marginally sized islet transplants receiving AAT as an adjunct, the graft functioned without need for insulin treatment 193-310 days post-transplant. In the second set of experiments, 3 NHPs were transplanted with exceptionally small islet allografts. The islets cultured with AAT and transplanted into recipients treated with anti-CD40mAb+RPM+ IL-2. In the absence of insulin treatment, the recipients quickly became and remained normoglycemic for 200-360 days post-transplant. Using CytOF we were able to individualize the IL-2 doses needed for Treg expansion without expending other immune cells like Teff and NK. Conclusions: These results demonstrate that adjunctive AAT given with an anti-CD40mAb based regimen is efficacious in the NHP islet allograft model: (1) by blocking inflammation with a brief dose of AAT marginally sized islets functioned well for almost a year without the need of insulin despite cessation of treatment at day 120 (2) substitution of in vivo AAT treated islets promoted immediate and long-term function of tiny islet allografts. Transplantation of only 2,000 IEQ/kg can be used to achieve immunosuppressive drug-free insulin independence in NHPs for prolonged period (3) the use of ultra low dose of IL-2 at day 160 showed a beneficial effect in prolonging graft survival for greater then 360 days.

CITATION INFORMATION: Koulmanda M., Chipashivili V., Li L., Duggan M., Strom T. Ultra Low Dose of IL-2 Produces Long-Term Drug-Free Survival of Cynomolgus Islets Allografts Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress