Following upon highly beneficial effects observed with short-term alpha 1-antitrypsin (AAT) treatment in the marginally sized autologous cynomolgus islet transplant model, we are testing the hypothesis that short-term peri-transplant treatment with AAT, an acute phase protein with cytoprotective, anti-inflammatory and anti-thrombotic effects, will synergize with regimens that exert potentially tolerizing effects upon T-cells. We transplanted marginally sized (4,500 -7,700IEQ/kg) allogeneic islets, into recipients treated with a co-stimulation blockade-based protocol (anti-CD40mAb (2C10R4) 50mg/kg i.v D-0,14,28,60,90,120 +RPM 0.5mg/kg-0.1mg/kg i.m D-0-120) +/- AAT (60mg/kg i.v. D-1, 3, 7, 10). In the second set of experiments we cultured islets in AAT overnight and transplanted very marginally sized (3,000-4,000IEQ/kg) islets into MHC mismatched recipients treated with anti-CD40mAb+ RPM. 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 (3,000-4,000IEQ/kg). The islets were cultured with AAT and transplanted into recipients treated with anti-CD40mAb+RPM. In the absence of insulin treatment, the recipients quickly became and remain normoglycemic for over 200 days post-transplant. These results are without precedent. 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 and treating recipients with a brief dose of AAT marginally sized islets functioned well for almost a year without the need of insulin injections despite cessation of treatment at day 120. (2) substitution of in vivo AAT treatment with culture of islets for 18hrs with AAT promoted immediate and long-term function of tiny islet allografts. Transplantation of only 3,000 IEQ/kg can be used to achieve immunosuppressive drug-free insulin independence in NHPs for prolonged period.

CITATION INFORMATION: Koulmanda M, Chipashivili V, Duggan M, Strom T. Long-Term Drug-Free Survival of Tiny Cynomolgus Islet Allografts. Am J Transplant. 2017;17 (suppl 3).

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