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Ultra Low Dose of IL-2 Produces Long-Term Drug-Free Survival of Cynomolgus Islets Allografts

M. Koulmanda,1 V. Chipashivili,1 L. Li,1 M. Duggan,2 T. Strom.1

1Medicine and Surgery, Beth Israel Deaconess Medical Center, Boston, MA
2Surgery, MGH, Boston, MA.

Meeting: 2018 American Transplant Congress

Abstract number: 14

Keywords: Inflammation, Islets, Primates, Tolerance

Session Information

Date: Sunday, June 3, 2018

Session Name: Concurrent Session: Islet Cell and Cell Transplantation

Session Time: 2:30pm-4:00pm

 Presentation Time: 2:54pm-3:06pm

Location: Room 2AB

Related Abstracts
  • Long-Term Drug-Free Survival of Tiny Cynomolgus Islet Allografts.
  • Long Term Survival of PEGylated Murine Allogenic Islets Using Short Course Immunomodulation

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).

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To cite this abstract in AMA style:

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 [abstract]. https://atcmeetingabstracts.com/abstract/ultra-low-dose-of-il-2-produces-long-term-drug-free-survival-of-cynomolgus-islets-allografts/. Accessed January 27, 2021.

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