Immunomodulation with FasL Presenting Biomaterials Achieves Long-Term Survival of Allogeneic Islets in the Absence of Chronic Immunosuppression in a Non-Human Primate Model
1Surgery, Mass General, Boston, MA, 2School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 3School of Mechanical Engineering, University of Louisville School of Medicine, Louisville, KY
Meeting: 2020 American Transplant Congress
Abstract number: 318
Keywords: Apoptosis, Fas ligand, Graft acceptance, Islets
Session Information
Session Name: Immunosuppression Preclinical Studies
Session Type: Oral Abstract Session
Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:45pm
Presentation Time: 4:15pm-4:27pm
Location: Virtual
*Purpose: The full potential of islet transplantation will only be realized by the development of tolerogenic strategies that obviate the need for maintenance immunosuppressants. We report a clinically relevant strategy in which co-transplantation of islets and chimeric streptavidin-FasL(SA-FasL)-presenting biomaterials achieved long term islets acceptance and glycemic control in an allogeneic diabetic NHP model.
*Methods: Poly (ethylene glycol) [PEG]based microgels were engineered for controlled densities and presentation of an apoptotic SA-FasL. For the experimental group, allogeneic islets from single donor were co-transplanted with SA-FasL-presenting PEGs to the omentum of STZ-induced diabetic NHPs with Rapamycin for the first 3 months post-transplant as the only maintenance therapy. No IS therapy was administered after 3-months. Animals were followed for 6 months to demonstrate the reproducible long-term grafts survival and tolerance.
*Results: 4 experimental diabetic NHPs were co-transplanted with average 17K IEQ/kg and SA-FasL-presenting PEGs. Post-tx, each recipient promptly achieved excellent glycemic control with normal fasting BGs during the 180-day study endpoint. IVGTTs performed at 3 and 6-month post-tx revealed excellent islet function with BG disposal as robust as healthy animals. Insulin and C-peptide were greater than 1.5 mU/L and 50 pmol/L respectively for all animals. After removal of the islets-containing omentum, all animals returned to a hyperglycemic state immediately. Recipients demonstrated Treg expansion and reduction of effector memory T cells by flow and donor hypo-responsiveness by ELISPOT and MLR. In control group, 3 diabetic NHPs are to be co-transplanted with islets and non-FasL presenting PEGs to the omentum and Rapamycin as the only maintenance therapy (one completed). The completed control NPH achieved glycemic control post-tx but it was sustained for just 9 days, which is consistent with similar IS regimen in the literature. The control recipient demonstrated no evidence of Treg expansion and donor hypo-responsiveness.
*Conclusions: Co-transplantation of allogeneic islets with an off-the shelf immunomodulatory agent, SA-FasL presenting microgels resulted in long-term islet acceptance and glycemic control in a diabetic NHP model. Importantly, this strategy does not require long-term continuation of systemic immunosuppression. These are critical considerations in the clinical translation of this novel strategy for broad application of islet transplantation for the treatment of type 1 diabetes.
To cite this abstract in AMA style:
Lei J, Deng H, Chen T, Lee K, Peters C, Yang Z, Deng K, Rickert G, Rosales I, Serifis N, Coronel M, Hunckler M, Yolcu E, Shirwan H, García A, Markmann J. Immunomodulation with FasL Presenting Biomaterials Achieves Long-Term Survival of Allogeneic Islets in the Absence of Chronic Immunosuppression in a Non-Human Primate Model [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/immunomodulation-with-fasl-presenting-biomaterials-achieves-long-term-survival-of-allogeneic-islets-in-the-absence-of-chronic-immunosuppression-in-a-non-human-primate-model/. Accessed May 31, 2025.« Back to 2020 American Transplant Congress