FasL-Presenting PEG Microgels Supports Sustained Graft Survival in Nonhuman Primates in the Absence of Continuous Immunosuppression
1University of Missouri at Columbia, Columbia, MO, 2Surgery, Mass General, Boston, MA, 3Georgia Institute of Technology, Atlanta, GA, 4Massachusetts General Hospital, Boston, MA, 5Xiamen University Medical School, Xiamen, China
Meeting: 2022 American Transplant Congress
Abstract number: 174
Keywords: Apoptosis, Fas ligand, Islets, Tolerance
Topic: Basic Science » Basic Science » 12 - Immunosuppression & Tolerance: Preclinical & Translational Studies
Session Information
Session Name: Immunosuppression and Tolerance: Preclinical and Translational Studies
Session Type: Rapid Fire Oral Abstract
Date: Sunday, June 5, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 6:40pm-6:50pm
Location: Hynes Ballroom A
*Purpose: Broad application of allogeneic islets for T1D treatment is curtailed by the use of chronic immunosuppression to control rejection. Teff cells are the major culprit of rejection and become sensitive to Fas-mediated apoptosis upon repeated engagement with alloantigens. We have previously reported the efficacy of PEG microgels presenting a novel form of FasL (SA-FasL) in inducing localized tolerance in allogeneic rodents. We herein demonstrate the efficacy of this approach in achieving sustained survival in an allogeneic NHP model.
*Methods: PEG microgels fabricated to display biotin on their surface were engineered for positional display of SA-FasL protein on the surface. SA-FasL presenting microgels were co-transplanted at 2:1 PEG:islet ratio into the omentum of STZ-diabetic allogeneic cynomolgus monkeys. PEG without SA-FasL co-transplanted with islets served as controls. Recipients were kept on a 3-month rapamycin regimen as the only maintenance therapy. Animals were monitored for graft survival for 6 months and subjected to IVGTT and surgical removal of the graft to assess function.
*Results: PEG-SA-FasL supported sustained graft survival in all 4 animals for a ~180-day observation period. In marked contrast, acute rejection was observed in 3 controls with PEG microgels without SA-FasL under the same rapamycin regimen. Graft recipients promptly achieved excellent glycemic control with normal fasting BGs. IVGTTs performed at 3- and 6-month post-transplantation revealed excellent islet function comparable to naive animals. Surgical removal of the transplant resulted in prompt hyperglycemia, demonstrating graft function, which was further confirmed by fasting and stimulated insulin and c-peptide levels. Graft survival was associated with increased number of T regulatory cells in the graft site.
*Conclusions: Immunomodulation with PEG-SA-FasL results in sustained allogeneic islet graft survival in a NHP model in the absence of chronic immunosuppression. PEG-SA-FasL as an off-the-shelf product presents a novel approach with considerable translational potential for the treatment of type 1 diabetes. Funded by JDRF (2-SRA-2016-271-S-B) and NIH (U01 AI132817).
To cite this abstract in AMA style:
Yolcu ES, Lei J, Coronel MM, Deng H, Yang Z, Zhang A, Chen T, Lee K, Peters C, Rosales I, Wang Z, Markmann J, Garcia A, Shirwan H. FasL-Presenting PEG Microgels Supports Sustained Graft Survival in Nonhuman Primates in the Absence of Continuous Immunosuppression [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/fasl-presenting-peg-microgels-supports-sustained-graft-survival-in-nonhuman-primates-in-the-absence-of-continuous-immunosuppression/. Accessed March 26, 2023.« Back to 2022 American Transplant Congress