SA-FasL-engineered PEG microgels as a novel means of modulating immune response to allogeneic islet grafts

• DOI: 10.4049/jimmunol.200.supp.55.36
• Publication Date: 2023-01-01T11:26:55Z
• Authors: Haval Shirwan; Kyle B Woodward; Devon M Headen; Hong Zhao; Pradeep Shrestha; Min Tan; William S Bowen; María M Coronel; Michael D Hunckler; Jessica D Weaver; Esma S Yolcu; Andrés J García
• Keywords: Fas ligand; Immunosuppression

Abstract Allogenic islet transplantation is an effective therapy for type 1 diabetes in the clinic. Sustained graft survival requires chronic immunosuppression that has adverse effects. Islet rejection initiated and perpetuated by T effector cells (Teffs). Teffs upregulate Fas death receptor on their surface undergo apoptosis following engagement with FasL. Therefore, FasL potential as immunomodulator to establish immune tolerance grafts eliminate alloreactive Teffs. This study used PEG microgels engineered a novel form of FasL, SA-FasL, prevention allogeneic rejection. Poly(ethylene glycol) were produced biotin surface. Biotinylated SA-FasL (1 μg/103 microgels) taking advantage high affinity interaction between streptavidin (SA) domain molecule. SA-FasL-PEGs induced expressing A20 lymphoid vitro. Co-transplantation naïve islets led prolonged compared control group (islets + unmodified PEGs), 20% surviving 200-day observation period. A short (15 days) treatment low dose rapamycin further improved immunomodulatory efficacy SA-FasL-PEGs, > 90% CD4+CD25+FoxP3+ Tregs required survival, depletion this cell population day 50 post-transplantation resulted prompt These findings provide strong proof-of-efficacy feasibility use SA-FasL-engineered off-the-shelf product modulation responses significant therapeutic potential.