Aptamer-Engineered Human Islets to Prevent IBMIR in Islet Cell Transplantation

Introduction and Objective: The instant blood-mediated inflammatory reaction (IBMIR) significantly damages transplanted islets. Blocking pro-inflammatory mediators can improve engraftment post-transplantation. This study hypothesized that aptamers targeting key proteins could reduce IBMIR and enhance islet graft survival. The focus was on surface immobilization of three anti-inflammatory aptamers targeting interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and factor VIIa (FVIIa). Methods: Aptamer conjugation on human islets was demonstrated using Bissulfosuccinimidyl Suberate (BS3) without loss of function and viability. Each aptamer was tested in vitro against pro-inflammatory cytokines to evaluate their protective effects on islets. Gene expression of downstream pro-inflammatory proteins and apoptotic markers was analyzed using qPCR. The anti-coagulative property of FVIIa aptamers was also tested. In vivo studies involved transplanting human islets in nude mice intraportally to evaluate IBMIR activation. Results: Conjugation with IL-1β and TNFα aptamers was safe for cells at concentrations up to 100µM and showed excellent anti-inflammatory effects in vitro. Both IL-1βApt and TNFαApt reversed the upregulation of pro-inflammatory and apoptotic genes induced by IL-1β and TNFα in human islets, comparable to established antagonists. FVIIa aptamer significantly inhibited coagulation and the downstream coagulation process. Ongoing in vivo experiments involve evaluating IBMIR activation in transplanted human islets in nude mice. Conclusion: The tested anti-IBMIR aptamers have the potential to improve islet engraftment in clinical settings. This study identifies a new target for improving islet engraftment and sets the stage for further research on these aptamers in allogeneic settings, especially when combined with established immune-suppressive platforms. Disclosure: J. Kalivarathan: None. P. Saravanan: None. B.A. Fuglestad: None. A. Khan: None. M.A. Kanak: None. Funding: DOD (W81XWH-22-1-0102)