2423-P: Staphylococcus aureus Skin Infection Erodes Islet Allograft Acceptance Induced by Subcutaneous Nanotherapy

Introduction and Objective: Islet transplantation (TX) is a promising alternative to insulin therapy for patients with insulin-dependent diabetes, but remains burdened by lifelong immunosuppression and associated infection risk.The threat posed by infections to long-term allograft survival has been clinically obscured due to steroids which blunt inflammatory cytokines that destabilize immune tolerance. As clinical protocols shift away from steroids and towards targeted immunotherapies, the link between infection and tolerance erosion endangers long-term islet graft survival. Methicillin-resistant Staphylococcus aureus (MRSA) is a common infection among TX recipients. We previously demonstrated that rapamycin-loaded polymersome nanoparticles (rPS) can achieve normoglycemia in 83% of diabetic mice in an allogeneic islet transplantation model, prompting us to investigate whether rPS can preserve superior allograft acceptance among MRSA infected TX recipients. Methods: Streptozotocin-induced diabetic C57BL/6 recipients received rapamycin or rPS (SC, 6 doses, 1 mg/kg/dose, q3d) starting on POD -1. Recipients were transplanted with islets from 2 Balb/C donors. Recipients were infected with MRSA (SC, 5x108 CFUs) on POD 1. Results: All untreated mice rejected all grafts by POD 21 regardless of infection status, whereas infected rapamycin-treated mice showed no graft survival beyond POD 30. In contrast, infected rPS-treated mice maintained 43% graft survival through POD 60 (p=0.001). This decline in graft survival following rPS treatment is likely driven by a marked surge in IL-6 production 16h post-infection (p<0.0001), an increase in TNF levels for rPS-treated mice along with pronounced neutrophilia at 13 days post-infection. Conclusion: We demonstrate that MRSA can erode islet allograft acceptance induced by rPS. Future work will explore combination therapies between rPS and anti-inflammatory agents capable of reducing infection risk for TX recipients and making islet TX a more viable option for insulin dependent patients. Disclosure E. Mbaye: None. S. Wang: None. N. Klug: None. D. Botura Scariot: None. E. Scott: Other - Founder, CEO & Board Member; Current; SNC Therapeutics, Inc. J. Burke: Consultant; Current; SNC Therapeutics, Inc. Stock/Shareholder; Current; SNC Therapeutics, Inc.