Local immunomodulatory strategies to enhance allogeneic pancreatic islet engraftment in a vascularized subcutaneous platform for the treatment of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease marked by pancreatic β-cell destruction, leading to lifelong dependence on exogenous insulin therapy. Pancreatic islet transplantation offers a functional cure, but clinical application is limited by poor graft engraftment, hypoxia-related cell loss, and dependence on chronic systemic immunosuppression. This thesis investigates local immunomodulation approaches to improve allogeneic islet engraftment in a vascularized subcutaneous platform, the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device. Specifically, it evaluates the immunomodulatory and proangiogenic roles of mesenchymal stem cells (MSCs) and the localized delivery of clinically relevant immunosuppressive agents. Experiments were conducted in immunocompetent diabetic rats, with sex included as a biological variable. MSC-loaded NICHE devices promoted robust vascularization and improved islet engraftment, even in the context of diabetes-associated vascular dysfunction. High-dimensional immune profiling demonstrated that MSCs transiently reduced innate immune infiltration and inflammatory cytokines and preserved regulatory T cells. Sex-specific differences were observed, with female rats exhibiting improved vascularization and immune regulation. Additionally, local immunosuppression was explored revealing different immunomodulatory profiles, and drug retention at the graft site with minimal systemic exposure. Together, this work supports a combinatorial local immunomodulation approach integrating MSCs and targeted immunosuppression. The NICHE platform provides a clinically relevant strategy for long-term islet engraftment without systemic immunosuppression, advancing safer, more effective therapies for T1D.