Microgels Containing Protease Resistant CXCL12 and FasL Enable Long-term Allo-Islet Function Without Systemic Immunosuppression
Fatma Dogan, Assia El Babsiri, Esin Ozkan, Sitong Ye, Katie Lu, Aaruni Arora, Kento Kawai, Ryo Otsuka, Timothy A. Brauns, Patrick M. Reeves, Ann E. Sluder, Mark C. PoznanskyType 1 diabetes (T1D) is a chronic disease characterized by the autoimmune destruction of insulin-producing β-cells in the pancreas. Replacement of β-cells by islet transplantation has proven to be successful in providing a functional cure for T1D. We previously showed that microencapsulation of allogeneic islets (allo-islets) or xenogeneic islets with CXCL12 promotes β-cell function, provides immune protection, and facilitates vascularization at the graft site in both small- and large-animal models of T1D. In addition, streptavidin-Fas ligand (SA-FasL) microgels induce immune acceptance of allo-islets through expansion of T regulatory cells (Tregs) in combination with short-term systemic immune suppression. This study evaluated a combination of these two complementary approaches for extending allo-islet graft survival in a mouse model of T1D through the codelivery of SA-CXCL12 or a protease-resistant variant of the chemokine (SA-prCXCL12) and SA-FasL within biotinylated microgels in an allogeneic-transplant setting. We demonstrated that microgels coated with SA-FasL and SA-prCXCL12, when cotransplanted with allo-islets, sustained long-term (6 months) diabetes reversal in streptozotocin-treated mice without any systemic immunosuppression more effectively than either agent alone. Our findings demonstrate in this murine model of diabetes that microgels delivering a combination of SA-prCXCL12 and SA-FasL induce long-term local immune protection of the allo-islet graft, enhance intragraft Treg recruitment, and improve graft vascularization while abrogating the need for any systemic immune suppression.
Article Highlights
Cotransplantation of allogeneic islets with microgels coated with streptavidin fused with Fas ligand and protease-resistant CXCL12 results in robust and sustained diabetes reversal for over 6 months in streptozotocin-induced diabetic mice and induces local immunomodulation, enhances Treg recruitment within the graft, and improves graft vascularization. This study addresses a critical challenge in cell transplantation, namely the need to develop technologies that enable local immunoprotection of the graft while eliminating the need for systemic immunosuppression. This combination microgel technology could offer a more favorable risk-benefit profile by reducing infection risks, organ toxicity, and tumorgenicity associated with the use of systemic immunosuppression. This novel combinatory immune modulatory approach is feasible and achieves anatomic site-specific immune protection while supporting long-term islet graft function without systemic immune suppression.