Localized immunomodulation with cytokine-producing cells to mitigate host immune rejection responses in rodents and a non-human primate

Abstract

The efficacy of cell-based therapeutics is often compromised by host immune recognition of implanted cells and biomaterials, resulting in fibrotic encapsulation and loss of function. Here, we address this challenge with an immunomodulatory cell-based therapy, in which alginate-encapsulated retinal pigment epithelial cells continuously secrete cytokines to locally modulate the implant microenvironment. In a healthy rodent model, the localized production of interleukin-10 (IL-10) or IL-12 from encapsulated cytokine-producing cells prevented host immune rejection and fibrosis of alginate capsules. Mechanistically, treatment was associated with reduced expression of pro-fibrotic genes and immune shifts consistent with macrophage and T-cell regulation, supporting a cytokine-mediated mitigation of foreign body response. In a diabetic murine model (streptozotocin-induced C57BL/6J), co-implantation of human islets with IL-10-producing cells attenuated pericapsular fibrosis, preserved islet viability, and restored normoglycemia for up to 100 days (4.76 times longer than islets alone). Significantly, IL-10-producing cells were also effective in enabling the durability and function of encapsulated cells in a healthy non-human primate, showing translational feasibility. Collectively, these findings suggest that localized cytokine delivery can reduce fibrotic encapsulation and support durable graft function, offering a path to lessen reliance on systemic immunosuppression in islets transplantation and other implantable biomaterial therapies. TeaserEncapsulated IL-10-producing cells locally suppress fibrosis and extend graft function in rodent models and a non-human primate.