Development of Biomaterial Scaffolds to Modulate the Local Immune Microenvironment and Support Allogeneic Islet TransplantationPublic Deposited
Intrahepatic islet transplantation is a promising therapeutic option for the treatment of Type-1 diabetes that offers the ability to restore endogenous insulin production. Widespread use of islet transplantation is currently limited by poor survival of transplanted islets due to the harsh environment of the liver portal vein, prompting investigation into alternative transplantation sites. The Shea lab has been at the forefront of developing biomaterial scaffold platforms to support the engraftment of islets into intraperitoneal fat. However, the inefficacy of general immune suppression protocols required to prevent immune-mediated graft destruction remains an unsolved issue. This dissertation presents novel strategies seeking to use biomaterial-based immune intervention to extend allogeneic islet transplant survival. A layered poly(lactide-co-glycolide) (PLG) scaffold system was designed to incorporate the immunosuppressive cytokine TGF-β1. Localized delivery of TGF-β1 strongly reduced leukocyte infiltration into the scaffold environment seven days post-transplant, in addition to co-activation markers on antigen-presenting cells and inflammatory cytokine expression. TGF-β1 scaffolds showed biocompatibility with transplanted syngeneic islets and significantly extended survival of transplanted allogeneic islets, demonstrating the protective effects of limiting early leukocyte infiltration. The scaffold was then used to characterize the delivery of a novel immunomodulatory cytokine IL-33 to assess whether adipose tissue-specific anti-inflammatory immune cell lineages could be used to prevent graft rejection. IL-33 potently expanded local CD4+ Foxp3+ regulatory T cells (Tregs) in a blank implantation model. IL-33 delivery also expanded Tregs expressing the IL-33 receptor ST2 while decreasing proliferation of graft-destructive CD8+ T cells in an allogeneic islet transplant model. We found IL-33 release was able to significantly extend allograft survival, demonstrating local allograft-protective effects. However, we also found that IL-33 delayed engraftment of transplanted islets in syngeneic and allogeneic models. IL-33 delivery induced a Type 2 cytokine response, specifically increasing expression of IL-4 and IL-5, which coincided with expansion of locally enriched eosinophils and Group 2 innate lymphoid cells (ILC2s). Finally, nondegradable poly(ethylene-glycol) (PEG) hydrogel designs were compared for their abilities to support islet engraftment and their interaction with the host immune system. Both nonporous macroencapsulation hydrogel and a microporous scaffold designs supported stable engraftment of islets that restored normoglycemia by three weeks post-transplantation. The microporous design restored normoglycemia in response to glucose challenge at the same rate as endogenous islets while the macroencapsulated hydrogel showed a delayed response. The microporous design provoked a foreign body response leading to a large population of neutrophils within the scaffold correlating to a period of hyperglycemia when transplanted with syngeneic islets. This dissertation demonstrates the promise of leveraging biomaterials to develop localized immunomodulatory strategies to control the local microenvironment and support survival of allogeneic islets.
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