Biomaterial-mediated approaches for persistent, localized, and targeted delivery of immunomodulatory proteins
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Medina, Juan
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Abstract
Type 1 diabetes (T1D), an autoimmune disorder prevalent in 1.6 million Americans, is growing rapidly with 64,000 yearly diagnoses and costing the U.S. $16 billion annually. Although pancreatic islet transplantation has shown promise in treating T1D, immune rejection and continuous use of immunosuppression to control rejection limit clinical islet transplantation to those already immunosuppressed or suffering from severe hypoglycemic episodes. Despite advances in immunosuppressive protocols, significant adverse effects are still prevalent, and immunosuppression is attributed to negatively impacting long-term graft survival – with only ~50% of recipients maintaining insulin independence at five years. Therefore, there is a significant need to prevent graft rejection without an immunosuppressive regimen.
The objective of this project is to engineer biomaterial-mediated approaches for the delivery of bioactive ligands to induce immune tolerance towards foreign antigens in a targeted and localized manner. This overarching objective was divided into two aims: 1) to engineer and evaluate a synthetic PEG-4MAL hydrogel platform for the co-delivery of immunomodulatory proteins for pancreatic islet allografts, and 2) to engineer and characterize a nanoparticle (NP) platform for the targeted delivery of immunomodulatory proteins to lymph nodes (LNs). For Aim 1, cell-mediated degradable poly(ethylene) glycol-based (PEG) hydrogels were engineered and characterized for the delivery of IL-2D alongside SA-FasL-presenting hydrogel microparticles (microgels). This hydrogel/microgel platform was co-transplanted with allogeneic islets into murine epididymal fat pads (EFPs); protein delivery was assessed via in vivo imaging and T cell subpopulation effects were assessed via flow cytometry immune profiling. This biomaterial platform was then tested for preventing rejection of islet allografts in chemically induced, fully mismatched, diabetic mice. We hypothesized that IL-2D and SA-FasL delivery would induce immune tolerance at the graft site. For Aim 2, we sought to expand immunomodulation beyond islet transplantation by targeting LNs, where significant immune activation and regulation occurs. To do so, we engineered and characterized biotinylated nanoparticles (NPs), whose size (~30 nm) and surface composition allow for targeted and sustained delivery/retention to LNs. SA-FasL-coated NPs were injected subcutaneously (sc); protein delivery was assessed via in vivo imaging and immune cell population effects were assessed via flow cytometry immune profiling.
For Aim 1, we found that hydrogels encapsulating IL-2D did not negatively affect bioactivity of either immunomodulatory protein, was compatible with pancreatic islets for cell replacement therapies, and induced significant changes in T cell subpopulations in a dose-dependent manner. Although long-term allograft function was not achieved, this study showcases a biomaterial-mediated approach for delivery of bioactive immunomodulatory proteins that results in enhanced residence time in a localized manner. For Aim 2, we found that SA-FasL coated on biotinylated NPs retained its bioactivity, significantly extended its residence time at the injection site, localized at draining LNs, and induced significant changes in T cell subpopulations at draining lymph nodes in the absence of significant off-target effects in antigen-presenting cell (APC) populations nor systemic immune effects.
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2022-07-30
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Dissertation