Widener, A. E. | bioRxiv Science

bioRxiv2025

Anti-CD3 microporous annealed particle hydrogel protects stem cell derived beta cells from autoreactive T cells

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic beta cells, leaving patients dependent on exogenous insulin and at risk of severe hypoglycemic episodes. Stem cell-derived beta-like cells (sBCs) offer a promising approach for beta cell replacement therapy, but clinical translation is limited by immune-mediated rejection, recurrent autoimmunity, and inhospitable transplantation sites. Biomaterials have been investigated to provide localized immune-isolation and immunomodulation, but foreign body responses and rapid depletion of therapeutic agents remain as obstacles to clinical translation. Here, we present a microporous annealed particle (MAP) hydrogel functionalized with an anti-CD3 monoclonal antibody (CD3) to provide a localized immunomodulatory microenvironment for beta cell replacement therapy. MAP hydrogels consisting of guest-host interlinked polyethylene glycol-maleimide (PEG-MAL) microgels supported rapid vascularization, minimal foreign body response, and engraftment of syngeneic islets in mice. CD3 MAP hydrogel halted T cell migration in vitro and protected transplanted sBCs from immune-mediated destruction by HLA-matched diabetogenic T cells in vivo. Subcutaneous CD3 functionalized MAP hydrogel also protected the endogenous islets in the pancreas, demonstrating potential for systemic immune modulation. These findings establish CD3 MAP hydrogels as a promising strategy for localized immune modulation in cell replacement therapy.

bioengineering↗

bioRxiv2024

Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis

The loss of insulin secretory function associated with type 1 diabetes (T1D) is attributed to the immune-mediated destruction of beta cells. Yet, at onset of T1D, patients often have a significant beta cell mass remaining while T cell infiltration of pancreatic islets is sporadic. Thus, we investigated the hypothesis that the remaining beta cells in T1D are largely dysfunctional using live human pancreas tissue slices prepared from organ donors with recently diagnosed T1D. Beta cells in slices from donors with T1D had significantly diminished Ca2+ mobilization and insulin secretion responses to glucose. Beta cell function was equally impaired in T cell-infiltrated and non-infiltrated islets. Fixed tissue staining and gene expression profiling of laser-capture microdissected islets revealed significant decreases of proteins and genes in the glucose stimulus secretion coupling pathway. From these data, we posit that functional defects occur in the remaining mass of beta cells during human T1D pathogenesis.

physiology↗