2087-LB: Novel Human Islet Spheroid Models of Type 1 Diabetes

Recently, it has emerged that β-cells co-orchestrate their own demise by increasing their visibility to the immune system, stressing the importance of studying both the immune and the β-cell components of T1D simultaneously. To enable accurate, high-throughput and longer-term studies of these mechanisms in vitro, we established three islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. We developed a wide variety of biochemical and 3D microscopy based-methods to assess dynamic and static insulin release, insulin production, β-cell survival, cytokine secretion and T cell infiltration, at a single islet resolution. In all models, the decline in β-cell health manifested as increased basal and decreased glucose-stimulated insulin release (GSIS), and decreased intracellular insulin content. Additional hallmarks of T1D progression such as loss of the first-phase insulin response (FFIR), increased proinsulin-to-insulin ratios, HLA-class I expression, and inflammatory cytokine release were also observed. Using these models, we evaluated the effects of multiple intervention strategies including a glucagon-like peptide 1 (GLP-1) receptor agonists and HLA Class I inhibition, on human islets under T1D-relevant stress. We were able to successfully prevent the loss of GSIS under cytokine- and immune-mediated stress, notably by increasing β-cell survival, preserving the FFIR, decreasing immune cell infiltration and cytokine secretion. Our results support the anti-inflammatory effect of GLP-1R agonists and importance of HLA Class I modulation for protecting β-cells from the immune-mediated attack that leads to T1D. The described biomimetic islet-immune assays represent ideal in vitro models for long-term, high-throughput and precise study of early-stage T1D immunopathology and β-cell dysfunction. Disclosure A.C. Title: Other Relationship; Biomea Fusion, Inc., Boehringer-Ingelheim, Novo Nordisk, Merck Boehringer-Ingelheim, Novo Nordisk, Merck Boehringer-Ingelheim, Merck Biomea Fusion, Inc., Boehringer-Ingelheim, Merck Biomea Fusion, Inc., Novo Nordisk, Boehringer-Ingelheim, Merck Novo Nordisk, Boehringer-Ingelheim, Biomea Fusion, Inc., Merck & Co., Inc.