Diabetes and other autoimmune endocrine diseases
Type 1 Diabetes (T1D) is an autoimmune disease where insulin-releasing pancreatic β-cells are destroyed by islet-antigen-specific autoreactive T-cells. One of the marquee unknowns in T1D research is the mechanism by which autoreactive T-cells survive and activate in the periphery. Our published research has shown that blocking IL-7 signaling using an anti-IL-7Rα antibody (aIL-7Ra) prevents the onset of T1D and reverses early cases of T1D in Non-Obese Diabetic (NOD) mice; however, the precise mechanisms by which IL-7 signaling blockade inhibits T1D development has not been fully elucidated. We hypothesized that inhibition of IL-7 signaling causes changes in Nuclear Factor of Activated T-cells (NFAT) expression and mitochondrial metabolism in autoreactive T-cells, compromising their function through cell stress responses.
To test this idea, NOD mice were injected with anti-IL-7Ra antibody or rat IgG2a isotype control antibody twice during one week. Spleens were harvested from the mice and CD4+/CD8+ T cells were isolated. NFAT expression was quantified by qPCR and flow cytometry. Mitochondrial respiration was measured using the Agilent Seahorse platform and T-cell functionality was assessed by cytokine production with ELISA assays.