Immunomodulatory oligonucleotide IMT504 direct trigger on regulatory T cells in adult non-obese diabetic mice.

GÓMEZ BUSTILLO S; BIANCHI MS; LUX LANTOS VAR; HIPP H; KRAL M; SER I; DANIEL C; MONTANER A

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias: LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), LXX Reunión Anual de la Sociedad Argentina de Inmunología (SAI) & 3rd French-Argentine Immunology Congress (FAIC), Reunión Anual 2022; 2022

SAIC

Type 1 diabetes (T1D) is a multifactorial autoimmune disease in which insulin-producing pancreatic β-cells are destroyed by autoreactive T cells. Currently, there are no effective clinical interventions for T1D, and patients are treated with insulin for life. There is a consensus that new innovative approaches to predict, treat, and prevent T1D are urgently needed. Several strategies to modulate the immunological response and restore β-cell mass have been performed but are limited by the availability of grafts and the need for chronic immunosuppression. IMT504 is the prototype of the PyNTTTTGT family of immunomodulatory oligonucleotides (ODNs), which are known for their regenerative properties and have been shown to be effective in lowering glycemia in nonobese diabetic (NOD /LtJ or simply NOD) mice. Here, we investigate the effect of IMT504 on T cells from NOD mice. Infiltrating T cells were isolated from the pancreas and lymph nodes of pre-diabetic and diabetic NOD mice. Cells were then sorted and treated in vitro with 0.5 µg/ml IMT504 or control ODN. After treatment, lymphocyte activity and functionality were characterized (differentiated T cell subsets, gene expression (cytometry), activated signaling pathways (qPCR), and induction of regulatory T cells (cytometry)). IMT504 induced TGF-β (*p < 0.05 vs PolyC), a cytokine that stimulates regenerative properties in stem cells and higher β-cell number. We analyzed the molecular signaling pathways involved in the deregulation of T1D. We measured lower levels of PI3K (*p < 0.01 vs control), mTOR (*p < 0.05 vs control), and STAT (*p < 0.01 vs control). Downregulation of these genes is associated with higher levels of glucose transporter 1 (GLUT1), normalized glycemia, and cellular reprogramming into β-like cells, respectively. MAP3K7 expression which is associated with β cell destruction was also downregulated (*p < 0.05 vs control). In conclusion, our results indicate that IMT504 exerts an effect on T cells that may prevent the onset of diabetic autoimmunity.