Early Improvement in Type I Diabetes in Mice By Oligodeoxynucleotide IMT504

MARIA SILVIA BIANCHI, ; ALEJANDRO MONTANER; LEANDRO MARTINEZ; STEFANIA BIANCHI; NORMA ALEJANDRA CHASSEING; CARLOS LIBERTUN; VICTORIA ADELA LUX-LANTOS

Chicago, ILL

Congreso; The Endocrine Society (USA). 96th Annual Meeting and XVI International Congress of Endocrinology.; 2014

The Endocrine Society (USA).

Abstract #14633 Early Improvement in Type I Diabetes in Mice By Oligodeoxynucleotide IMT504 Maria Silvia Bianchi, PhD1, Alejandro Montaner, PhD2, Leandro Martinez3, Stefania Bianchi1, Norma Alejandra Chasseing, PhD3, Carlos Libertun, MD, PhD1 and Victoria Adela Lux-Lantos, PhD1, (1)Lab Neuroendocrinology, IBYME-CONICET, Buenos Aires, Argentina, (2)Fundaci¨®n Pablo Cassar¨¢ (ICT Milstein-CONICET), Buenos Aires, Argentina, (3)Lab Immunohematology, IBYME-CONICET, Buenos Aires, Argentina IMT504, the prototype of the PyNTTTTGT class of immunomodulatory oligonucleotides, accelerates tissue repair in models of bone injury and sciatic nerve crush. In addition, we have previously shown that IMT504 induces a marked recovery of single-dose streptozotocin (STZ)-induced toxic diabetes in male rats that correlates with early expression of progenitor cell markers (1), without altering immune parameters (2).IMT504 also improves the diabetic condition in an autoimmune diabetes model induced by multiple low doses of STZ in mice (MLDZ), evaluated 25 days after the end of IMT504 treatment. Here, we evaluated the early effects of IMT504 in MLDZ diabetic mice and its mechanism of action. Male Balb/C mice were ip-injected with STZ (40mg/kg) for 5 consecutive days or diluent as control (C). STZ mice with blood glucose ¡Ý 250 mg/dl and controls were daily sc-injected with IMT504 (IMT: 20mg/kg/dose) (STZ-IMT, C-IMT, respectively) or saline (STZ, C) and killed after two consecutive decreases in glycemia in STZ-IMT mice (2-5 doses of IMT). Blood samples and pancreases were collected for hormonal/cytokine determinations and histological studies. The prompt normalization observed in STZ-IMT blood glucose [glycaemia at sacrifice (mg/dl): C=137¡À14, C-IMT: 103¡À8, STZ: 352¡À41*, STZ-IMT: 145¡À9, * different from all: p<0.001] was accompanied by a decrease in apoptosis rate (apoptotic positive cells/total islets: C: 0.05¡À0.03*, C-IMT: 0.18¡À0.05, STZ: 0.70¡À0.23*, STZ-IMT: 0.37¡À0.13, *: p<0.01) without changes in the number of islets/pancreas area between the animal groups. Furthermore, a change in cytokine profile was accompanied by a clear reduction of leukocyte infiltration in and around islets and by an increase in indolamine 2,3-dioxigenase expression (IDO positive islets/total islets: C: 0.41¡À0.13, C-IMT: 0.49¡À0.19, STZ: 0.72¡À0.31, STZ-IMT: 0.93¡À0.07*, *: significantly different from C and C-IMT, p<0.03). Taken together, these results suggest that IMT504 promotes rapid blood glucose normalization by modulating the immune system and preserving/recovering pancreatic islets.