IMT504 INHIBITS INSULITIS AND LOWERS BLOOD GLUCOSE IN NOD/Ltj FEMALE MICE IN A SHORT-TERM TREATMENT

STEFANIA BIANCHI; MILENA MASSIMINO; CARLOS LIBERTUN; MARÍA SILVIA BIANCHI; VICTORIA ADELA LUX-LANTOS,

Ciudad Autónoma de Buenos Aires

Congreso; reunión Conjunta de Sociedades de Biociencias; 2017

Immunomodulatory oligonucleotide IMT504 (IMT) induceda marked recovery of glycemia, glucose clearence, insulin secretion and betacell function (by HOMA beta cell index) on aspontaneous autoimmune diabetes model (in male and female NOD/Ltj mice).We analyzed the minimun dose at which the IMT has an earlyeffect on glycemic control and insulitis. Diabetic female NOD/LtJmice (two consecutive non-fasted glycemia (Gly) levels ≥ 250 mg/dl) were treatedwith a daily dose of IMT for five days (IMT: 2, 6 or 20 mg/kg/day, IMT2, IMT6and IMT20) or saline as control (DC). Mice were sacrificed the day following the last injection. In fastedconditions, blood samples and pancreases were obtained for Gly and insulinemiameasurment and for histological studies respectively.We observed that 12.5% (1/8) DC mice showedspontaneous reversion of diabetic condition, whereas IMT improved Gly in 62.5% (5/8),50% (4/8) and 75% (6/8) of mice treated with 2, 6 and 20 mg/kg/day, respectively(X2: DC vs IMT20: p<0.025). Glydid not vary with time (day 6 vs day 1) in DC mice while it significantly diminished with IMT treatment [(mg/dl):interaction, p<0.01, DC:Day 1: 330 ± 71 vs Day 6: 333.± 118, IMT2: Day 1: 303 ± 49 vs Day6: 233 ± 57, IMT6: Day 1: 283 ± 22 vs Day 6: 194 ± 44, IMT20: Day 1: 313 ± 42vs Day 6: 147 ± 42, IMT20: Day 1 vs Day 6: p<0.02]. Bodyweights did not differ among groups. Fasted glycemia also diminshed significantlywith IMT20 treatment (DC vs IMT20: p<0.04). Since IMT20 showed the mosteffective response, we analyzed insulitis in this group.Treated mice showed a marked reduction in leukocyte islet infiltration (insulitisindex: DC: 0.66 ± 0.05 vs IMT20: 0.48 ± 0.05, p<0.05).Taken together, these results demonstrate that IMT20treatment promotes an early, significant improvement in the diabetic conditionin NOD/Ltj mice warranting further investigation of its mechanism of action.