Cytokine production in NOD mice on prophylactic insulin therapy

We investigated whether cytokines produced primarily by monocytes/macrophag es (IL-1 alpha), Th1-lymphocytes (IFN gamma), or Th2-lymphocytes (IL-4) are modulated in diabetes-prone NOD mice by insulin treatment as used in proph ylaxis studies. The cytokines were measured by ELISA in plasma and in super natants of spleen cells activated ex vivo by lipopolysaccharide plus phytoh emagglutinin. Insulin, 0.25-0.50 IU/day, was given subcutaneously for 8 wee ks starting in 4-week-old female mice. The insulin-treated and control NOD mice showed similar weight gains and, by the end of the study, both groups exhibited cell infiltration in about 25% of their islets. IL-1 alpha, IFN g amma and IL-4 were generally below detection in plasma of prediabetic anima ls and controls. Diabetic NOD mice, aged 28-45 weeks, had significantly ele vated plasma IL-1 alpha: 154+/-39 pg/ml (mean+/-SEM, p<0.0001). While ex vi vo activated NOD splenocytes released similar amounts of IL-1 alpha, insuli n therapy increased the levels from 99+/-17 to 155+/-19 pg/10(6) cells (p<0 .05). Supernatants of activated splenocytes from prediabetic NOD mice had l ower levels of IL-4 (<15 pg/10(6) cells) compared with those from BALB/c mi ce (88+/-22 pg/10(6) cells; p<0.01), and this deficiency was partially comp ensated for when the NOD mice were given insulin (27+/-8; p<0.01). The leve ls of IFN gamma were comparable and largely unaffected by insulin treatment . Hence, insulin therapy appears to partially normalize an otherwise defici ent Th2 response in NOD mice.