COMBINATION OF OK432 AND HUMAN INTERFERON-ALPHA FOR TREATING VIRAL-INDUCED DIABETES-MELLITUS IN MICE

We investigated the therapeutic effects of OK432 (picibanil; CAS39325- 1-4), an immunomodulator that is derived from the Su strain of Strepto coccus pyogenes. This agent was administered alone or combined with hu man interferon-alpha in a murine model of insulin-dependent diabetes m ellitus. Interferon-alpha inhibits viral replication, reducing the inc idence of virus-induced IDDM. Groups of DBA/2 mice (N= 25 per group) r eceived an intraperitoneal injection of OK432 and interferon-alpha dai ly for 16 d beginning 1 d after inoculation with 500 plaque-forming un its of encephalomyocarditis virus (EMCV). The dose of OK432 was one cl inical unit (corresponding to 0.1 mg dried cells) per mouse, and that of interferon-alpha was 1 x 10(4) u/g. The animals were killed at rand om at 3 or 7 d after inoculation with EMCV. The survival rate of mice treated with the combination of OK432 and with interferon-alpha was si gnificantly greater than that of the non-treated infected control anim als (P < 0.01). Fasting levels of blood glucose were significantly low er in the mice administered the combination, than in the controls, bot h on day 3 (68 +/- 21 mg/dl vs. 270 +/- 135 mg/dl, P < 0.01) and on da y 7 (101 +/- 29 mg/dl vs. 219 +/- 112 mg/dl, P < 0.01). Serum levels o f insulin were significantly higher in the treated mice than in the co ntrols (65 +/- 5 vs, 55 +/- 1 mu U/ml, P < 0.05), However, in the mice treated with OK432 or interferon-alpha alone, the survival rate and t he blood level of glucose and insulin did not differ from those of inf ected controls. Natural killer (NK) cell activity was significantly hi gher in the mice treated with the drug combination than in the control s on both days evaluated: day 3, 65 +/- 5 vs. 55 +/- 1%, n = 3, P < 0. 05; day 7, 44 +/- 3 vs. 22 +/- 8%, n = 3, P < 0.05). Serum levels of m urine interferon in the treated mice exceeded those in controls on bot h days evaluated (day 3, 671 U/ml vs. 442 U/ml; day 7, 57 U/ml vs. 43 U/ml). There were no significant differences in NK cell activity or in the interferon level in mice treated with either OK432 or interferon- alpha alone as compared with the infected, non-treated controls. Resul ts suggest that the combination of OK432 and interferon-alpha protects against virally induced IDDM by increasing the activity of NK cells a s well as the plasma level of interferon. (C) 1998 Elsevier Science B. V.