Basic study on prevention and treatment of type 1 diabetes mellitus with biological respomse modifiers.

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We previously reported that a streptococcal preparation (OK-432), one of BRMs, inhibited insulitis and prevented insulin-dependent (type 1) diabetes mellitus (IDDM) in NOD mice. In this project, we extended our previous observation to two studies; 1) effect of OK-432 on IDDM in BB rats as an another model of IDDM and 2) analysis of mechanisms of OK-432-action by usingNOD mice. The results and conslusions are as follows.1)The cumulative incidence of diabetes was 27.7% (13/47) by 30 weeks of age in BB rats, whereas that was significantly suppressed in the rats (7.4%, 4/54, p<0.01) who were weekly and intraperitoneally treated with 0.2 mg of OK-432. Histological examinations revealed that the OK-432-treated BB rats retained a greater number of intact islets without lymphocytic infiltrations than did thenon-treated rats. The cytotoxic activities of spleen cells directed against a rat insulinoma cell line, RIN, were significantly suppressed in the OK-432-treated BB rats as compared with tho … More se in the non-treated rats, Thus, the OK-432 treatment suppressed insulitis and inhibited development of diabetes not only in NOD mice but also in BB rats.2) Approximately 85% of the non-treated NOD mice developed diabetes by 25 weeks of age. On the other hand, the weekly injection (ip or iv) of 0.1mg of OK-432 from 4 or 5 to 15 ro 20 weeks of age completely inhibited development of diabetes and these NOD mice did not develop diabetes even after ceasing the OK-432-treatment. Cyclophosphamide enhanced the development of diabetes in thenon-treated NOD mice but not in the OK-432-treated mice. The diabetes wastransfered by the spleen cells from the non-treated NOD mice but not by the cells from the OK-432-treated mice. In addition, the spleen cells from the OK-432-treated mice inhibited the development of diabetes in the cyclophosphamide-treated mice and this inhibitory effect was eliminated by the treatment of cells with anti-Thy-1 antibody and complement. These indicate that the OK-432-treatment inhibited the induction of cytotoxic effector cells directed against pancreatic B cells and this effect was mediated by suppressor T cells. Less