Study on mechanism of action of biological response modifier (BRM) in prevention of type 1 diabetes mellitus.

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We previously reported that a streptococcal preparation (OK-432), a non-immunosuppressive biological response modifier (BRM), inhibited insulitis and development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats as animal models of IDDM. In this study we analyzed the mechanism of action of BRM in the inhibition of IDDM by using OK-432 and the animal models. The following results were obtained.1. Administration of OK-432 to NOD mice inhibited the generation of effector cells for the pancreatic B cell destruction. However, the same treatment did not suppress the induction of cytotoxic T lymphocytes directed against allogenous tumor cells and the production of anti-SRBC antibody.2. NOD mice sera after intravenous injection of OK-432 also suppressed development of IDDM in NOD mice. These sera contained approximately 25 U/ml of TNF, but not detectable IL-1, IL-2 and IFN gamma with a bioassay. The 0K-432 sera lost the suppressive effect on diabetes after the treatment with anti-TNF antibody.3. Recombinant human and mouse TNFalpha significantly inhibited diabetes in both NOD mice and BB rats.4. NOD mice had not only the effector cells, but also L3T4-positive suppressor T lymphocytes for the pancreatic B cell destruction.These results showed a rationale for the possible therapeutic use of BRMs to human IDDM and indicate that the various BRMs in the natural environment may have inhibitory effect on the development of genetically-determined IDDM.