Toru Kino

FK-506, A NOVEL IMMUNOSUPPRESSANT ISOLATED FROM A STREPTOMYCES

The immuno-pharmacological profile of a novel immunosuppressive agent, FK-506 produced by a streptomycete, is presented here. We proceeded to test the effect of the agent on various in vitro immune systems. It showed that mixed lymphocyte reaction, cytotoxic T cell generation, the production of T cell-derived soluble mediators such as interleukin 2 (IL-2), interleukin 3 and gamma-interferon and the expression of the IL-2 receptor were suppressed by this agent. The IC50 values of FK-506 and ciclosporin (CS) in all tests were approximately 0.1 nM and 10 nM, respectively. Therefore, the novel agent, FK-506 suppressed in vitro immune systems at about hundred times lower concentration than CS.

CHAPTER 12 – Immunomodulators

Publisher Summary This chapter describes the screening for immunosuppressants. There are several types of cells responsible for specialized functions in the immune system that act through hormone-like substances, much as in the nervous system. It was found that T cells could be cultured indefinitely in the presence of immunological hormone interleukin 2. It has been demonstrated time and again that this interleukin plays a crucial role in the immune response. On the one hand, the immune system protects the body against diseases from invasion by foreign organisms, but on the other hand, it can attack a lifesaving organ transplant or mistakenly respond to the bodys own molecules that, in turn, results in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and juvenile diabetes. A large accumulation of data shows that activated T cells are associated directly with damage to the tissues during graft rejection and autoimmune diseases. This finding rationalizes the idea that activated T cells can be treated as a pathogen, similar to pathogenic microbes in an infectious disease, and this is leading to new therapeutic approaches for abnormal immune reactions. Depressed function of activated T cells can lead to the suppression of an abnormal immune response. One of the targets for the depression of cell function is IL-2. Selective inhibition of IL-2 production could inhibit T cell growth, which in turn, would result in suppression of the immune response.

Immunosuppressive Properties of FK-506

FK-506, a novel immunosuppressant from Streptomyces tukubaensis, was a selective anti-T lymphocyte agent like ciclosporin (CS). This agent suppressed both cell-mediated and humoral immunity, without depressing the bone marrow. Futhermore, it was effective in a rat skin allograft model. These results provided a strong motivation to develop FK-506 for clinical application to organ transplantation.