| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Immunosuppressants have important clinical roles in organ transplantation and the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Both cyclosporin A (CsA) and tacrolimus (FK506) suppress immune responses by inhibiting the production of interleukin-2 (IL-2) in antigen-stimulated helper T-cells, and are standard medicines for preventing graft rejection after transplant surgery. Since their clinical use is restricted by severe side effects, notably renal and liver toxicities, they are used in combination with glucocorticoids or other immunosuppressants such as azathioprine and mizoribine. Novel immunosuppressants should therefore not only be safer but also possess unique mechanisms of action.
In the late 1980s Fujita et al. of our group isolated a unique immunosuppressant, ISP-I (myriocin), from the fermentation broth of Isaria sinclairii (ATCC24400). It has been reported that ISP-I inhibits serine palmitoyltransferase of an IL-2
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dependent mouse cytotoxic T cell line, CTLL-2,at picomole concentrations. We simplified the structure of ISP-I in order to reduce its toxicity, to improve its physicochemical properties, and to identify the structure essential for immunosuppressive activity to give FTY720 (2-amino-2-(2-(4-(octylphenyl)ethyl)propane-1 ,3-diol
In spite of the established therapeutic effectiveness of FTY720, little clinical and experimental knowledge is yet available about its pharmacokinetic properties, disposition, and so on, due to the lack of an antibody against FTY720. An antibody was prepared by immunizing rabbits with an ovalbumin conjugate of 2-amino-2-(2-(4-(4-mercaptobutyl)phenyl)ethyl)propane-l ,3-diol HCl (AMPD-4), which contains the essential structure of the novel immunosuppressant FTY720. As the antibody reacted to not only AMPD-4, but also FTY720, it should be useful for immunoassay of FTY720 in body fluids, tissues and cells. However, the antibody showed a cross immuno-reaction with FTY720 metabolites. This report deals with synthesis of hapten, AMPD-8, which is closer to FTY720, and preparation of monoclonal antibody against FTY720. Less
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