Immunosuppressants are used in various autoimmune diseases, and these agents are important in the therapy of patients with vasculitis (polyarteritis nodosa (PN), Wegener's granuloma (WG) ) and steroid resistant systemic lupus erythematosus (SLE) or polymyositis/dermatomyositis (PM/DM) . Cyclophosphamide (CY) is mainly used in these diseases. Especially, in patients with PN and WG, this agent is received as the initial therapy. In patients with steroid resistant SLE, interavenus CY (IVCY) is recently used. In other therapy resistant disease, CY are also first used, while azathioprine (AZ) is secondly used in patients with side effects by CY. MTX is used in patients with refractory RA, PM and adult onset Still disease (AOSD) . However, this agent can not be used in patients with interstitial pneumonitis. In patients with refractory pneumonitis, cyclosporine A (CyA) is recently used. This agent is also used in patients with refractory SLE, RA, psoriasis and Behçet's disease. Thus, various immunosuppressants are used in various autoimmune diseases. However, since the method of therapy for these agents are not completely established, the further study will be needed.

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Objective. To elucidate the role of neurologic, endocrine, and immune system interactions in the development of pathologic responses in patients with rheumatoic arthritis (RA), we studied neuropeptide production and neuropeptide receptor expression in RA synovium and its function in patients with RA.
Methods. The effects of neuropeptides on proinflammatory cytokine (interleukir (IL) -6 and IL-8) and collagenase production by RA synovial cells were estimated by enzyme-linked immunosorbent assay, and their messenger RNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) using-limiting dilutions of the complementary DNA. The expression of receptors for neuropeptides by RA synovial cells was also studied by RT-PCR and radioreceptor assays. Local production of neuropeptides was estimated by RT-PCR and immunohistochemical staining. Functions of some neuropeptides for the synovial cells were studied by using antagonists for the peptides.
Results. Some neuropeptides inhibited proliferation of and proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells both at the level of mRNA expression and at the protein level, and another neuropeptides did rather upregulate them. Expression of receptors for the neuropeptides studied on RA synovial cells was confirmed by RT-PCR and radio-receptor assays. Functions of the neuropeptide receptors were inhibited by their receptor antagonists. Some, but not all, neuropeptides inhibited nuclear translocation and phosphorylation of transcription factor, cyclic AMP responsive element binding protein (CREB), in RA synovial cells, while prolactin acted via translocation of STAT-5 to nuclei in RA synovial cells.
Conclusion. Neuropeptides upregulated or downregulated synovial cell functions, suggesting regulation of inflammatory responses by neuropeptides in patients with RA and possible clinical application of certain neuropeptides.

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Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. Since the most important clinical feature is thought to be the fibrosis of systemic organs, a lot of studies concerning tissue fibrosis were performed in vivo and in vitro. Several cytokines and growth factors were reported to be increased in SSc patients' sera and to be excessively expressed in various tissues, suggesting that they might play crucial roles in the immunopathogenesis of SSc.
Hepatocyte growth factor (HGF) was first described as a potent mitogen for adult rat hepatocytes in primary culture. Recent studies revealed that HGF targets a wide variety of epithelial cells including fibroblasts and that it has multiple biological properties in regulating cell proliferation, migration, morphogenesis, development and regeneration. Increased levels of serum HGF were observed in several fibrotic disorders including fulminant hepatitis, and HGF may be one of the promising candidates for serum marker of the tissue fibrosis.
In this study, we examined whether the level of serum HGF increased in SSc patients compared to that in normal controls and estimated the relationship between the level of serum HGF and the extent of the fibrosis in SSc.

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The effect of Agaricus blazei Murri (CJ-01) was studied in animal experimental models for arthritis to evaluate its efficacy. Spontaneous polyarthritis in MRL/Mp1pr/1pr (MRP/1pr) mice and type II collagen-induced arthritis (CIA) in DBA/1J mice were studied. CJ-01 significantly reduced the incidence and severity of paw swelling in CIA in DBA/1J mice. And suppressed in serum C-reactive protein, lactate dehydrogenase and IgG-type rheumatoid factor levels in MRL/1pr mice. A high level of serum anti-type II collagen antibody was also suppressed in the group treated with dexamethasone but not CJ-01. Histopathological examination showed that CJ-01 proliferative inflammatory articular lesions were suppressed and a bone-remodelling effect was observed under a microscope. The boneremodelling effect indicates both suppression of absorption and new bone formation. These results suggest that CJ-01 has and anti-arthritic effect and may be avaluable therapeutic drug for inflammatory disease.

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Leukopenia is clearly the single most important risk factor for infection in cancer patients. We investigated the clinical usefulness of Z-100, a polysaccharide-rich extract from the Mycobacterium tuberculosis strain Aoyama B, on the protection of infection in patients with leukopenia induced by radiotherapy for lung cancer. This study was designed as a placebo-controlled double-blind clinical trial and was performed from April 1995 to September 1998. A total of 428 patients were preregistered before radiotherapy, and finally 65 patients with a leukopenia of less than 3, 000/mm³ were enrolled in the study. The average level of the white blood cell count had been higher in the Z-100 group since 4 weeks from administration but the difference was not statistically significant. The frequency of infection was 6.7% in the Z-100 group (n=30) and 21.2% in the control group (n=33) . The accumulated occurrence of infection was significantly higher in the control group since 4 weeks and thereafter. When the patients were classified as “definitely infected”, “possibly infected” (febrile with CRP> 3 mg), and “not infected”, the occurrence of infection was significantly less frequent in the Z-100 group by the Mantel test. These results suggest that Z-100 is useful in preventing the occurrence of infection induced by leukopenia, possibly by increasing the number of leukocytes as well as by other immunological reactivating mechanisms.

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