FK506 is an immunosuppressive drug that inhibits T cell receptor (TCR) -mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. We investigated the effects of FK506 on T cell apoptosis induction.
Staphylococcal enterotoxin B (SEB) injection in mice resulted in splenic T cell apoptosis. FK506 augmented this SEB-induced peripheral T cell apoptosis. Also, profound reduction of SEB-reactive CD4⁺Vβ8⁺T cells was observed in SEBFK506-treated mice.
Similary, pretreatment with FK506 significantly augmented thymocyte DNA fragmentation induced by dexamethasone (DEX) injection. Increased thymic apoptosis resulted in the reduction of thymocytes after FK506/DEX injection. Similary, FK506 synergistically enhanced DEX-mediated apoptosis of human peripheral blood T cells in vitro.
Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. These findings suggest that FK506-triggered apoptosis following elimination of T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.

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The authors investigated anti-allergic and anti-inflammatory mechanisms in iodine enriched eggs. Both total and neutral lipid fractionation in iodine enriched eggs suppressed the histamine release in response to an antigen challenge of passively immunized lung mast cells in a dose dependent manner. LT-C₄ production in antigen challenged atopic leukocytes was also suppressed by both total and neutral lipid fractionation. The suppressive mechanisms of iodine enriched eggs were investigated using leukocyte lysate as enzyme preparations of 5-lipoxygenase system. Neutral lipid fractionation did not inhibit LT-B₄ production, ie., 5-lipoxygenase activity, but did inhibit LT C₄ production, i.e., LT-C₄ synthase activity. Polar lipid fractionation inhibited neither LTB₄ production nor LT-C₄. These results suggested that neutral lipid fractionation of iodine enriched eggs modulated histamine release in lung mast cells and LT-C₄ production in leukocytes with antigen provocation. Furthermore, it was possible for neutral lipid fractionation to inhibit LT C₄ synthase activity in leukocytes.

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We investigated the immunosuppressive effect of FK 506 on adjuvant arthritis in rats as an experimental model of rheumatoid arthritis.
FK 506 was intramuscularly administered at a dose of 0.32 mg/kg/day from day 0 to day 28 after adjuvant injection. The severity of arthritis was evaluated by macroscopic score graded from 0 to 4 for each limb and histopathological examination of joints stained with hematoxylin and eosin. We also examined the expression of fibroblast growth factor (FGF) -1 and tyrosine phosphorylated proteins (phosphotyrosine, P-Tyr) in the inflamed synovia by immunoperoxidase staining.
FK 506 macroscopically prevented the development of arthritis and suppressed the proliferation of synovial tissues, the infiltration of inflammatory mononuclear cells and the destruction of bone and cartilage when compared with the control group. The expression of FGF-1 and P-Tyr of synovial sections was suppressed by treatment with FK 506. The intensity of immunostaining observed within synovial lining cells, sublining stromal fibroblast-like cells and cartilage chondrocytes decreased.
These findings suggest that FK 506 is a useful drug for the treatment of rheumatoid arthritis.

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Objective : At present, mechanisms of hyaluronic acid (HA) synthesis are poorly understood. Specific antibodies against HA have not been produced, and the genetic study of HA production has not been conducted. The purpose was to understand HA production and deposition in the synovium of patients with rheumatoid arthritis (RA) exhibiting different degrees of inflammation.
Materials and methods : Each patient meeting the criteria of RA (American College of Rheumatology, ACR, 1987) was classified into 4 histological stages according to the degree of synovial inflammation ; A : early, B : moderate, C : active, and D : fibrotic stages. Synovia from 28 patients with RA were examined and as controls non inflamed and osteoarthritic synovia were studied. We investigated the distribution of HA by demonstrating a hyaluronic acid binding protein (HABP) histochemically, and the localization of HA producing cells was demonstrated by uridine diphosphoglucose dehydrogenase (UDPGD) activity using a technique described by Mehdizadeh (1991) . UDPGD is a key enzyme in the synthesis of proteoglycans including HA. The results were analyzed by a new quantitative technique using an image processor for analytical pathology (IPAP ; Sumitomo, Osaka) . Positive areas of HABP reaction, the number of UDPGD positive cells and the density of color developed by UDPGD activity, were measured with the IPAP system. HABP and the UDPGD activity were demonstrated by double staining.
Results : HA was highly concentrated in the superficial lining layer of synovia. The extent of HABP positive area, the number and optimal density of UDPGD positive cells, measured by IPAP, were highest in A (early) type synovia, (A>B>C>D) .When double staining was applied to synovial sections HABP positive area and UDPGD activating area overlapped.
Conclusion : Results indicate that HA distribution and UDPGD activity are affected by synovial inflammation. HA distribution and production normally decreases by inflammation.

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Objective : Lipoprotein (a) [Lp (a) ], a low density lipoprotein particle bound to apolipoprotein (a) by a disulfide bond with apo B-100, has been strongly suggested to be an independent risk factor for atherosclerotic disease. Since cardiovascular disease and cerebrovascular disease are major causes of death in patients with systemic lupus erythematosus (SLE), we analyzed serum Lp (a) concentrations and Lp (a) phenotypes in these patients.
Methods : Serum Lp (a) and other lipids were measured by a specific ELISA and the standard methods, respectively, in 58 patients with SLE, 28 patients with progressive systemic sclerosis (PSS), and 37 healthy subjects as normal controls. The Lp (a) phenotype was determined by immunoblotting analysis.
Results : SLE patients had a significantly higher mean Lp (a) concentration than PSS patients [26.0 ± 25.8 (SD) vs. 14.5 ± 10.5, p<0.05], but there was no statistical difference in the other lipids. The S 3 phenotype accounted for 52% of SLE patients and possibly had a higher frequency than in the normal population.
Conclusion : Higher serum Lp (a) levels may contribute to an increased incidence of atherosclerosis in patients with SLE.

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Few cases with myopathy related to ciclosporin (CS) have been reported. The author has, however, experienced four cases of myopathy thought to be caused by CS. Based upon these clinical experiences, CS is considered to affect the skeletal and cardiac muscles. The histological examinations of skeletal and cardiac muscles were carried out in SD-strain rats treated with CS at 25 mg/kg/day for six weeks. The results showed that myogenic changes were induced despite a relatively low CS plasma concentration. Neurogenic changes were not observed in a histological examination. In cardiac muscle, the results suggested the induction of myocarditis coupled with infiltration of inflammatory cells at a relatively high CS plasma concentration. Careful observation is necessary to monitor the occurrence of skeletal muscle damage and cardiomyopathy when treating patients with this agent.

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In order to objectively compare the efficacy and the safety of Bredinin for longterm treatment of rheumatoid arthritis, a multicenter, randomized, post-marketing surveillance study was conducted using two different daily doses of 150 and 300 mg per day. One hundred and thirty-three patients participated in this study which lasted 48 weeks or longer. Efficacy was assessed with a total of 104 cases (63 cases: 150 mg/day, 41 cases: 300 mg/day) . Safety was assessed with a total of 133 cases (77 cases: 150 mg/day, 50 cases: 300 mg/day) . The following are a summary of the study.
1. In the assessment of efficacy, there were no significant differences in the clinical parameters between the 150 and 300 mg/day patient groups.
2. The combined percentages of patients with a final grobal assessment of “improved” and better in the 150 and 300 mg groups were 33.1 % and 53.7 % respectively. The percentages of patients with a final grobal assessment of “slightly improved” and better in the 150 and 300 mg groups were 00.7 % and 80.5 % respectively. Althougt the differences were not statistically significant, the percentage of patients showing improvements was higher in the 300 mg group than in the 150 mg group.
3. The overall safety rating showed the incidence of adverse reactions in the 150 and 300 mg groups to have been 1.3 % and 7.1 %, respectively, which were not statistically different.
4. As for rheumatoid arthritis activity measures which include swollen and painful joint counts, grip strength, morning stiffness, Lansbury's activity index and ADL scores, similar degrees of improvements were observed both in the 150 and 300 mg groups. However, improvement in swollen joint count was more marked in the 300 mg group than in the 150 mg group.
5. The results of the present study indicate than mizoribine (150 or 300 mg/day) is useful drug for the long-term treatment of rheumatoid arthritis.

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