Rheumatoid arthritis (RA) is a chronic destructive inflammatory disease. Although key inducing agent (s) for RA have not been indentified, many investigators believe that delayed type hypersensitivity driven by T cells reactive to joint components is critically involved in this disease. Therefore, monoclonal antibodies (MAbs) directed against T cells may have a beneficial effect on RA. Indeed, a number of recent studies have shown that experimental arthritis including adjuvant arthritis and collagen-induced arthritis which resemble RA in certain clinical and histological aspects can be suppressed by treatment with anti-T cell MAbs. More recently, treatment with anti-T cell MAbs also have been shown to improve at least some cases of RA. Thus, anti-T cell MAb therapy for RA appears to be promising.

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Substance P causes granulocyte infiltration in mouse skin, which is mediated through mast cell degranulation. However, it is not yet known which mediator is responsible for this granulocyte infiltration and whether the direct effect of substance P on vascular endothelial cells is involved in this response. The subcutaneous administration of substance P (10^-7-10^-5 M) caused granulocyte (neutrophil and eosinophil) infiltration in the skin of BALB/c mice 6 h after the injection. SP_1-9 (10^-5-10^-4 M) also caused granulocyte infiltration of mouse skin which was associated with mast cell degranulation. In contrast, SP_6-11 (10^-7-10^-4 M), which was found to increase the vascular permeability of endothelial cells in mouse skin, induced no significant granulocyte infiltration nor mast cell degranulation. However, SP_6-11 (10^-5-10^-4 M) enhanced SP_1-9-induced granulocyte infiltration in the skin without any significant increase in mast cell degranulation.
We also found that pretreatment with a leukotriene B₄ (LTB₄) antagonist decreased substance P-induced granulocyte infiltration in mouse skin at 6 h to the same extent that an inhibitor of mast cell degranulation disodium cromoglycate decreased the response. However, an antagonist for platelet activating factor had no effect on substance P-induced granulocyte infiltration.
We conclude that LTB₄ is a major mast cell-derived chemotactic mediator for initiating substance P-induced granulocyte infiltration in mouse skin and that the activation of vascular endothelial cells is also involved in this granulocyte infiltration.

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We investigated parameters of acute lung injury and white blood cell kinetics following intravenous injection of 2 mg/kg endotoxin (ETX) in guinea pigs.
We sacrificed the animals at 1, 2, 4, and 6 hours after ETX administration (1 hour group, 2 hour group, 4 hour group and 6 hour group, respectively) . We also had control group which was sacrificed at time 0 without ETX injection. ¹²⁵I-albumin lung tissue to plasma ratio (T/P), ¹²⁵I-albumin broncho-alveolar lavage (BAL) fluid to plasma ratio (B/P) and lung wet-dry weight ratio (W/D) were estimated to assess capillary endothelial permeability, alveolar septal permeability and pulmonary edema, respectively. T/P was increased in 1, 2 and 4 hour groups as compared with the control group. B/P did not increase in any of the EXT-treated groups as com-pared with the control group, whereas W/D increased in 1, 4 and 6 hour groups. Peripheral white blood cells decreased in every ETX-treated group. Cell count in BAL fluid increased only in 6 hour group as compared with the control group.

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We evaluated whether or not eosinophil infiltration induced by an antigen (ovalbumin) inhalation caused the damage of the bronchial epithelium. The inhibitory effects of the anti-allergic drug, Ibudilast (Ibd), on eosinophil infiltration, eosinophil activation and epithelial tissue damage were also examined. Fourteen days pretreatment of Ibd inhibited eosinophil infiltration in the epithelial and subepithelial tissue 6, 24 hours after an antigen inhalation. A significant correlation was noted between change of the electron densities of the eosinophil specific granules and the damage of tracheal epithelium 6 hours after an antigen inhalation. Changes of the electron densities of the eosinophil specific granules suggest the activation of the cells.
The observation in this study shows that infiltrated eosinophils were activated and contributed to the damage of the bronchial epithelium by releasing toxic granules proteins and may explain the mechanism that Ibd exerts bronchial hypersensitivity.

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It has been shown that immunomodulators are effective as a remittive agent in the treatment of rheumatoid arthritis (RA) . But their modes of action are not fully understood yet although they are significantly different from the effects of the non-steroidal anti-inflammatory drugs. Most of the im-munomodulators have been shown to have in vitro and in vivo effects on the immune system which are probably related to their therapeutic effectiveness.
In the present study, we investigated in vitro effects of immunomodulators, bucillamine (Bc), auranofin (AF), salazosulfapyridine (SASP), on the production and secretion of monoclonal IgM rheumatoid factor (RF) by human-mouse hetero hybridoma (YES8c) .
Each drug exerted inhibitory effects on expression of messenger RNA, production and secretion of RF protein. These results suggest that Bc, AF and SASP have immunomodulatory characteristics which may be related to their direct inhibitory effects on B lymphocytes in vivo.

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A single injection of monocrotaline (MCT) in rats, 60 mg/kg, could consistantly cause interstitial pneumonia 3-4 weeks after the injection. A preventive effect of cyclophosphamide, injected 4 times at 20 mg/kg each, on the rat pneumonia was studied in counting the 5-bromodeoxyuridine (BrdU) positive cells in the lung and measuring IL-1 and TNF levels in the culture supernatants of the bronchoalveolar lavage fluid (BALF) cells in the rats.
The CPA pulse therapy suppressed significantly the proliferation of BrdU positive cells in the lung and the levels of IL-1 (P<0.001) and TNF (P<0.001) in the cultured BALF cells. It was suggested that macrophage and their products, IL-1 and TNF, would participate to the MCT-induced interstitial pneumonia of the rats and CPA could suppress the function of the macrophage.

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The superoxide anion (O^-₂) release from circulating neutrophils (c-PMN) in interstitial lung diseases, idiopathic interstitial pneumonitis (IIP), sarcoidosis (SA) and rheumatic pneumonitis (RA) was studied. At the same time, we demonstrated that the mechanism of acceleration of phorbol myristate acetate (PMA) -induced O^-₂ release in c-PMN by using animal model of bleomycin (BLM) -induced lung injury and pulmonary fibrosis. (1) Spontaneous O^-₂ release was not differ from healthy volunteer group and TIP, RA, SA groups. (2) Time course of PMA-induced O^-₂ release from c-PMN in TIP was increased significantly compared with that of healthy volunteer, RA and SA groups. (3) f-MLP-induced O^-₂ release of c-PMN in TIP group was lower than that of healthy volunteer group. (4) On the stage of acute inflammation induced by intratracheal injection of BLM to guinea pigs, f-MLP and alpha-TNF-induced O^-₂ release from c-PMN in BLM group were increased significantly, but not in spontaneous and PMA stimulation. (5) On the progress stage of BLM-induced fibrosis, various stimulants-induced and spontaneous O^-₂ release were not differ from saline injected group and BLM group.
These results suggested that c-PMN in IIP patients may affect in pathogenesis of interstitial pulmonary fibrosis which was under the stable stage. And this accelerated PMA-dependent O^-₂ release could be induced by the change of intracellular signal pathways which transmitted from protein kinase C stimulation to NADPH oxidase activation.

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Anti-rheumatic effects of UFT, in which tegafur and uracil were mixed at the molar ratio of 1 to 4, were studied experimentally and clinically.
Ratio of 5-FU concentrations in plasma, inoculated foot and non-inoculated of adjuvant arthritic rat after administration of UFT were examined in comparison with those of tegafur (FT) . Concentrations of FT in plasma, inoculated foot or non-inoculated foot after oral administration of FT or UFT (15 mg/kg) were nearly equal, whereas 5-FU levels on plasma, inoculated foot and non-inoculated foot after UFT administration were significantly higher than those of FT.
Clinical trial of UFT was carried out in 6 RA patients and the clinical response was evaluated according to the Lansbury index and other inflammatory parameters. The dose of UFT was 300 mg/ day.
Clinical response was observed in all 6 cases consisted of 2 marked improvement, 2 moderate improvement and 2 slightly improvement. Lansbury index and ADL showed a significant improvement as com-pared with pretreatment and UFT decreased the titer of RAHA and level of IgM.
The present study suggests that UFT may be useful in the treatment of RA.

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Thirty-eight patients with rheumatoid arthritis (RA) were evaluated by retrospective study, in which the effect of methotrexate (MTX) and bucillamine (Buc) on radiologic progression were analyzed. Nineteen patients were treated by MTX with a dosage of 2.5-7.5 mg once a week (MTX group) . Another 19 patients were treated by Buc with a daily use of 100-300 mg (Buc group) . All these selected patients were administrated MTX or Buc over 6 months without serious side effects. Patients who had side effects were excluded from this study. The term of medication with MTX was 12.5±3. 8 months (mean ± SD), and that of Buc was 14.0±3.1 months. There was no significant difference in the clinical background between two groups.
Radiologic progression was evaluated by erosion score; [post-pre], erosion index; [ (post-pre) /month], and erosion rate; [ (post-pre) /pre] . Erosion index of Buc group (0.16±0.2) was significantly less than that of MTX group (0.27 ± 0.3) (P<0.05) . Although erosion score and erosion rate of Buc group were lower than those of MTX group, they did not reach the statistical significance. Laboratory findings were also improved after Buc treatment.
Our data suggest that Buc was more effective than MTX on retardation of radiologic progression in RA.

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TA-383 inhibited significantly IL-1 production by peripheral blood mononuclear cells and monocytes from healthy volunteers. The inhibitory effect of TA-383 was recognized more distinctly in monocytes as compared to mononuclear cells. The inhibitory effect of TA-383 on IL-1 production by monocytes from rheumatoid arthritis (RA) patients was comfirmed by both lymphocyte activating factor assay and ELISA. The proliferation of synovial cells from RA patients was suppressed by TA-383.
These results suggest that TA-383 is expected to be useful as DMARD.

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Effects of TA-383 on the proliferation and cytokine production of rheumatoid synovium were studied. TA-383 suppressed the proliferation of synoviocytes. Moreover, TA-383 significantly suppressed the production of IL-1 and IL-6 from synovial cells in 2 cases.
These findings may suggest that TA-383 belongs to a new type of cytokine suppressive anti-rheumatic drug.

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The simple extraction technique of urinary IL-6 was developed, so urinary IL-6 levels can be measured by enzyme linked immunosorbent assay (ELISA) method without the influences of non-specific reactions and/or inhibitors. The urinary IL-6 levels in active stage of MesPGN cases were higher than those of remission stage of MesPGN cases, healthy cases and other glomerular disease cases. And in remission stage of MesPGN cases, urinary IL-6 levels were same level as in healthy cases.
These data suggest that measurement of levels of urinary IL-6 is helpful for the diagnosis and evaluation of clinical activities of MesPGN.

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