Autoantibodies against cytokines including IL-1α, IL-2, IL-6, interferons, TNF α have been recently reported by several investigators. Some of them [IL-1α, interferons (IFNs) and TNFα] are found in some normal sera. However, increased frequencies and titers of these autoantibodies have been demonstrated in certain pathological conditions. In patients with rheumatoid arthritis, the frequency of anti-IL-1α autoantibody was about 3 times (15%) more frequent than in normal subjects. Potent neutralizing activities and high affinity to IL-1α of the autoantibodies are also characteristics. Other investigators have reported the increased frequency of anti-IFNγ autoantibody in patients with recent virus infection and anti-TNF α autoantibody in patients with gram-negative bacterial infections.
The mechanism by which these anti-cytokine autoantibodies are induced rematins to be determined. Antigenic stimulation of cytokines seems to be involved as a cause of the development of these autoantibodies in certain pathological states. Though pathophysiological roles of these anti-cytokine autoantibodies are still obscure, demonstration of neutralizing activities of most of these antibodies suggest a possible regulatory role in in vivo cytokine activities.

抄録全体を表示

Granulomas are focal, predominantly mononuclear tissue inflammations evoked by persistent irritants. The lesions are classified as hypersensitivity and foreign-body granulomas. In view of the predominant participation of macrophages in granulomas such as hypersensitivity, foreign-body and tuberculous lesions, it is reasonable that macrophages and their products may be involved in granulomatous inflammation. We developed experimental murine models of hypersenstivity, foreigin-body and BCG granulomas. Presence of macrophage-derived cytokines (monokines) such as interleukin 1 (IL-1) is a common feature in granulomatous lesions. IL-1 activity is well associated with size/activity of lesions. Also, our studies have demonstrated that macrophages and monokines such as IL-1 and tumor necrosis factor-α (TNF-α) play a critical role in the development of granulomas in vivo and in vitro. To investigate modulatory mechanisms of granuloma formation, we examined the effects of various mediators such as IL-1, TNF-α, interferon-γ (IFN-γ), IL-4, IL-6, transforming growth factor-β (TGF-β), dexamethasone and prostaglandin E₂ (PGE₂) on the development of lesions. The lesions were suppressed by dexametheasone, PGE₂ or certain T cellderived lymphokines such a IL-4 and IFN-γ. These results suggest that suppressive signals are different from granulomatogenic cytokines including IL-1 and TNF-α and that granulomas are regulated by multiactor dependent mechanisms.

抄録全体を表示

Cathepsin G is one of serine proteases with chymotrypsin-like proteolytic activity and known to exist in neutrophils and spleens. We purified the protease from human bone marrow cells by extraction with 1 M potassium phosphate buffer (pH 7.0) and ap-plying to column chromatography of DEAF-cellulose, Sephadex G-100, CM-cellulose, and Mono-S. We further separated it into three isozymes by employing hydrophobic chromatography, and named them cathepsin.
Purified cathepsin G potentiated the effect of mitogens such as Con A and PHA on human lymphocytes. The protease further stimulated synthesis of both DNA and RNA of lymphocytes in the absence of mitogens. Effect of cathepsin G on the lymphocyte activity was prevented by inhibitors of cathepsin G. Therefore, the effect of it on lymphocyte activity is considered to be due to its proteolytic activity. The effect of cathepsin G on the function of lymphocytes differed among isozymes of the protease. From these results, we suppose that cathepsin G plays an important role in biophylaxis by regulating functions of lymphocytes.

抄録全体を表示

The effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on natural killer (NK) cell activity in human peripheral blood lymphocytes (PBL) was studied. The direct addition of trieicosa-pentaenoyl-glycerol (EPA-TG) or tridocosahexaenoil-glycerol (DHA-TG) emulsion to a cytotoxicity assay system significantly suppressed NK cell activity. The addition of a lipoxygenase inhibitor AA861 also inhibited NK cell activity. The inhibition was proportional to the concentraton of EPA-TG emulsion, DHA-TG emulsion or AA861. The inhibitory effect caused by these lipids or lipoxygenase blockade could not be reversed by adding back exogenous leukotrienes to the assay system. Preincubation of reflector cells with EPA-TG or DHA-TG emulsion resulted in a significant inhibition of their NK cell activity. NK cell activity of human lymphocytes was markedly decreased after the EPA-TG emulsion infusion in healthy volunteers. Thus, in vivo use of EPA-TG or DHA-TG emulsion may influence immune reactivity of the host, although the mechanism has not yet been elucidated.

抄録全体を表示

Superoxide production of human neutrophils was enhanced within 10 min by the treatment of interferon-γ, when phorbol 12-myristate 13-acetate (PMA) was used as a stimulant. The enhancement of superoxide production by interferon-γ occurred only under the presence of calcium, and that it was inhibited by 1- (5-isoquinolinesulfonyl) -2-methylpiperazine (H-7), an inhibitor of protein kinase-C and 8- (N, N-diethylamino) -octyl- (3, 4, 5-trimethoxy) benzoate hydrochloride (TMB-8), an intracellular calcium antagonist. Quin 2 (acetoxy-methylester) fluorescent revealed that intracellular calcium arose immediately after the addition of interferon-γ.
These data suggest that the enhancement of superoxide production by interferon-γ is closely related to protein kinase-C activation followed by the arising of intracellular calcium.

抄録全体を表示

It has recently been reported that anti-endothelial cell antibody is present in several diseased conditions, but their roles in the pathogenesis of the disease are largely unknown. The aim of the present review is to summarize the events following the interaction of antibodies with plasma membrane antigens of the endothelial cells in vivo with special reference to the mechanisms of the immune deposit formation.
A series of studies using antibodies to rabbit angiotensin converting enzyme (ACE) revealed that; (1) the interaction of anti-ACE antibodies with cell surface ACE induced a rapid redistribution of ACE, and the formed immune complexes were shed from the plasma membrane, (2) the fate of immune com-plexes was different according to the structure and the function of each organ, i.e., deposition of immune complexes in the adjacent basement membrane in the glomerulus, vs, disappearance of ACE and its antibodies from the lung, (3) these processes were better observed in the mature oocytes in viva.
The results obtained in these studies might have the relevance to the events occuring in human dis-eases in which organ injury is caused by antibody-mediated endothelial damage.

抄録全体を表示

To clarify the anti-inflammatory effect of eicosa-pentaenoic acid (EPA), we investigated the effect of EPA administration on A23187-stimulated LTB₄ formation by rat leukocytes. LTB₄ is known to be an important mediator of inflammation and the decreased formation of LTB₄ is thought to be one of the important mechanism of anti-inflammatory effect of EPA. EPA ethyl ester (EPA-E) administration (100 mg, 300 mg and 1, 000 mg/kg/day) for 4 weeks dose dependently suppressed the formation of LTB₄ and increase in the formation of LTB₅ with the increase in EPA content in rat leukocytes. The content of docosapentaenoic acid (DPA) also dose-dependently increased and the content of arachidonic acid (AA) and docosahexaenoic acid (DHA) were decreased by the administration of 300 mg and 1000 mg of EPA-E daily. The formation of LTB₄ in stimulated leukocytes and the content of AA are positively correlated.
FMLP-induced chemotactic activity of leukocytes were suppressed with the EPA-E treatment but FMLP stimulated β-glucuronidase release was not affected by EPA administration.
In conclusion, highly purified EPA-E administration reduced the formation of proinflammatory LTB₄, increased the LTB₅, which would competitively inhibit the action of LTB₄ and suppressed the chemotactic activity of leukocytes, these might result in the suppression of inflammatory response.

抄録全体を表示

Microcirculatory distrubances are thought to be a cruicial step for the development of hemorrhagic changes in the gastric mucosa. In recent years, the interest in the pathophysiological role of endothelin has increased considerably. Nevertheless the influence of endothelin in gastric microcirculation has not been fully demonstrated. In this study, we investigated the role of endothelin in the process of gastric microcirculatory derangement followed by the mucosal damage. The stomach of male Wistar rat (200 g) was used in this study. Endothelin-1 was injected into the SCA to give final concentrations of 50-500 pmol/kg. Endothelin-induced microvascular changes in the submucosal layer were visualized through a SIT camera. The mucosal blood flow was also monitored using a laser doppler flowmeter. Thirty minutes after the injection of endothelin-1, the stomach was opened for estimating hemorrhagic lesion and histological changes. Endothelin-1 caused a sustained microvascular constriction and subsequent decrease in mucosal blood flow. This constrictive change was enhanced in the terminal arteriole. Thirty minutes after the administration, the mucosal lesion occured in a dose-dependent manner of endothelin-1. In conclusion, the present study revealed that the constrictive change in the terminal arteriole may be important in the developement of endothelin-induced gastric mucosal damage.

抄録全体を表示

A controlled double blind study was performed for 29 healthy volunteers in order to assess the damaging action on the gastroduodenal mucosa induced by an inactive form of NSAIDs (as prodrug) in comparison with diclofenac Na (D) .
Subjects received either of the following three drug combinations; (1) prodrug: loxoprofen Na, L: pro-glumetacin maleate (PGM), placebo and D: placebo, (2) prodrug (PGM) L placebo and D: placebo, (3) D, L: placebo and PGM placebo. Endoscopic findings were evaluated before and 2 weeks after drug administration. Moreover, in order to investigate the mechanism of NSAIDs gastropathy, pH of gastric juice, mucosal blood flow, levels of prostaglandin E₂ (PGE₂) and hexosamine (H) on biopsy specimens were simultaneously measured before and after ingestion of each medication.
Gastroduodenal damages were significantly less for both prodrug group (L and PGM) compared with the D group. The enhancement of gastric acid output, decrease in mucosal blood flow and reduction of hexosamine contents were observed in D group when eompared with both prodrug group.
These findings suggest that prodrugs have a very low frequency to produce mucsosal damages, and NSAIDs gastropathy might be associated with increase of offensive factor and breakdown of defensive mechanism.

抄録全体を表示

The autologous mixed lymphocyte reaction (AMLR) which is suggested as a possible indicator of immunoregulation in inflammatory diseases, was evaluated in the patients with adult periodontitis. Thirty one of 80 patients (39%) showed significantly lower responses in AMLR (<mean-2SD of the healthy control group; low-AMLR patients) . However, there was no significant differences in the clinical parameters between low-AMLR and normal-AMLR patients. Phenotypic analysis of T cell and non-T cell fractions revealed that the percentage of CD45R (A) -positive cells in CD4-positive cells (CD4⁺CD45R⁺cells) was significantly lower in low-AMLR patients than in normal-AMLR patients, while no significant differences was found in the percentages of CD4⁺, CD8⁺ T cells, B cells and monocytes.
Interleukin-2 production in AMLR was also significantly depressed only in low-AMLR patients. Depressed AMLR responses and lower proportions of CD4⁺CD45R⁺ cells in the low-AMLR patients were recovered during conventional periodontal therapy. These results suggested that there could be a subgroup showing low AMLR responses in clinically-diagnosed“adult periodontitis”patients. It was also suggested that there could be phenotypic and functional disorders in peripheral blood T cells in these patients, which might be closely related to the depression of AMLR. In addition, depressed AMLR responses in these low-AMLR patients might reflect changes in regulatory T cell function induced by the state of periodontal diseases.

抄録全体を表示

LTB₄ in the aqueous humor of the 18 eyes with Behçet's disease examined, 10 were active and 8 were stable. The average LTB₄ concentrations in the aqueous humor for the active cases were 26.22± 8.96 pmol/ml. The average for the stable cases was 10.87 ± 4.68 pmol/ml. The difference between active and stable averages was statistically significant [P<0.05], and the stable averages were higher than those of controls. These results clearly indicate the significance of LTB₄ in ocular inflammation, and patients with Behçet's disease are likely to occur uveitis

抄録全体を表示

We examined whether or not some protease inhibitors prevent endothelial cell injury due to PMA-activated leukocytes. The effects of protease inhibitors on the cytotoxicity were determined by measuring the release of ⁵¹Cr from prelabeled cultured endothelial cells. We also examined the leukocyte produced active oxygen spPcics by measuring luminol-chenliluminescence.
Among the protease inhibitors tested, aprotinin and urinastatin decreased the endothelial cell injury in a dose dependent manner.
These data suggest that the protease inhibitors suppress priming effect of the leukocyte produced proteases on the endothelial cell injury induced by active oxygen species.

抄録全体を表示

The effect of mizoribine (MZR), an immunosuppressive agent on adjuvant arthritis in rats was investigated. The drug was administrated continuously 28 days after immunization with complete adjuvant.
Twice daily p.o doses of 5 or 10 mg/kg of MZR showed a marked inhibition of swelling in hind legs. Moreover mizoribine treatment improved the bone lesion of hind legs. In mizoribine treatment, a decrease of alkaline phosphatase and an increase of serum albumin-globulin ratio was suppressed and the change of wet weight of thymus, spleen, adrenal and liver tissues were inhibited.

抄録全体を表示