Angiogenesis is well known to be deeply involved in many pathological conditions such as rheumatoid arthritis, ocular disease in diabetes mellitus and tumor growth in vivo. As a specific growth factor and permeability factor for endothelial cells, recently a new protein molecule VEGF and its receptor (Fit tyrosine kinase family) have been identified. VEGF mRNA is upregulated or overexpressed in a variey of normal or tumor cells under many conditions like hypoxia, hypoglycemia, hormones and growth factor stimulation.
On the other hand, Flt family (Flt-1 and KDR as VEGF receptors) are basically expsessed only on endothelial cells. Thus, except for a rare case, VEGF-Flt system is used through a paracrine mechanism in vivo. Regulation of this system with some chemicals, nucleic acids or polypeptides may be quite useful and important for the control of abnormal angiogenesis/hyperpermeability processes.

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Mouse mammary tumor virus (MMTV), a replication-competent B-type murine retrovirus, causes mammary adenocarcinomas in some strains of laboratory mice and it can be transmitted exogenously via milk or endogenously through the germ line. It has been established that the immune system is directly involved in the infection pathway of MMTV, because thymectomy in neonates can decrease or delay mammary tumor incidence, and both T and B cells become infected with the virus. It has been shown that exogenous and endogenous MMTV have an open reading frame (ORF) encoding superantigen in the 3' long terminal repeat, which binds to MHC class II molecules and leads to stimulation and subsequent deletion of T cells bearing particular Vβ gene products.
MMTVORF product is a type II transmembrane molecules where the COOH-terminal is extracellular and the COOH-terminal is responsible for the Vβ specificity of the superantigens. As T cell recognition of superantigens is predominantly mediated by the TCR Vβ domain, superantigen can stimulate much higher proportions of T cells than conventional peptide antigens. This characteristic of superantigens plays an important role in infection with exogenous MMTV.

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We investigated the mechanism by which the synthetic protease inhibitor, gabexate mesilate, inhibits the production of the superoxide anion by human neutrophils and its active site of gabexate mesilate. We found that gabexate mesilate suppressed lucigenin-dependent chemiluminescence in intact neutrophils activated with PMA, but its degraded analog, methylparaben and another degraded product, guanidinocaproic acid did not.
Dose-dependent suppression of SOD-inhabitable cytochrome c reduction was also detected in gabexate mesilate-treated neutrophils activated with phorbol ester. Gabexate mesilate slightly scavenged the superoxide anion in the pyrogallol assay. Gabexate mesilate also inhibited superoxide anion production in a dose-dependent manner in a cell-free oxidase-activating system. Translocation of the cytosolic respiratory burst oxidase components, the 47- and 65-kDa proteins, to membranes was suppressed by gabexate mesilate in intact cells stimulated with phorbol ester. Gabexate mesilate also reduced arachidonic acid-induced translocation of the components to the membrane fraction in the cell-free system.
These results demonstrate that gabexate mesilate suppresses superoxide anion production by inhibiting the translocation of the 47- and 65-kDa proteins to the plasma membrane and suppression of superoxide anion production requires whole molecule of gabexate mesilate.

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Production of MAPP (1-MAPP and s-MAPP) which can be recovered in CPD-stored platelets after incubation with precursor of MAPP (pre-MAPP) and stimulation in the presence of Ca²⁺ was not observed in those stimulated by any platelet activators or proteases except thrombin. The use of freeze thawed supernatant of stored platelets, instead of stored platelets, induced MAPP production after incubation with thrombin in the absence of Ca²⁺, and this reaction was inhibited by antithrombin III.
These results suggest that MAPP are produced from pre-MAPP which have been taken up into platelets in the presence of Ca²⁺ and modified to the active forms, MAPP, by the action of thrombin in the presence of some platelet factor, and released by activated platelets.

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NIF is a novel 41-kD glycoprotein from canine hookworm and potently inhibits CD 11/CD 18 dependent neutrophil adhesion in vitro, by binding to CD 11 b/CD 18. We examined the effects of NIF on neutrophil-dependent endothelial cell injury. Studies were made in bovine pulmonary microvessel endothelial monolayer and the injury was estimated as an increase of transendothelial ¹²⁵I-albumin permeability.
Layering of neutrophils onto monolayer followed by activation of neutrophils with 500 nM of phorbol 12-myristate 13-acetate (PMA) increased the permeability (by 3-4 folds over control that is monolayers) .
Pretreatment of neutrophils with NIF completely protected the increase of permeability in a dose-dependent manner at 100 nM and above. Neutrophils pretreated with monoclonal antibody (mAb) IB 4, an anti-CD 18 mAb, also prevented the increase of permeability.
In contrast, pretreatment of neutrophil with OKM-1, a control anti-CD 11b mAb, did not affect the neutrophil-dependent permeability increase.
We conclude that NIF protects the neutrophil-dependent endothelial cell injury by preventing CD 18 dependent neutrophil activation.

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Mycobacterium avium complex (MAC) constitutes one of the most important agents of nontuberculous mycobacteria. It is difficult to eradicate, because most strains of MAC are resistant to antimicrobial agents. MAC is a facultative intracellular microorganism that mainly infects and multiplies within macrophages. Host defense mechanisms against nontuberculous mycobacterial infections are poorly understood. Cellmediated immunity plays an important role in the host defense. Interleukin-12 (IL-12), a cytokine produced mainly by macrophages, is a critical component in the development of cellmediated immunity.
In the present study, by using a mouse model of disseminated M. avium infection, we have demonstrated that treatment with recombinant murine IL-12 (0.25 μg intraperitoneally/day) reduces significantly the number of viable bacteria in infected mice. IL-12 itself, however, could not inhibit mycobacterial growth in vitro.
Thus, IL-12 exerts a potent antimycobacterial activity in vivo, probably by enhancing host defense mechanisms against the infection. There were relatively few IL-12 toxicities at the dose. IL-12 may prove to be of therapeutic value by promoting cellmediated immunity to infection with MAC.

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Nitric oxide (NO) produced by the inducible NO synthase (iNOS) in the some tissue is associated with acute and chronic inflammatory process. This study is to examine that the effect of methotrexate (MTX) on the NO production from rat peritoneal macrophages by the iNOS. Macrophages from normal rats were cultured in the presence of drug followed by activation with lipopolysaccharide (LPS) . After 24 hrs, NO^-₂ as a metabolite of NO was measured by Griess reaction. MTX, bucillamine (BU), and indomethacin (IM) did not influence on the NO^-₂ accumulation with LPS. Aminoguanidine (AG), a preferential inhibitor of iNOS, and dexamethasone (DEXA) abolished NO^-₂ accumulation with LPS in concentration dependent manner.
On the other hand, adjuvant-induced arthritis (AA) was induced in rats by the injection of Mycobacterium tuberculosis into the right hind foot pad. Drugs were administered daily by the oral route from day 1 to day 21. On day 22, macrophages from AA rats had an enhanced capacity to produce NO in vitro. MTX (0.1 mg/kg), DEXA (0.5 mg/kg) and IM (1 mg/kg) reduced the paw swelling and inhibited the increased NO production by macrophages. AG (100 mg/kg) only partly inhibited the increased NO production, while BU (10 mg/kg) did not influence the paw swelling and the increased NO production.
Our data revealed that oral administration of MTX to AA rats significantly inhibited ex vivo LPS-induced NO production from peritoneal macrophages in accordance with its in vivo prophylactic effect of arthritis, suggesting that NO blockade might be one of the important mode of action for MTX in animal models of arthritis.

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In order to objectively compare the efficacy and the safety of Predinin, an immunosuppressive drug, on rheumatoid arthritis at two different dosage levels of 150 mg and 300mg, we conducted a 24-week multicenter, randomized, post-marketing surveillance study.
(1) Efficacy was assessed with a total of 499 cases (251 cases, 150mg/day group ; 248 cases, 300mg/day group) . No significant biases in the patients' background factors between the two groups were found.
(2) The final global improvement rates for the clinical evaluations of improved or better were 21.1% and 25.5/ in the 150 mg/day group and the 300mg/day group, respectively. The improvement rates for the clinical evaluations of slightly improved and better were 45.9% in the 150mg/day group and 57.5% in the 300 mg/day group. The difference were statistically significant between the 150mg/day and 300 mg/day groups (P<0.05) .
(3) Improvement in joint swelling was markedly higher in the 300mg/day group than in the 150 mg/day group. The 300 mg dose was superior to the 150mg dose in cases where a patient failed to respond to strong DMAPDs (methotre ate or salazosulfapyridine) .
(4) Safety was assessed with a total of 488 cases (252 cases ; 150mg/day group ; 230 cases ; 300mg/day group) .
(5) In the overall safety rating, the incidence of the adverse reactions in the 150mg/day group and the 300mg/day group was 15.5% and 27.1%, respectively. The difference was statistically significant (P<0.01) .
(6) The incidence and degree of the adverse reactions were dose-dependent. The type and timing of the adverse reactions were unrelated to the dose level.

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