Intravenous bacterial endotoxin, or endogenous pyrogen, in high concentration both caused biphasic fever in rabbits. In low concentration they produced only monophasic fever. Human recombinant interleukin 1 also caused the same pattern of febrile response, dependig on their doses administered, to those with bacterial endotoxin or endogenous pyrogen.
Subcutaneous indomethacin suppressed the first phase of fever produced by high concentraion of intravenous endotoxin or endogenous pyrogen, but not the second phase. Intracerebroventricular injection of indomethacin reduced only the second phase of fever produced by high concentration of intravenous endotoxin or endogenous pyrogen, but not the first phase. Intraventricular injection of endotoxin or endogenous pyrogen caused slow monotonic fever. This was suppressed by intraventricular, but no by subcutaneous, indomethacin.
Hence, it is concluded that the first phase of biphasic fever is caused by pyrogen acting via structures outside the blood-brain barrier and the second phase by pyrogen acting via structures within the blood-brain barrier.

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It is experimentally know that vitamin E enhances both humoral immune response and protection against micro-organism infection, but the mechanism has not been clarified. On the other hand, T-kininogen, a kinin precursor, cysteine proteinase inhibitor, and acute phase protein, is suggested to be induced by activation of macrophages. In order to clarify the action of vitamin E on the immune response, we investigated the relationship between vitamin E and T-kininogen in rat. T-kininogen level in rat serum was determined by single radial im-munodiffusion using specific antiserum against T-kininogen. Vitamin E provides a potent stimulus in vivo for the production of T-kininogen, such as seen in lipopolysaccharide (LPS) administration. Namely, T-kininogen level in rat serum, that was given intraperitoneal injection of vitamin E for six days ranging from 1.5 mg to 25 mg per day, increased from 758±218 to 3, 220±263, μg protein/ml with an increase of vitamin E level in the serum (12.9±1.1 to 38.8±6.2μg/ml) . Whereas normal and vehicle (polyethylene 60-hydrogenated castor oil) -received rats were 452 ± 77 to 483 ± 82 μg/ml of T-kininogen and 7.4±0.7 to 7.2±0.9 μg/ml of vitamin E. In addition, vitamin E enhanced induction of T-kininogen by LPS administration. From these results, the pharmacological action of vitamin E on the immune response was discussed.

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Medullasin, a serine protease found in bone marrow cells, resembles pancreatic elastase but has no elastinolytic activity. The protease exists in both erythroblasts and granulocytes. Medullasin in granulocytes plays an important role in biophylaxis. The protease activity in granulocytes elevated in patients with chronic inflammation in active phase, and decreased to normal levels in remission. Injection of a small amount of medullasin into the skin caused inflammation characterized by the infiltration of a large number of macrophages. Therefore, the protease in granulocytes is speculated to play an important role in the development of inflammation. Treatment of human lymphocytes with a small amount of medullasin caused an increment of both RNA and DNA synthesis of them, and also mitogens' effect on human lymphocytes was potentiated by medullasin treatment. Medullasin enhanced human natural killer cell activity by inducing the maturation of natural killer cells from immature large granular lymphocytes. The effect of medullasin was not mediated through the production of interferons or interleukin-2. Chemotactic activity of monocytes was inhibited, and superoxiside production of them stimulated by medullasin treatment. The protease also enhanced the cytotoxic activity of monocytes. From these results described above, medullasin in granulocytes is considered to play an important role in biophylaxis.

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Periapical granuloma is a common chronic inflammatory lesion and is considered the forerunner or initial stage of the radicular cyst. It has been well established that prostaglandins, osteoclast-activating factor and LPS are responsible for bone resorption. Few studies, however, have been done on the degradation of collagen in the bone matrix.
We extracted high collagenase activities directly from human periapical grnuloma (47.8-734.6 U/g tissue, n=18) and experimental dog granuloma (52.8-286.9 U/g tissue, n=22) with 4M urea solution. Either human and dog collagenase activities were inhibited by calf serum, EDTA, o-phenanthroline, DTT, and bovine dental pulp collagenase inhibitor. SDS-PAGE of the reaction mixtures revealed that both enzymes were typical vertebrate collagenases. They broke down collagen I selectively over collagen III, which suggests the collagenase activities were mainly derived from PMN leukocytes. These results indicate that both human and dog periapical granulomas closely resemble each other in respect to the collagenase activity. Therefore, dog granuloma seems to be a good experimental model for human granuloma.

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Platelet-activating factor (PAF) acetylhydrolase has been recognized as an enzyme to inactivate PAF. We developed the convenient method to determine human serum PAF acetylhydrolase activity, that was based on the measurement of [¹⁴C] -acetate from 1-O-alkyl-2- [¹⁴C] -acetyl-sn-glycero-3-phosphocholine on the precipitation of the complex of radioactive substrate and albumin by adding trichloro acetic acid to the incubation mixture. Thirty-two subjects with the deficiency of serum PAF acetylhydrolase were found in 816 healthy adult Japanese. The low PAF acetylhydrolase activity in the deficient serum was not due to the presence of the enzyme inhibitor. Both the sensitivity to PAF and the metabolism of PAF in platelets from subjects with PAF acetylhydrolase deficiency were almost the same as that of the normal subjects. The deficiency in serum PAF acetylhydrolase is apparently transmitted according to autosomal recessive heredity among four Japanese families.
Asthmatic children were grouped into five classes (Remission, Wheezy, Mild, Moderate and Severe groups) on the basis of symptoms according to the grade of bronchial asthma of Japanese Society of Pediatric Allergy and Clinitical Immunology. The probability of PAF acetylhydrolase deficiency in group with severe symptoms (Moderate and Severe, 5 subjects per 42) was significantly higher than that in a healthy group without a history of wheezy (one subject per 36), a group with slight symptoms (Remission and Wheezy, one subject per 100) and healthy adult Japanese (32 subjects per 816) .
These results suggest that the deficiency of serum PAF acetylhydrolase might be one of factors which lead asthmatic children to more severe state in respiratory symptoms.

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We studied the changes in serum level of α₁-acid glycoprotein (α₁AG) in patients with rheumatoid arthritis (RA), systemic lupus erythematodes (SLE), and Behçet's disease and its roles in immune system employing lymphocytes from normal peripheral blood. The level of α₁AG in serum from RA, SLE, and Behçet's disease was increased significantly when compared to normal control (RA: P<0.001; SLE, Behçet's disease: P<0.05) . The degree of α₁AG value was very correspondent to the intensity of inflammatory parameters in RA, but not in SLE. In the method of plaque forming assay, IgM and IgG production by lymphocytes stimulated by pokeweed mitogen was suppressed, and also, blastogenesis of lymphocytes stimulated by phytohemagglutinine and concanavalin A was suppressed in physiological concentration (80 mg/dl) of α₁AG. This suppressive effects by α₁AG had no relation to interleukin-2 production from lymphocytes.
These results suggested that α₁AG might play an important role in immunoregulatory system pathophysiologically for the early inflammatory process in the development of collagen diseases.

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In order to elucidate the localization of an anti-allergic agent, Tranilast, in mast cells, light and electron microscopic radioautographies (LMRAG and EMRAG) were performed. The mast cells collected from rat peritoneal cavity were incubated for 0 to 60 min in a medium containing ³H-labeled Tranilast. After incubation, they were fixed, embedded in epoxy resin and processed for LMRAG and EMRAG. In LMRAG, the radioautographic silver grains were frequently localized over and around the cytoplasmic granules and their number increased according to the prolongation of incubation time. In EMRAG, many silver grains were localized over the specific granules, especially on the perigranular membranes. From these results, it was demonstrated that Tranilast was rapidly taken into the cytoplasm of mast cells and that the specific localization of this agent on pengranular membranes and/or their adjoining structures might participate in the inhibition of degranulation of mast cells.

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The effect of cepharanthine on the metabolism of arachidonic acid from peritoneal exudate cells was examined using rats. The following results were obtained: (a) When the peritoneal exudate cells labeled with ¹⁴C-arachidonic acid were stimulated with formyl-methionine-leucine-phenylalanine in the presence of cepharanthine, the release of arachidonic acid from the cells was markedly suppressed. (b) When the peritoneal exudate cells were activated with calcium ionophore A23187 in the presence of cephar-anthine, the production of leukotriene B₄ from the cells was also suppressed. These results indicate that cepharanthine may be able to inhibit inflammation by blocking the metabolism of arachidonic acid.

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The clinical response to ciclosporin (CYA) in 8 patients with complete Behçet's disease was analyzed. The frequency of ocular attacks became fewer after the initiation of CYA treatment (10mg/kg/day), however, it increased again 80-100 weeks later with reduction of CYA dosage. Extra-ocular symptoms (oral aphthous ulcer, skin eruption and genital ulcer) had been in remission throughout the treatment period for 150 weeks. Several adverse events, such as nephrotoxicity, hypertrichosis, gingival hypertrophy or neurologic lesions were noted in the majority of the patients, which necessiated the reduction of the drug dosage. Hence, the initial dosage will be lessened below 8 mg/kg/day and great care must be exercised in close monitoring of the serious side effects of CYA.

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