Interleukin-6 (IL-6) is a pleiotropic cytokine which shows multiple biological functions. Pathological significance of IL-6 has been elucidated in various diseases including multiple myeloma, Castleman's disease, and rheumatoid arthrtis. Thus the blockade of IL-6 signal transduction may be therapeutically effective for these diseases. For this purpose, humanized anti-IL-6 receptor antibody was prepared, and its therapeutic efficacy has been examined. Immediately after administration of humanized anti-IL-6 receptor antibody to the patients with multiple myeloma, fever and systemic edema disappeared followed by the stability of M-protein which had been rapidly increased before the treatment. Humaniged anti-IL-6 receptor antibody also improved not only the chronic inflammatory symptoms but also laboratory findings such as hemoglobin, C-reactive protein, erythrocyte sedimentation rate observed both in Castleman's disease and in rheumatoid arthritis. The data suggest that the blockade of IL-6 signal transduction can be a new therapeutic approach based on the pathological significance of IL-6 in these diseases.

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The human genes MAGE-1 and MAGE-3 encode tumor rejection antigens recognized on melanoma cells by cytotoxic T lymphocytes (CTL). These antigens are potentially useful as targets for specific immunotherapy. Expression of MAGE genes in some malignant tumors has been reported, but MAGE gene expression in colorectal carcinomas has not been studied adequately. Therefore, we studied MAGE-1, 2, 3, and 4 a/4 b expression at the mRNA level, in 40 cases of surgery for colorectal carcinoma, using the reverse transcription polymerase chain reaction (RT-PCR). MAGE-1, 2, 3, and 4 a/4 b genes were expressed in 3 (7.5%), 6 (15.0%), 13 (32.5%), and 5 (12.5%), respectively, of these 40 cases. A total of 19 of the 40 samples (47.5%) expressed at least one of the MAGE genes. The relationships between clinicopathologic factors and MAGE gene expression were also examined. The frequency of lymph node metastasis was significantly higher in MAGE-3-positive than in MAGE-3-nagative cases (p<0.05). All the cases classified as Dukes' D expressed the MAGE-3 gene. This rate of expression was significantly higher than that for all other the Dukes' classifications together (p<0.05). Our findings suggest that MAGE-specific immunotherapy against colorectal carcinomas may be feasible.

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We investigated the association between the phenotypes of human leucocyte antigens (HLA) class I on the surface of lymphocytes and serum concentrations of soluble HLA (sHLA) in normal and Human immunodeficiency virus (HIV) infected subjects.
Serum concentrations of sHLA in normal subjects with HLA-A 24 were significantly higher than those in such subject without HLA-A 24. The similar relation was found in HIV infected subjects whose level of sHLA significantly increased compared with that of normal subjects. These results might suggest that the mechanism which causes the increase in secretion of sHLA in HIV infected subjects does not change the association between HLA phenotype and serum concentration of sHLA.

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The effect of fibronectin (FN) on IL-1 α, IL-1 β, TNF-α, and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by ELISA. FN markedly stimulated the secretion of IL-1 α, IL-1 β TNF-α, and IL-6 from cultured monocytes. Northern blot analysis revealed the up-regulated expression of mRNA specific for each monokine on exposure of monocytes to FN. GM-CSF, IFN-γ, and LPS synergistically enhanced FN-induced IL-1 α production. We further investigated the signal transduction pathways involved in FN-stimulated monokine secretion. FN-stimulated TNF-α secretion was markedly inhibited by either herbimycin A or genistein, inhibitors of protein tyrosine kinase (PTK), but was not affected by staurosporin, a inhibitor of protein kinase C (PKC). The results suggest that PTK is required for FN-stimulated TNF-α secretion. In contrast, LPS-stimulated TNF-α secretion was markedly inhibited by not only herbimycin A or genistein, but also staurosporin. Therefore, both PTK and PKC may be involved in LPS-stimulated TNF-α secretion. We also demonstrated that, in monocytes, cytoplasmic proteins of about 70 and 240 kDa were phosphorylated after FN stimulation. Our results indicate that FN may contribute to the inflammatory response of monocyte by inducing monokine production.

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Here we report an autopsy case with anti-neutrophil antibodies (ANCA) associated vasculitis accompanied by autoimmune hepatitis and hepatocellular carcinoma. A 69-year-old woman was admitted to Tokyo Metropolitan Ohtsuka Hospital in October 1995 because of leg edema. She had presented cough in 1990 and diagnosed as interstitial pneumonia, esophageal varices and liver chirrosis.
On admission, laboratory data showed mild anemia, hypoproteinemia, and marked gammagloblinemia. IgM-HA antibody, HBs antigen, HBs antibody, HCV antibody and HDV antibody were negative. Anti-nuclear antibody, anticentromere antibody, anti-neutrophill cytoplasmic antibody against myeloperoxidase and cathepsin G (MPO-ANCA and cathepsin G), rheumatoid factor and direct coombs test were positive. Serum level of AFP and CEA were elevated. Ultrasonography and computed tomography of abdomen scowed liver chirrosis and tumor in left lobe of liver. The diagnosis of liver chirrosis based on autoimmune hepatitis and Interstitial pneumonia was made with clinical course, laboratory findings and radiographic findings although liver biopsy was not performed. She complained of bloody stool due to ulcer of the large intestine, and died of liver failure which progressed rapidly. The autopsy findings detected that pulmonary fibrosis, liver fibrosis with multiple hepatocellular carcinoma, necrotizing crescentic glomerulonephritis, and vasculitis of small artery in colon.
This was the first report of MPO-ANCA associated vasuculitis complicated with autoimmune hepatitis and hepatocellular carcinoma. Clinical significance of ANCA and immunogenetic background of these diseases were discussed.

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A 40-year-old male was admitted to our hospital on August 30, 1994 to receive a new ulcerative colitis (UC) therapy, leukocytapheresis (LCAP). On the admission day, he hed bloody stool 5 to 6 times/day, abdominal pain, slight fever, and hypoproteinemia. His UC type was moderately severe left-sided colitis with pseudopolyposis. Prior to admission to our hospital, his condition had not improved for about 9 months, despite drug therapies such as salicylazosulphapyridine, intravenous high dose prednisolone, protease inhibitor, intraarterial hydrocortisone sodium succinate, 4 series of pulse therapies with metylpredonisolone, enema of corticosteroid, azathioprine (Imuran), and cyclosporine at another hospital. Thus he was introduced to our college hospital and treated by LCAP since September 1. After 10 LCAP sessions, remission was observed and the patient was discharged on December 23. Until he was later operated on for heavy bleeding after he had discontinued treatment and had drunk heavily, he had maintained remission for 13 months with LCAP only once a month even after we gradually decreased the other medical supports and stopped all of them. After LCAP, the normalization of high percentage of leukocytes presented HLADR⁺ and lymphocytes presented CD 11 a⁺ CD 8⁺ was also observed. This suggests LCAP intercepts the excess immune reaction in UC by removing leukocytes.

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We report a case of severe thrombocytopenia after cytomegalovirus mononucleosis and the changes of the platelet count in 13 cases (including documented case) with CMV mononucleosis (4 cases) or Epstein-Barr virus mononucleosis (9 cases), who were admitted to our hospital from 1991 to 1995. A decrease of the platelet count was observed in some patients at diagnosis compared to the following days, suggesting that thrombocytopenia may be induced by CMV as well as EBV, and mild thrombocytopenia may be more frequent than expected after CMV infection in immunocompetent adults, although severe thrombocytopenia is rare.

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A 69-year-old woman was admitted to Department of Orthopedic Surgery in our hospital because of lumbago on April 4, 1995. Since laboratory data showed thrombocytopenia (platelet count 2.1×10⁴/mm³) on admission, she was transferred to Department of Internal Medicine for further examination on April 11. She noticed abnormal taste and showed remarkable sicca symptoms. Schirmer test, gum test and electrogustometry were positive, and parotid sialogram findings and histology of minor salivary glands of the lip were compatible with those of typical Sjögren's syndrome. Thus, she was diagnosed as Sjögren's syndrome. Although the antibodies to SS-A/SS-B were negative in her serum, anti-nuclear and anti-centromere antibodies were strongly positive (×1280). Serum IgM level was increased. The decreased platelet count was observed when EDTA was used as anticoagulant. The binding activity of the anti-platelet antibody activated by EDTA was dependent on temperature. Its immunoglobulin class was shown to be IgM by enzymelabelled antibody method. We here report a case of Sjögren's syndrome associated with EDTA-dependent pseudothrombocytopenia.

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