アタラシイ リウマチ チリョウホウ

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the progressive destruction of joints. Cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and IL-8 have a critical role in the pathogenesis of RA. Recently, etanercept and infliximab, which block the action of TNF-α, can reduce the disease activity of RA. They act more rapidly to decrease symptoms and slow joint damage in patients with early active RA than methotrexate. This article describes recent studies on anti-cytokine therapy in RA

Tumor suppressor genes in human lung cancer

Lung cancer is the most common cause of cancer death in Japanese males, the incidence having increased markedly in recent years. Carcinogen exposure such as to tobacco-smoke and air pollution are associated with the probability of developing lung cancer. Aquired somatic mutations play an important role in the pathogenesis of environmentally induced lung cancers. Cytogenetic and molecular analysis of lung tumors has made it possible to examine this hypothesis and to search for candidate genes that may be targeted by chronic exposure to these carcinogens. Early studies implicate several distinct chromosomal loci (3p, 9p, 13q, 17p, and others) and suggest sequential genetic events occur during the initiation and progression of lung carcinogenesis. Several suppressor genes including Rb (13q), P53 (17p), and P16 (9p) have been identified and cloned at these chromosomal loci. The identification of putative tumor suppressor gene at chromosome 3p is still under work. Understanding the interaction of P53, RB, cyclins, and protein kinase inhibitors including P16 will be essential to the development of the next generation of diagnostic and therapeutic studies for lung cancer

ATP-dependent reversible association of proteasomes with multiple protein components to form 26S complexes that degrade ubiquitinated proteins in human HL-60 cells

AbstractThe role of proteasomes in ubiquitin (Ub)-dependent protein degradation was studied by analyzing lysates of human promyelocytic leukemia HL-60 cells by glycerol density gradient centrifugation. High succinyl-Leu-Leu-Val-Tyr-4-methylcoumaryl-7-amide hydrolyzing activity was found in the 26S fraction, whereas the 20S fraction containing proteaomes had no activity. Addition of 0.05% sodium dodecylsulfate to the latter fraction, however, induced marked activity. The 26S, but not the 20S fraction catalyzed ATP-dependent degradation of [125I]lysozyme-Ub conjugate. Depletion from the lysate of ATP caused complete shift of the active 26S complex to the latent 20S form, whereas in the lysate prepared from ATP-depleted cells, ATP converted 20S proteasomes to 26S complexes. The immunoprecipitated 26S complexes were found to consist of proteasomes and 13–15 other proteins ranging in size from 35 to 110 kDa. We conclude that in the lysate, latent proteasomes undergo reversible, ATP-dependent association with multiple protein components to form 26S complexes that catalyze ATP-dependent degradation of Ub-protein conjugates

Protease-induced leukocyte chemotaxis and activation: roles in host defense and inflammation

The migration of leukocytes such as neutrophils, monocytes and lymphocytes into inflamed lesions is one of the critical events of inflammation. Although the traditional function of neutrophil-derived antimicrobial proteases is to ingest and kill bacteria, some neutrophil serine proteases have been shown to induce leukocyte migration and activation. Mast cell-derived chymase also has the chemotactic activity for leukocytes. During the acute phase of inflammatory and allergic diseases, the predominantly migrated cells are neutrophils and mast cells, respectively, and in the subsequent chronic phase, monocytes and lymphocytes are mainly migrated. The chemotactic activity for monocytes and lymphocytes of neutrophil-derived serine proteases and mast cell-derived chymase may have a role in switching acute inflammation to chronic inflammation and delayed-type hypersensitivity. Recently, aminopeptidase N and endothelin were shown to induce chemotactic migration of leukocyes. Thus, protease-induced leukocyte chemotaxis and activation may play an important role in immunologic events of inflammatory and allergic diseases

ナンジセイ コケイガン ニ タイスル ガン コウゲン ペプチドパルス ジュジョウ サイボウ オ モチイタ ガン ワクチン リョウホウ : トランスレーショナル リサーチ トシテノ テンカイ

Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs pulsed with peptides of tumor-associated antigens (TAA) have been used in cancer immunotherapy. An early clinical study demonstrated the safety of these trials, but the clinical effect was not sufficient. Most studies have used immature DCs generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Here, we conducted phase I clinical trial of active immunotherapy using mature DCs induced by a streptococcus derivatives OK-432. DCs were generated from blood monocytes by culturing with GM-CSF and IL-4 for 6 days and then GM-CSF, IL-4 and OK-432 for 2 days. Before injection, DCs were pulsed with MAGE-3 peptide (IMPKAGLLI), which is restricted for HLA-A*2402, and keyhole limpet hemocyanin (KLH) as a control antigen. We selected HLA-A*2402-positive patients who had advanced solid tumors expressing MAGE-3 mRNA. DC vaccine was administered subcutaneously every 2 weeks for a total of four vaccinations in a dose-escalation design at the dose level per cohort of 0.1 (Group 1), 0.3 (Group 2) and 1 (Group 3) ×10８DCs/injection. Immunological monitoring with delayed type hypersensitivity (DTH) reaction and MHC tetramer was performed. Three patients with advanced solid tumor (two lung cancer and one melanoma patients) were so far enrolled in Group 1 of this study. This protocol was well tolerated. A mild fever (Grade 1 to 2) and local reaction of injection site (erythema and induration : Grade 1) were found in all patients. DTH for MAGE-3 peptide became to be positive after forth vaccination in one patient. The decrease of tumor marker (CEA) was found in one patient. However, clinical responses in all three patients were not observed. These results indicated that vaccination with mature DCs (0.1×10８DCs/injection) was safe and feasible, but further analysis using the higher dose of DCs was required to assess the immunological and clinical responses

Interferon-γ activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B

The mechanism of increased chloride currents by inflammatory cytokine, interferon-gamma (IFN-γ), was investigated in cultured a human bronchial epithelial cell line (BEAS-2B) using cell-attached and inside-out patch configurations. The channel sensitive to chloride ion was activated by forskolin, an activator of adenylate cyclase, or 100μM dibutyryl 5'-cyclic monophosphate in cell-attached configurations. The conductance of this channel was 40±4 pS in symmetrical 150 mM chloride solution between membrane potentials of 0 to +50 mV, and this channel was blocked by 500μM 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), suggesting that this channel was an outwardly rectifying chloride channel (ORCC). Treatment of 10-1000 U/ml IFN-γ for 3 hours, but not IFN-α, significantly increased channel activities of ORCC, and this activation was observed at least 24 hours after treatment. Erythromycin, a macrolide antibiotic, at a concentration of100μM inhibited the activation of ORCC induced by IFN-γ. The findings of the present study indicate that increased mucus secretion during inflammation might be partly due to activation of chloride permeability by cytokine and erythromycin might improve oversecretion of mucus from bronchial epithelium by blocking ORCC