研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan (RECONFIRM)

Yamanaka Hisashi, Tanaka Yoshiya, Sekiguchi Naoya, Inoue Eisuke, Saito Kazuyoshi, Kameda Hideto, Iikuni Noriko, Nawata Masao, Amano Kouichi, Shinozaki Mikiko, Takeuchi Tsutomu

Modern Rheumatology 17 （ 1 ） 28 - 32 2007年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

This study aims to reconfirm the clinical efficacy and related factors of infliximab therapy, the first biological agent introduced to Japanese patients with rheumatoid arthritis (RA). Data of 351 RA patients with infliximab were collected retrospectively from three major centers for management of rheumatic diseases in Japan. Infliximab was infused according to the approved method, and the clinical response was evaluated following 22 weeks of infliximab therapy in 258 patients using the European League Against Rheumatism (EULAR) response criteria. DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein) with a threshold of 4.1 or 2.7 for the high or low disease activity cut-off was also used. A total of 90.3% of patients exhibited high disease activity before infliximab therapy. After 22 weeks of infliximab therapy, the proportions of patients exhibiting high activity, moderate activity, low activity, or in clinical remission were 27.9%, 33.3%, 10.9%, or 27.9%, respectively, thereby indicating good overall efficacy of infliximab therapy. A good or moderate overall response to therapy was achieved in 84.5% of patients. Male sex, rheumatoid factor (RF) negativity, low CRP, lower swollen joint count and a low prednisolone dose were significantly related to the clinical response. Furthermore, male sex, older age, and a high tender joint count had a significant correlation with treatment discontinuation as a result of adverse reactions. In conclusion, we have reconfirmed the effectiveness of infliximab in Japanese patients with RA by using DAS28-CRP and EULAR response criteria. These data will facilitate more efficacious use of this expensive biological agent in the daily practice of rheumatology in Japan. © Japan College of Rheumatology 2007.

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Development and validation of handy rheumatoid activity score with 38 joints (HRAS38) in rheumatoid arthritis patients receiving infliximab

Kameda Hideto, Sekiguchi Naoya, Nagasawa Hayato, Amano Koichi, Takei Hirofumi, Suzuki Katsuya, Nishi Eiko, Ogawa Hiroe, Takeuchi Tsutomu

Modern Rheumatology 16 （ 6 ） 381 - 388 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

The parameters involved in the Disease Activity Score of 28 joints (DAS28) are not mutually independent, and the evaluation excludes ankle and foot joints. We developed a new quantitative and comprehensive assessment of the activity of rheumatoid arthritis (RA), called the handy rheumatoid activity score, with 38 joints (HRAS38), to overcome these disadvantages of DAS28. Forty-six RA patients who recently completed a 1-year infliximab therapy were evaluated for DAS28 (C-reactive protein; CRP) and HRAS38 at 0, 2, 6, 14, 22, 30, 38, 46, and 54 weeks. The 38-joint evaluation in HRAS38 includes 28 joints of DAS28 except for the shoulder joints, with the addition of ankle and metatarsophalangeal joints. The extent of joint swelling was rated on a scale of 0-3. The HRAS38 score is the cumulative sum of three parameters including: (1) a global assessment of disease activity [visual analog scale (VAS) 0-100-mm] by the patient, (2) swollen joint score based on a 38-joint assessment by a physician (0-114), and (3) serum concentration of CRP (mg/l). Scatter plots of HRAS38 and DAS28(CRP), and subsequent linear regression analysis demonstrated a statistically significant correlation between methodologies (r = 0.846, P < 0.0001). Infliximab treatment resulted in a statistically significant (P < 0.001) decrease in the mean HRAS38 score from 130.5 to 56.5 within 2 weeks of treatment and at 52 weeks of therapy scores were still reduced at 52.5. The mean DAS28(CRP) was also significantly (P < 0.001) reduced from a baseline value of 5.8 to 3.7 after 2 weeks treatment with a final value of 3.2 after 52 weeks of therapy. Infliximab reduced the progression of joint destruction by 85%, for terms before infliximab as determined by radiographic analyses. The degree of progression appeared to be associated with the mean HRAS38, although this observation was not shown to be statistically significant by regression analysis (r = 0.307). The HRAS38 score comprises minimal and independently acquired parameters and is an effective and comprehensive measure of disease activity in RA patients. © Japan College of Rheumatology 2006.

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Molecular abnormalities of T-cells in systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Kameda Hideto, Amano Kouichi

APLAR Journal of Rheumatology 9 （ 4 ） 365 - 371 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0219-0494

Abstract: Substantial evidence supports that T-cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). To explore the molecular basis of the defective function of SLE T-cells, we focused on the signal transduction system via T-cell antigen receptor (TCR) in peripheral blood T-cells from SLE patients. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR ζ chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR ζ chain, including spliced variants lacking exon 7 and with a short 3′-UTR, were detected in SLE T-cells. Although attenuated expression of the TCR ζ chain is also observed in patients with cancers, infections, and other autoimmune diseases, sustained attenuation of TCR ζ expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR ζ defects in SLE. © 2006 Asia Pacific League of Associations for Rheumatology.

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TCR zeta mRNA splice variant forms observed in the peripheral blood T cells from systemic lupus erythematosus patients

竹内勤

Springer Seminars In Immunopathology 28 （ 2 ） 185 - 193 2006年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0344-4325

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The efficacy and safety of infliximab in patients equal and over 65 years in the treatment of Japanese 5,000 patients with rheumatoid arthritis.

竹内勤

Arthritis and Rheumatism 54 （ 9 ） S426 - S426 2006年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Aberrant expression of BAFF in T cells of systemic lupus erythematosus, which is recapitulated by a human T cell line, Loucy

Yoshimoto Keiko, Takahashi Yasue, Ogasawara Mie, Setoyama Yumiko, Suzuki Katsuya, Tsuzaka Kensei, Abe Tohru, Takeuchi Tsutomu

International Immunology 18 （ 7 ） 1189 - 1196 2006年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

B cell-activating factor of the tumor necrosis factor (TNF) family, or BAFF, is mainly produced in monocytes and dendritic cells, and indispensable for proliferation, differentiation and survival of B cells. BAFF is a type II membrane-bound protein and the extracellular C-terminal fragment is released from the cells as soluble BAFF (sBAFF), which binds to specific receptors on B cells. Accumulating evidence suggests that BAFF plays an important role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). In this study, we developed a sensitive sandwich ELISA system to quantify the amount of sBAFF using our own mAb. Treatment of peripheral T cells of SLE patients with an anti-CD3 antibody triggered robust expression of BAFF and subsequent release of sBAFF from the cells. On the other hand, the stimulus induced only marginal elevation of sBAFF from normal T cells. These data indicate that BAFF is expressed in T cells upon stimulation at least under pathological conditions. Expression of BAFF was also largely induced in a human T cell line, Loucy (American Type Tissue Collection CRL-2629), in response to several stimuli, while other T cell lines so far examined produced the cytokine almost constitutively. These data suggest that Loucy recapitulates some of the characteristics of SLE T cells. Investigation of molecular and cellular mechanisms of production of BAFF in Loucy demonstrated that expression of BAFF was regulated through a signal transduction pathway which involves c-jun NH₂-terminal kinase and p38, and that shedding of BAFF was catalyzed by a membrane-bound protease, furin. © 2006 Oxford University Press.

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Elucidation of apoptosis induced by serum deprivation in cultured conjunctival epithelial cells

竹内勤

British Journal OF Opthalmology 90 （ 6 ） 760 - 764 2006年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0007-1161

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Imatinib mesylate inhibits proliferation of rheumatoid synovial fibroblast-like cells and phosphorylation of Gab adapter proteins activated by platelet-derived growth factor

Kameda H., Ishigami H., Suzuki M., Abe T., Takeuchi T.

Clinical and Experimental Immunology 144 （ 2 ） 335 - 341 2006年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

Receptors for platelet-derived growth factor (PDGF) are abundantly expressed on synovial fibroblast-like (SFL) cells from patients with rheumatoid arthritis (RA), and stimulation with PDGF enhances both the anchorage-dependent and -independent growth of RA-SFL cells. To elucidate the molecular mechanisms responsible for the excessive growth of RA-SFL cells and to seek a novel molecular-targeting therapy for RA, we examined the expression of adapter proteins and the effect of the specific inhibition of PDGF receptor activation by imatinib mesylate. Cultured SFL cells were used in the present study after 2-5 passages. The anchorage-dependent and -independent growth patterns of the SFL cells were evaluated using a tetrazolium-based assay and colony formation in 0.3% agar, respectively. Adapter proteins Gab1 and Gab2 were expressed in RA-SFL cells, and both proteins were rapidly (< 1 min) tyrosine-phosphorylated after the stimulation of RA-SFL cells with 10 ng/ml of PDGF and, to a lesser extent, after stimulation with 100 ng/ml of epidermal growth factor (EGF). The inhibition of PDGF receptor tyrosine kinase activation by 1 μM or less of imatinib mesylate specifically suppressed the PDGF-dependent, but not EGF-dependent, tyrosine phosphorylation of various proteins. Moreover, imatinib mesylate abolished both the anchorage-dependent and -independent proliferation of RA-SFL cells induced by PDGF stimulation. These results suggest that Gab adapter proteins are expressed and likely to be involved in the growth signalling of rheumatoid synovial cells and that imatinib mesylate, a key drug in the treatment of chronic myeloid leukaemia, may also be effective for the treatment of RA. © 2006 British Society for Immunology.

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Efficacy and safety of bucillamine, a D-penicillamine analogue, in patients with active rheumatoid arthritis

Sekiguchi Naoya, Kameda Hideto, Amano Koichi, Takeuchi Tsutomu

Modern Rheumatology 16 （ 2 ） 85 - 91 2006年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study. © Japan College of Rheumatology 2006.

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DNA microarray gene expression profile of T cells with the splice variants of TCRζ mRNA observed in systemic lupus erythematosus

Tsuzaka Kensei, Nozaki Kyoko, Kumazawa Chika, Shiraishi Kiyono, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 176 （ 2 ） 949 - 956 2006年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

We have reported that the TCRζ mRNA with alternatively spliced 3′ UTR (ζ mRNA/as-3′-untranslated region (UTR)) and ζ mRNA lacking exon 7 (ζ mRNA/exon 7-) observed in systemic lupus erythematosus patient T cells can lead to down-regulation of both ζ and TCR/CD3 complexes. To determine whether these T cells expressing decreased ζ exhibit differential transcription patterns, we transfected retrovirus vectors containing wild-type ζ cDNA, ζ cDNA/as-3′ UTR, and ζ cDNA/exon 7- into murine T cell hybridoma MA5.8 cells which lack ζ expression to construct the MA5.8 mutants WT, AS3′ UTR, and EX7-, respectively. FACS analyses demonstrated reduced cell surface expression of ζ and TCR/CD3 complexes on the AS3′ UTR mutant and the EX7- mutant in comparison to that on the WT mutant. Total RNA was collected after stimulating the MA5.8 mutants with anti-CD3 Ab. Reverse-transcribed cDNA was applied to the mouse cDNA microarray containing 8691 genes, and the results were confirmed by real-time PCR. The results showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-β2, were down-regulated in both the AS3′ UTR mutant and the EX7- mutant. Another 16 genes were up-regulated in both, and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus receptor-related 2, syndecan-1, and granzyme A. Increased protein expression of these genes was confirmed by Western blot and FACS analyses. Identification of these responsive genes in T cells in which the ζ and TCR/CD3 complexes were down-regulated may help to better understand the pathogenesis of systemic lupus erythematosus. Copyright © 2006 by The American Association of Immunologists, Inc.

A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis

竹内勤

Journal of Rheumatology 33 （ 1 ） 37 - 44 2006年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis

Kameda Hideto, Nagasawa Hayato, Ogawa Hiroe, Sekiguchi Naoya, Takei Hirofumi, Tokuhira Michihide, Amano Koichi, Takeuchi Tsutomu

Journal of Rheumatology 32 （ 9 ） 1719 - 1726 2005年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. Acute/subacute interstitial pneumonia (A/SIP) in patients with polymyositis/dermatomyositis (PM/DM) is frequently fatal within months despite high dose prednisolone (PSL) therapy. Our objective was to improve the survival rate of patients with A/SIP associated with PM/DM; and to characterize patients with PM/DM who are at high risk of developing A/SIP. Methods. We conducted a pilot trial of combined immunosuppressive therapy with high dose PSL, 10-30 mg/kg of intravenous pulse cyclophosphamide (IVCYC) every 3-4 weeks, and 2-4 mg/kg/day of cyclosporin A (CSA) for patients with A/SIP. A/SIP was diagnosed based on a history of rapidly worsening respiratory symptoms, progressive radiological findings or hypoxemia, and compatible findings in high resolution computed tomography images. Results. Before December 2000, 12 patients with DM among 83 PM/DM patients developed A/SIP, and 9 patients died despite treatment using high dose PSL with or without a choice of CSA, cyclophosphamide, or azathioprine. Thereafter, 10 patients with DM among 27 PM/DM patients developed A/SIP, and they were given combination therapy with PSL, CSA, and IVCYC. Five patients survived and are doing well for more than 2 years, although the remaining 5 patients died of respiratory failure within 3 months. DM patients with A/SIP showed the following characteristic features: mild myositis, palmar papule, fever, and negative or low titer of antinuclear antibody. Conclusion. Immediate institution of intensified immunosuppressive therapy should be considered for patients with A/SIP complicating DM. However, even early recognition of A/SIP and immediate commencement of a regimen including CSA and IVCYC in addition to high dose PSL may not be sufficient for some of those patients.

Critical role of the fifth domain of E-cadherin for heterophilic adhesion with α_Eβ₇, but not for homophilic adhesion

Shiraishi Kiyono, Tsuzaka Kensei, Yoshimoto Keiko, Kumazawa Chika, Nozaki Kyoko, Abe Tohru, Tsubota Kazuo, Takeuchi Tsutomu

Journal of Immunology 175 （ 2 ） 1014 - 1021 2005年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The integrin α_Eβ₇ is expressed on intestinal intraepithelial T lymphocytes and CD8⁺ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between α_Eβ₇
⁺ T and epithelial cells is mediated by the adhesive interaction of α_Eβ₇ and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and α_Eβ ₇, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When α_Eβ₇
⁺ K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of α_Eβ₇
⁺ K562 cells. In contrast, the binding of α_Eβ₇
⁺ K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with α_Eβ₇
⁺ K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with α_Eβ₇, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to α_Eβ₇ and may be a potential target for treatments altering the adhesion of α_Eβ₇ ⁺ T cells to epithelial cells in inflammatory epithelial diseases. Copyright © 2005 by The American Association of Immunologists, Inc.

A splice variant of the TCR ζ mRNA lacking exon 7 leads to the down-regulation of TCR ζ, the TCR/CD3 complex, and IL-2 production in systemic lupus erythematosus T cells

Tsuzaka Kensei, Setoyama Yumiko, Yoshimoto Keiko, Shiraishi Kiyono, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 174 （ 6 ） 3518 - 3525 2005年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The reduction or absence of TCR ζ-chain (ζ) expression in patients with systemic lupus erythematosus (SLE) is thought to be a factor in the pathogenesis of SLE. We previously reported a splice variant of ζ mRNA that lacks the 36-bp exon 7 (ζ mRNA/exon 7(-)) and is accompanied by the down-regulation of ζ protein in T cells from SLE patients. In this study, we show that EX7-mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζ mRNA/exon 7(-)) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab, compared with that in wild-type (WT) mutants (MA5.8 cells transfected with the WT ζ mRNA). Furthermore, real-time PCR analyses demonstrated that ζ mRNA/exon 7(-) in EX7- mutants was easily degraded compared with ζ mRNA by the WT mutants. Pulse-chase experiment showed ζ protein produced by this EX7- mutants was more rapidly decreased compared with the WT mutants. Thus, the lower stability of ζ mRNA/exon 7(-) might also be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells. Copyright © 2005 by The American Association of Immunologists, Inc.

Official Japanese guidelines for the use of infliximab for rheumatoid arthritis

Miyasaka Nobuyuki, Takeuchi Tsutomu, Eguchi Katsumi

Modern Rheumatology 15 （ 1 ） 4 - 8 2005年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Differences in ethnic backgrounds as well as in medical and socioeconomic status often affect both the efficacy and adverse effects of medications. Recent data suggest an increased risk of opportunistic infections, especially tuberculosis (TB), among rheumatoid arthritis (RA) patients receiving infliximab, a chimeric monoclonal anti-tumor necrosis factor α (TNF-α) antibody. In this regard, the annual incidence of TB is approximately five times higher in Japan than in the United States. Furthermore, since Bacillus Calmette-Guérin vaccination is mandatory in childhood when the skin test for purified protein derivative (PPD) is negative, a high incidence of false-positive PPD skin tests is observed among the Japanese population. In addition, the upper limit of methotrexate dosage to be used for RA is lower in Japan. We have therefore established official guidelines for the proper use of infliximab in Japanese RA patients. In this review, an algorithm for the diagnosis and management of TB in RA is presented in an evidenced-based form. © Japan College of Rheumatology and Springer-Verlag Tokyo 2005.

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Factors predicting the response to low-dose methotrexate therapy in patients with rheumatoid arthritis

Kameda Hideto, Amano Koichi, Sekiguchi Naoya, Takei Hirofumi, Ogawa Hiroe, Nagasawa Hayato, Takeuchi Tsutomu

Modern Rheumatology 14 （ 6 ） 442 - 446 2004年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) throughout the world. In Japan, MTX is recommended by the Japanese Ministry of Health, Labour, and Welfare to be given as the second or third DMARD and at a dosage of no more than 8 mg/week. We analyzed the efficacy of MTX in Japanese patients with RA in order to determine whether it is comparable to that in Western countries, where 15-20 mg/week of MTX is used, as well as to elucidate the factors associated with the favorable response to MTX. Around 8 mg/week of MTX was effective in half of the RA patients in the current study, and male sex was the only factor associated with a good response to MTX from a multivariate regression model analysis. Some of the patients who had a poor response to MTX showed an improvement with the addition of bucillamine or prednisolone. For the remaining patients, an increase in the MTX dosage to more than 8 mg/week or the use of biologics such as the anti-tumor necrosis factor (TNF)-α monoclonal antibody may be required. © Japan College of Rheumatology and Springer-Verlag Tokyo 2004.

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Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy

Mori Takehiko, Kameda Hideto, Ogawa Hiroe, Iizuka Atsushi, Sekiguchi Naoya, Takei Hirofumi, Nagasawa Hayato, Tokuhira Michihide, Tanaka Toshio, Saito Yumiko, Amano Koichi, Abe Toru, Takeuchi Tsutomu

Journal of Rheumatology 31 （ 7 ） 1349 - 1351 2004年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To evaluate the incidence and effect of cytomegalovirus (CMV) reactivation in patients with inflammatory connective tissue diseases (CTD) undergoing immunosuppressive therapy. Methods. A total of 18 consecutive CMV seropositive patients undergoing immunosuppressive therapy for inflammatory CTD were enrolled. CMV reactivation was determined by detection of CMV-DNA in peripheral blood leukocytes (PBL) or plasma using quantitative real-time polymerase chain reaction. Results. CMV reactivation was detected in PBL in 7 of 17 evaluable patients (41%), and in plasma in 5 of 17 patients (29%). Patients with detectable CMV-DNA in plasma were exclusively positive for CMV-DNA in PBL. Conclusion. Patients with inflammatory CTD under immunosuppressive therapy are at high risk for CMV reactivation. The clinical significance of such an event and indications for antiviral therapy should be examined further.

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody

Nishimoto Norihiro, Yoshizaki Kazuyuki, Miyasaka Nobuyuki, Yamamoto Kazuhiko, Kawai Shinichi, Takeuchi Tsutomu, Hashimoto Jun, Azuma Junichi, Kishimoto Tadamitsu

Arthritis and Rheumatism 50 （ 6 ） 1761 - 1769 2004年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. Methods. In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. Results. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. Conclusion. Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

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TCRζ mRNA with an alternatively spliced 3′-untranslated region detected in systemic lupus erythematosus patients leads to the down-regulation of TCRζ and TCR/CD3 complex

Tsuzaka Kensei, Fukuhara Izumi, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 171 （ 5 ） 2496 - 2503 2003年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The reduction or absence of TCR ζ-chain (ζ) expression in systemic lupus erythematosus (SLE) patients is thought to be related to the pathogenesis of SLE. Recently, we reported the predominant expression of ζ mRNA containing an alternatively spliced 3′-untranslated region (3′UTR; ζmRNA/as-3′UTR) and a reduction in the expression of ζ mRNA containing the wild-type 3′UTR (ζmRNA/w-3′UTR) in T cells from SLE patients. Here we show that AS3′UTR mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζmRNA/as-3′UTR) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab compared with that in wild-type 3′UTR mutants (MA5.8 cells transfected with ζmRNA/w-3′UTR). Furthermore, the real-time PCR analyses demonstrated that the half-life of ζmRNA/as-3′UTR in AS3′UTR mutants (3 h) was much shorter than that of ζmRNA/w-3′UTR in wild-type 3′UTR mutants (15 h). Thus, the lower stability of ζmRNA/as-3′UTR, which is predominant in SLE T cells, may be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells.

Abnormal protein profiles in tears with dry eye syndrome

Ohashi Yoshiki, Ishida Reiko, Kojima Takashi, Goto Eiki, Matsumoto Yukihiro, Watanabe Katsuhiko, Ishida Naruhiro, Nakata Katsuhiko, Takeuchi Tsutomu, Tsubota Kazuo

American Journal of Ophthalmology 136 （ 2 ） 291 - 299 2003年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-9394

PURPOSE: To verify the hypothesis that protein concentrations, such as lactoferrin, epidermal growth factor (EGF), and aquaporin 5 (AQP5), in tears are abnormal in patients with dry eye. DESIGN: Prospective case-control study. METHODS: One hundred three dry eye patients were divided into three groups: dry eye not associated with the Sjögren syndrome (non-SS; n = 71), Sjögren syndrome (SS; n = 23), and Stevens-Johnson syndrome (SJS; n = 9). Sixteen normal control subjects were also checked. The concentrations of lactoerrin, EGF, and AQP5 were measured by enzyme-linked immunosorbent assay. RESULTS: The concentration of lactoferrin was significantly decreased in tears of non-SS (P = .0001), SS (P = .00005), and SJS (P = .0006) patients compared with control subjects. The concentration of EGF was significantly decreased in non-SS (P = .0005), SS (P = .00002), and SJS (P = .0001) patients compared with control subjects. The concentration of AQP5 was significantly increased in tears of only SS patients (P = .01) compared with control subjects and increased in tears of only SS patients compared with non-SS patients (P = .007). CONCLUSIONS: The decrease in both lactoferrin and EGF was found not only in SS patients but also in non-SS patients, indicating that tear components in dry eyes differ in their quantity and quality. Quantification of AQP5 increased only in SS patients, suggesting that AQP5 protein leaks into the tears when acinar cells of the lacrimal gland are damaged by lymphocytic infiltration. © 2003 by Elsevier Inc. All rights reserved.

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