研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Induction of suppression following autologous mixed lymphocyte reaction; role of a novel 2H4 antigen

Takeuchi T., Rudd C. E., Schlossman S. F., Morimoto C.

European Journal of Immunology 17 （ 1 ） 97 - 103 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2980

In this study, we have investigated the cellular and molecular basis for immunoregulatory function of T4⁺ cells after autologous mixed lymphocyte reaction (AMLR) activation. We demonstrated that the T4⁺2H4⁺ subset but not the T4⁺2H4^- subset can proliferate maximally in response to autologous non-T cells. T4⁺ cells activated by AMLR exerted suppressor activity on pokeweed mitogen-driven IgG synthesis of autologous peripheral blood lymphocytes. The suppressor activity by AMLR-activated T4⁺ cells required the presence of fresh T8⁺ cells in the secondary culture, indicating that AMLR-activated T4⁺ cells functioned as a suppressor inducer rather than as a suppressor effector population. Following activation of T4⁺ cells in AMLR, it is the T4⁺2H4⁺ subset which induces suppression through the T8 population. Moreover, the treatment of AMLR-activated T4⁺2H4⁺ cells with anti-2H4 antibody, but not other antibodies, resulted in the abolishment of suppressor inducer function of such cells, suggesting that the 2H4 molecule itself may be involved in the suppressor induced function. The 2H4 antigen on such cells was shown to be comprised of 220-kDa and 200-kDa glycoproteins. These results support the notion that the AMLR may play an important role in generating suppressor inducer signals and in down-regulating the immune response following self major histocompatibility complex recognition. More importantly, the present studies indicate that the 2H4 antigen on T4 cells serves not only as a phenotypic marker of suppressor inducer cells, but may have a functionally important role itself in inducing suppression.

Direct demonstration of immunoregulatory T-cell defects in patients with systemic lupus erythematosus

Koide J., Takano M., Takeuchi T., Hosono O., Amano K., Homma M., Abe T.

Scandinavian Journal of Immunology 23 （ 4 ） 449 - 459 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

The present study was undertaken to determine directly whether immunoregulatory T cells have a defective suppressor function in patients with systemic lupus erythematosus (SLE), and whether anti-T-cell antibodies are essential for immunoregulatory T-cell defects. Peripheral blood T cells and T-cell subsets were determined in 52 SLE patients. The ratio of T4 to T8 cells was distributed over a wider range in patients with SLE than in the controls. Patients with SLE were divided into three groups (low, normal and high) by the T4/T8 ratio. Lymphocytes from 12 SLE patients (7 with low and 5 with high T4/T8 ratios) were studied extensively. Their disease was inactive or in remission. Anti-T-cell antibodies were not detected, and yet the patients had immunological abnormalities characterized by the presence of antinuclear antibodies and hypergammaglobulinaemia. The SLE patients with high T4/T8 ratios had a decreased number of T8 cells, and defective suppressor-effector cells. In contrast, patients with low T4/T8 ratios had decreased T4 cells and/or increased T8 cells, and defective suppressor-inducer cells. Two patients with low T4/T8 ratios had both suppressor-effector and suppressor-inducer cell defects. These results indicate that immunoregulatory circuits in SLE patients are heterogeneous and that immunoregulatory defects exist even when the disease is inactive or in remission. Anti-T-cell antibodies were not essential for such immunoregulatory defects. Thus, immunoregulatory T-cell defects and the development of SLE may be independent conditions due to other unknown causes.

DNA-daunorubicin complexes specifically suppress in vitro spontaneous anti-DNA antibody production in lymphocytes of patients with systemic lupus erythematosus

Takeuchi T., Koide J., Hosono O., Amano K., Homma M., Masuho Y., Morimoto C., Takano M., Abe T.

Arthritis and Rheumatism 29 （ 10 ） 1216 - 1222 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Elevated production of anti-DNA antibody in patients with systemic lupus erythematosus (SLE) is a central problem in the pathogenesis of tissue injury. In the present study, we attempted to manipulate anti-DNA antibody production through the antigen-cytotoxic drug conjugates, DNA-daunorubicin complexes. The effect of DNA-daunorubicin complexes was determined by examining SLE lymphocytes for spontaneous in vitro production of anti-DNA antibody. These complexes, at 2 μg/ml, suppressed anti-DNA antibody production, but not total IgG production, which suggests that specific suppression of anti-DNA antibody production was achieved at this concentration. We believe that the DNA-daunorubicin complexes affected mainly B cells, since such suppression was obtained by treating B cells, as well as B plus T cells. Furthermore, the complexes had no effect on the proliferative responses of SLE T cells to DNA, phytohemagglutinin, or concanavalin A. These results indicate that DNA-daunorubicin complexes may have the potential for selectively suppressing anti-DNA antibody production in patients with SLE.

The role of the 2H4 molecule in the generation of suppressor function in Con A-activated T cells

Morimoto C., Letvin N. L., Rudd C. E., Hagan M., Takeuchi T., Schlossman S. F.

Journal of Immunology 137 （ 10 ） 3247 - 3253 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The molecular basis for the suppression generated in a concanavalin A (Con A)-activated T cell culture remains unknown. In this study, we have attempted to determine whether the 2H4 and 4B4 molecules on Con A-activated T cells play some role in the generation of suppression by such cells. We have shown that Con A-activated suppressor cells belong to the 2H4⁺ subset of T cells but not the 4B4⁺ (2H4^-) subset. Con A-activated T cell exerted their optimal suppressor function on day 2 in culture, a time at which the expression of 2H4 on such cells was maximal and 4B4 was minimal. Furthermore, the stimulation of T cells with the higher concentration of Con A generated the stronger suppressor function. At the same time, both 2H4 expression and density were increased and 4B4 expression and density were decreased on such Con A-activated T cells. More importantly, the treatment of Con A-activated T cells with anti-2H4 antibody but not with anti-4B4, anti-TQ1, or anti-T4 antibodies can block the suppressor function of such cells. Taken together, the above results strongly suggest that the 2H4 molecule itself may be involved in the generation of suppressor function in Con A-activated T cells. The 2H4 antigen on such cells was shown to be comprised of 220,000 and 200,000 m.w. glycoproteins. Thus this study indicates that the 220,000 and 200,000 m.w. structure of the 2H4 molecule may itself play a crucial role in the generation of suppressor signals of Con A-activated cells.

Spontaneous production of antibodies to deoxyribonucleic acids in patients with systemic lupus erythematosus

Takeuchi Tsutomu

Clinical Immunology and Immunopathology 35 （ 1 ） 47 - 56 1985年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

In vitro spontaneous anti-DNA antibody production in patients with systemic lupus erythematosus (SLE) was examined. SLE lymphocytes produced IgG and IgM anti-DNA antibody from the third culture day, and reached a plateau on the seventh culture day. This anti-DNA antibody activity in 7-day culture suppernatant was abolished by pretreatment of the lymphocytes with cycloheximide, suggesting de novo immunoglobulin synthesis was required for this spontaneous anti-DNA antibody production. Lymphocytes from patients with rheumatoid arthritis (RA) and other collagen diseases including progressive systemic sclerosis, polymyositis/dermatomyositis, and polyarteritis nodosa did not produce IgG and IgM anti-DNA antibody spontaneously, but SLE lymphocytes produced substantial amounts of IgG and IgM anti-DNA antibody spontaneously. Furthermore, active SLE produced a larger amount of IgG anti-DNA antibody than inactive SLE. We observed a significant negative correlation between the number of Ia⁺ T cells and IgG, but not IgM, anti-DNA antibody production. Furthermore, spontaneous IgG anti-DNA antibody production was elevated after pretreatment of SLE T cells with anti-Ia and complement, suggesting that Ia⁺ T cells in SLE bring about suppression of autologous B cells producing IgG anti-DNA antibody. © 1985.

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Suppression of rheumatoid factor synthesis by antiidiotypic antibody in rheumatoid arthritis patients with cross-reactive idiotypes

Takeuchi T., Hosono O., Koide J., Homma M., Abe T.

Arthritis and Rheumatism 28 （ 8 ） 873 - 881 1985年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

The effect of antiidiotypic antibody on the in vitro production of rheumatoid factor was studied in rheumatoid arthritis patients with cross-reactive idiotypic determinants. Antiidiotypic antibodies (ascites IgG) were developed against monoclonal rheumatoid factor (Ka m-RF) by a cell fusion procedure. These antibodies were idiotype-specific, since: 1) they reacted only with F(ab')₂ fragment of Ka m-RF; 2) they failed to react with normal IgM without rheumatoid factor activity; and 3) their F(ab')₂ fragment inhibited the rheumatoid factor activity of Ka m-RF. The antiidiotypic antibody strongly suppressed the in vitro production of rheumatoid factor by lymphocytes from unrelated rheumatoid arthritis patients with cross-reactive idiotypes. The suppression was specific, since ascites IgG failed to suppress in vitro anti-keyhole limpet hemocyanin antibody production by the lymphocytes. These results indicate that antiidiotypic antibody may influence the regulation of rheumatoid factor production in patients with rheumatoid arthritis.

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Cellular mechanism of DNA-specific antibody synthesis by lymphocytes from systemic lupus erythematosus patients

Takeuchi T., Abe T., Koide J., Hosono O., Morimoto C., Homma M.

Arthritis and Rheumatism 27 （ 7 ） 766 - 773 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

The cellular mechanism of anti-DNA antibody synthesis in patients with systemic lupus erythematosus (SLE) was studied by DNA-specific solid-phase radioimmunoassay. Anti-DNA antibody synthesis in response to DNA was T-dependent, and the experiments with reconstituted lymphocytes from identical twins discordant for SLE showed that B cells and T cells from SLE patients must cooperate to synthesize anti-DNA antibody. Anti-DNA antibody synthesis by lymphocytes from patients with inactive SLE was enhanced by T4 cells and suppressed by T8 cells in response to DNA. Although T4 cells from patients with active SLE could enhance anti-DNA antibody synthesis by autologous B cells, their T8 cells could not suppress anti-DNA antibody synthesis by autologous B cells. These results indicate that elevated anti-DNA antibody synthesis in response to DNA in patients with active SLE is due to abnormalities of both SLE B cells and SLE T cells. They further indicate that dysfunction of T8 cells from patients with active SLE may, in part, be responsible for deficient regulation of anti-DNA antibody synthesis.

Anti-idiotypic antibodies in a patient with monoclonal rheumatoid factor after pneumococcal bacteremia

Abe T., Takeuchi T., Kiyotaki M., Koide J., Hosono O., Homma M., Otake T., Kano S.

Journal of Immunology 132 （ 5 ） 2381 - 2385 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

A 51-yr-old Japanese female patient with monoclonal IgM gammopathy with rheumatoid factor activity was admitted because of pneumococcal bacteremia. About 2 wk after admission, her rheumatoid factor activity became undetectable by RAHA test and radioimmunoassay, subsequent to the initial marked elevation. The suppressive capacity of the patient's IgG fraction on the rheumatoid activity of her monoclonal IgM on January 11 was determined. The IgG fraction obtained on February 22 blocked the binding of the rheumatoid factor to rabbit IgG. The suppressive activity in the IgG fraction of February 22 was shown to be localized within the F(ab')₂ fragment. Furthermore, the specificity of the suppressive serum factor was shown by the inability to block the binding of SRBC coupled with diazotized phosphorylcholine to anti-pneumococcal antibody. Thus, the marked reduction of rheumatoid factor activity was considered to result from anti-idiotypic antibody transiently appearing in her serum after pneumococcal bacteremia.

Suppressor T cell function in patients with rheumatoid arthritis complicated by vasculitis

Abe T., Takeuchi T., Koide J., Hosono O., Homma M., Morimoto C., Yokohari R.

Arthritis and Rheumatism 27 （ 7 ） 752 - 759 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Concanavalin A (Con A)-induced suppressor T cell activity was determined in 10 rheumatoid arthritis (RA) patients with vasculitis, 34 RA patients without vasculitis, and 10 healthy individuals. The percent Con A-induced suppression in RA patients with vasculitis was 24.6. In contrast, it was 68.4% in those RA patients without vascular lesions. Further, the proportion of T cells reactive with OKT8 monoclonal antibody was also decreased in RA patients with vasculitis. Accordingly, the reduced Con A-induced suppressor T cell activity in these RA patients resulted, in part, from the reduction in the number of cells of the suppressor T cell subset. Those patients with vascular lesions also had a higher percentage of positive antilymphocytotoxic antibodies than RA patients without vasculitis. Since the differences in Con A-induced suppressor T cell activity and frequency of positive antilymphocytotoxic antibodies were so great, we believe RA patients with vasculitis could be recognized as a disease group distinct from RA patients without vasculitis.

Functional differences of anti-T-cell antibody in patients with systemic lupus erythematosus and ulcerative colitis

Abe T., Morimoto C., Toguchi T., Kiyotaki M., Takeuchi T., Koide J., Asakura H., Tsuchiya M., Homma M.

Scandinavian Journal of Immunology 18 （ 6 ） 521 - 530 1983年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

The loss of suppressor T-cell function results in an abundant production of autoantibodies in systemic lupus erythematosus (SLE). As a cause of this suppressor T-cell defect, anti-T-cell antibody seems to be of prime importance. On the other hand, anti-T-cell antibodies can be detected in various other autoimmune diseases, but their functional characteristics have not been determined. In the present study, the functional characteristics of anti-T-cell antibody from a selected subgroup of patients with ulcerative colitis (UC) were compared with those from patients with SLE. Anti-T-cell antibody from the patients with SLE reacted with a T8 subset, resulting in a suppressor defect, whereas anti-T-cell antibody from the UC patients reacted primarily with a T4 subset. Functionally, SLE^- T cells failed to proliferate in response to concanavalin A, whereas UC^- T cells from UC patients failed to proliferate in response to phytohaemagglutinin. In the Ig synthesis system, both SLE^- and UC^- T cells increased Ig production of B cells. Since UC⁺ T cells did not contribute to the generation of Con-A-inducible suppressor activity, we believe that serum from the selected subgroup of patients with UC reacted with the inducer T-cell subset.

In vitro immune response of SLE lymphocytes. The mechanism involved in B-cell activation

Takeuchi T., Abe T., Kiyotaki M., Toguchi T., Koide J., Morimoto C., Homma M.

Scandinavian Journal of Immunology 16 （ 5 ） 369 - 377 1982年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

Peripheral blood lymphocytes from 26 patients with systemic lupus erythematosus (SLE) and six normal individuals were tested for IgG synthesis in the presence or absence of PWM. Lymphocytes from patients with active SLE synthesized increased amounts of IgG in the absence of PWM and reduced amounts of IgG in the presence of PWM. Serum from patients with active SLE had an enhancing effect on the in vitro IgG synthesis of normal lymphocytes. The IgG or F(ab')₂ fractions of SLE serum retained the enhancing effect on in vitro IgG synthesis, and the enhancing activity was absorbed by human spleen cells. As little as 4 h of incubation with SLE serum was needed for the enhancing activity of normal lymphocytes. Treatment of B lymphocytes appeared to be of main importance for an increase in the in vitro IgG synthesis of SLE serum-treated lymphocytes. These results suggest that anti-B-lymphocyte antibodies from patients with active SLE are responsible in part for the hyperactive response of SLE B lymphocytes.

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Mitogenic responses to lipopolysaccharide by B lymphocytes from patients with systemic lupus erythematosus

Abe T., Toguchi T., Takeuchi T., Kiyotaki M., Homma M.

Scandinavian Journal of Immunology 15 （ 5 ） 475 - 482 1982年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

Peripheral blood lymphocytes from 43 patients with systemic lupus erythematosus (SLE) and from age- and sex-matched normal controls were cultured with lipopolysaccharide (LPS) to examine the response to the polyclonal B-cell activator. Lymphocytes from active SLE patients incorporated 4840±471 (mean ±SE) cpm in response to LPS, whereas lymphocytes from inactive SLE patients incorporated 6906±897 cpm. In contrast, lymphocytes from normal individuals incorporated 7452±1126 cpm. Ig synthesis of lymphocytes from active SLE in response to LPS stimulation was also less than that of normal individuals. The helper T-cell function of active SLE, as examined by co-culturing irradiated SLE lymphocytes with unirradiated normal lymphocytes, was normal. These results thus suggested that a defect of B lymphocytes exists in active SLE patients. This B-cell defect and T suppressor cells apparently play an important role in the pathogenesis of SLE.

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In vitro anti-DNA antibody synthesis by peripheral blood lymphocytes in patients with systemic lupus erythematosus

Kiyotaki Masaya, Toguchi Takashi, Abe Tohru, Takeuchi Tsutomu, Morimoto Chikao, Homma Mitsuo

Clinical Immunology and Immunopathology 21 （ 2 ） 237 - 246 1981年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

In vitro anti-DNA antibody synthesis by peripheral blood lymphocytes from systemic lupus erythematosus (SLE) patients after native DNA (nDNA) stimulation was studied by the Farr assay after digestion with deoxyribonuclease I. Active SLE lymphocytes synthetized IgG and anti-DNA antibody with nDNA stimulation but inactive SLE and normal lymphocytes did not. Binding of ¹⁴C-labeled Ig and [³H]DNA showed that DNA-binding Ig was actively secreted by SLE lymphocytes. SLE antilymphocyte antibody (ALA)-sensitive T cells (SLE⁺ T cells) and unreactive T cells (SLE^- T cells) were separated by anti-human Ig antibody-coated dishes to determine their effect on antibody synthesis. Inactive SLE B cells synthetized both IgG and anti-DNA antibody after nDNA stimulation with autologous SLE^- T cells but stimulation with SLE⁺ T cells did not result in synthesis of either. Normal B cells did not synthetize IgG even with autologous SLE^- T cells. These results indicate that active and inactive SLE patients have autoreactive lymphocytes against nDNA which synthetize anti-DNA antibody and are regulated by ALA-sensitive T cells (possibly deficient in active SLE). © 1981.

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INVITRO ANTI-DNA ANTIBODY-SYNTHESIS BY PERIPHERAL-BLOOD LYMPHOCYTES IN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS

竹内勤

Clinical Immunology and Immunopathology 21 （ 2 ） 237 - 246 1981年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

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