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Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.

  • therapeutic targeting of the interleukin 6 receptor
    Annual Review of Pharmacology and Toxicology, 2012
    Co-Authors: Toshio Tanaka, Masashi Narazaki, Tadamitsu Kishimoto
    Abstract:

    Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized Anti-IL-6 receptor antibody (Anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of Anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases. In murine models of autoimmune diseases, Anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that Anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.

  • Immunobiology of IL-6 — Tocilizumab (humanised Anti-IL-6 receptor antibody) for the treatment of rheumatoid arthritis
    New Therapeutic Targets in Rheumatoid Arthritis, 2009
    Co-Authors: Yoshiyuki Ohsugi, Tadamitsu Kishimoto
    Abstract:

    The cloning of IL-6 cDNA in 1986 revealed that IL-6 is a multifunctional cytokine that plays important roles in the immunopathogenesis of rheumatoid arthritis (RA). A close relationship was observed between IL-6 levels in the synovial compartment and disease activity in RA patients, and overproduction of IL-6 could readily explain the abnormal laboratory findings and clinical symptoms seen in these patients. IL-6 therefore appeared to be a worthwhile and attractive therapeutic target for RA. In practice, blockage of IL-6 signalling by a humanised Anti-IL-6 receptor antibody [tocilizumab (TCZ); also known as MRA] has been found to be very effective in the treatment of patients with RA. In recent Japanese Phase III clinical studies in RA patients, TCZ clearly prevented radiographic progression of joint destruction and greatly improved signs and symptoms. Very interestingly and importantly, this therapy has also proved quite effective at improving fever, fatigue and anaemia. No serious adverse events have been reported. At present, several international clinical studies of TCZ are ongoing in more than 4000 patients with active RA in 41 countries. The results are continuing to confirm the efficacy and safety of TCZ in the treatment of patients with RA.

  • Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody.
    Annals of nuclear medicine, 2005
    Co-Authors: Kanji Sugimoto, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tsunehiko Nishimura
    Abstract:

    Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities.In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of Anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling Anti-IL-6-receptor antibodies and to investigate the feasibility of using radi-olabeled Anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydorazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled Anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized Anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.

  • anti interleukin 6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis
    Arthritis & Rheumatism, 2003
    Co-Authors: Hideko Nakahara, Tadamitsu Kishimoto, Kazuyuki Yoshizaki, Jian Song, Masamichi Sugimoto, Keisuke Hagihara, Norihiro Nishimoto
    Abstract:

    OBJECTIVE: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized Anti-IL-6 receptor monoclonal antibody (Anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of Anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS: Serum VEGF levels in RA patients before Anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with Anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, Anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.

  • blockage of interleukin 6 receptor ameliorates joint disease in murine collagen induced arthritis
    Arthritis & Rheumatism, 1998
    Co-Authors: Nobuhiro Takagi, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Masahiko Mihara, Yoichiro Moriya, Yasuhisa Takeda, Yoshiyuki Ohsugi
    Abstract:

    Objective To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). Methods CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (Anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. Results In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. Conclusion IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and Anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

Kazuyuki Yoshizaki - One of the best experts on this subject based on the ideXlab platform.

  • The Role of Interleukin-6 in Castleman Disease
    Hematology-oncology Clinics of North America, 2018
    Co-Authors: Kazuyuki Yoshizaki, Shinichi Murayama, Tomohiro Koga
    Abstract:

    Since its discovery, improvements in treating Castleman disease and its variants have centered on interleukin-6 (IL-6). IL-6 was discovered from T-cell factors (BCDF or BSF-2), which induced B-cell maturation. Most symptoms of the plasma cell variant of Castleman disease are linked to the hyperfunction of IL-6, constitutively produced in the affected lymph nodes (1989), suggesting IL-6 is key in the pathogenesis of multicentric Castleman disease (MCD). The results of several studies have shown that most MCD symptoms and abnormal laboratory results are improved by Anti-IL-6 MCD treatments, such as tocilizumab, a humanized Anti-IL-6 receptor antibody, and siltuximab, an Anti-IL-6 antibody.

  • Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody.
    Annals of nuclear medicine, 2005
    Co-Authors: Kanji Sugimoto, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tsunehiko Nishimura
    Abstract:

    Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities.In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of Anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling Anti-IL-6-receptor antibodies and to investigate the feasibility of using radi-olabeled Anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydorazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled Anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized Anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.

  • anti interleukin 6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis
    Arthritis & Rheumatism, 2003
    Co-Authors: Hideko Nakahara, Tadamitsu Kishimoto, Kazuyuki Yoshizaki, Jian Song, Masamichi Sugimoto, Keisuke Hagihara, Norihiro Nishimoto
    Abstract:

    OBJECTIVE: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized Anti-IL-6 receptor monoclonal antibody (Anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of Anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS: Serum VEGF levels in RA patients before Anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with Anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, Anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.

  • blockage of interleukin 6 receptor ameliorates joint disease in murine collagen induced arthritis
    Arthritis & Rheumatism, 1998
    Co-Authors: Nobuhiro Takagi, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Masahiko Mihara, Yoichiro Moriya, Yasuhisa Takeda, Yoshiyuki Ohsugi
    Abstract:

    Objective To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). Methods CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (Anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. Results In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. Conclusion IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and Anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

  • therapy of rheumatoid arthritis by blocking il 6 signal transduction with a humanized anti il 6 receptor antibody
    Springer Seminars in Immunopathology, 1998
    Co-Authors: Kazuyuki Yoshizaki, Norihiro Nishimoto, Masahiro Mihara, Tadamitsu Kishimoto
    Abstract:

    The pathogenesis of autoimmune disease comprises several stages; (1) sensitization phase, (2) autoimmune phase, (3) chronic inflammatory phase, and (4) organ destruction phase as shown in Fig. 1. The etiology of rheumatoid arthritis (RA) is still unclear, but probably involves two factors, the major histocompatibility antigens (MHC) as intrinsic factors, and extrinsic factors, possibly antigens of bacteria, viruses or other micro-organisms. Specific T cells activated with antigen/MHC complex on the antigenpresenting cells may cross-react with autoantigens. From the pathological point of view, chronic inflammation is observed in the affected tissues in which immunocompetent cells proliferate, differentiate and produce chemical mediators (cytokines and immunoglobulins) [51 ]. Therapeutic methods aimed at blocking each of these steps are being developed. Practically, blocking cytokine function in the chronic inflammatory phase is one of the most acceptable methods, because it is now known that de-regulated cytokine production plays a major role in the pathogenesis of chronic inflammatory autoimmune diseases. Interleukin-6 (IL-6) is one of the principal inflammatory cytokines. In this review, the role of IL-6 in the pathogenesis of RA is discussed, and new therapy blocking IL-6 signal transduction with humanized Anti-IL-6 receptor antibody is introduced.

Norihiro Nishimoto - One of the best experts on this subject based on the ideXlab platform.

  • Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody.
    Annals of nuclear medicine, 2005
    Co-Authors: Kanji Sugimoto, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tsunehiko Nishimura
    Abstract:

    Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities.In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of Anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling Anti-IL-6-receptor antibodies and to investigate the feasibility of using radi-olabeled Anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydorazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled Anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized Anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.

  • anti interleukin 6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis
    Arthritis & Rheumatism, 2003
    Co-Authors: Hideko Nakahara, Tadamitsu Kishimoto, Kazuyuki Yoshizaki, Jian Song, Masamichi Sugimoto, Keisuke Hagihara, Norihiro Nishimoto
    Abstract:

    OBJECTIVE: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized Anti-IL-6 receptor monoclonal antibody (Anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of Anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS: Serum VEGF levels in RA patients before Anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with Anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, Anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.

  • blockage of interleukin 6 receptor ameliorates joint disease in murine collagen induced arthritis
    Arthritis & Rheumatism, 1998
    Co-Authors: Nobuhiro Takagi, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Masahiko Mihara, Yoichiro Moriya, Yasuhisa Takeda, Yoshiyuki Ohsugi
    Abstract:

    Objective To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). Methods CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (Anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. Results In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. Conclusion IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and Anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

  • therapy of rheumatoid arthritis by blocking il 6 signal transduction with a humanized anti il 6 receptor antibody
    Springer Seminars in Immunopathology, 1998
    Co-Authors: Kazuyuki Yoshizaki, Norihiro Nishimoto, Masahiro Mihara, Tadamitsu Kishimoto
    Abstract:

    The pathogenesis of autoimmune disease comprises several stages; (1) sensitization phase, (2) autoimmune phase, (3) chronic inflammatory phase, and (4) organ destruction phase as shown in Fig. 1. The etiology of rheumatoid arthritis (RA) is still unclear, but probably involves two factors, the major histocompatibility antigens (MHC) as intrinsic factors, and extrinsic factors, possibly antigens of bacteria, viruses or other micro-organisms. Specific T cells activated with antigen/MHC complex on the antigenpresenting cells may cross-react with autoantigens. From the pathological point of view, chronic inflammation is observed in the affected tissues in which immunocompetent cells proliferate, differentiate and produce chemical mediators (cytokines and immunoglobulins) [51 ]. Therapeutic methods aimed at blocking each of these steps are being developed. Practically, blocking cytokine function in the chronic inflammatory phase is one of the most acceptable methods, because it is now known that de-regulated cytokine production plays a major role in the pathogenesis of chronic inflammatory autoimmune diseases. Interleukin-6 (IL-6) is one of the principal inflammatory cytokines. In this review, the role of IL-6 in the pathogenesis of RA is discussed, and new therapy blocking IL-6 signal transduction with humanized Anti-IL-6 receptor antibody is introduced.

  • Clinical application of interleukin-6 receptor antibody
    Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology, 1997
    Co-Authors: Norihiro Nishimoto, Yoshihito Shima, Sasai M, Danno N, Kazuyuki Yoshizaki
    Abstract:

    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 arthritis. 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-y 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 a 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.

Yoshiyuki Ohsugi - One of the best experts on this subject based on the ideXlab platform.

  • Immunobiology of IL-6 — Tocilizumab (humanised Anti-IL-6 receptor antibody) for the treatment of rheumatoid arthritis
    New Therapeutic Targets in Rheumatoid Arthritis, 2009
    Co-Authors: Yoshiyuki Ohsugi, Tadamitsu Kishimoto
    Abstract:

    The cloning of IL-6 cDNA in 1986 revealed that IL-6 is a multifunctional cytokine that plays important roles in the immunopathogenesis of rheumatoid arthritis (RA). A close relationship was observed between IL-6 levels in the synovial compartment and disease activity in RA patients, and overproduction of IL-6 could readily explain the abnormal laboratory findings and clinical symptoms seen in these patients. IL-6 therefore appeared to be a worthwhile and attractive therapeutic target for RA. In practice, blockage of IL-6 signalling by a humanised Anti-IL-6 receptor antibody [tocilizumab (TCZ); also known as MRA] has been found to be very effective in the treatment of patients with RA. In recent Japanese Phase III clinical studies in RA patients, TCZ clearly prevented radiographic progression of joint destruction and greatly improved signs and symptoms. Very interestingly and importantly, this therapy has also proved quite effective at improving fever, fatigue and anaemia. No serious adverse events have been reported. At present, several international clinical studies of TCZ are ongoing in more than 4000 patients with active RA in 41 countries. The results are continuing to confirm the efficacy and safety of TCZ in the treatment of patients with RA.

  • crucial role of the interleukin 6 interleukin 17 cytokine axis in the induction of arthritis by glucose 6 phosphate isomerase
    Arthritis & Rheumatism, 2008
    Co-Authors: Keiichi Iwanami, Yoshiyuki Ohsugi, Masahiko Mihara, Isao Matsumoto, Yoko Tanakawatanabe, Asuka Inoue, Mizuko Mamura, Daisuke Goto, Satoshi Ito
    Abstract:

    Objective To clarify the glucose-6-phosphate isomerase (GPI)–specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti–interferon-γ (anti-IFNγ) monoclonal antibody (mAb), anti–interleukin-17 (anti–IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti–IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFNγ mAb exacerbated arthritis. Neither anti–IL-17 mAb nor anti-IFNγ mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti–IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.

  • blockage of interleukin 6 receptor ameliorates joint disease in murine collagen induced arthritis
    Arthritis & Rheumatism, 1998
    Co-Authors: Nobuhiro Takagi, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Masahiko Mihara, Yoichiro Moriya, Yasuhisa Takeda, Yoshiyuki Ohsugi
    Abstract:

    Objective To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). Methods CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (Anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. Results In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. Conclusion IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and Anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

  • Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody.
    Cancer research, 1995
    Co-Authors: Youichi Mizutani, Yasuo Koishihara, Yoshiyuki Ohsugi, Benjamin Bonavida, Kenichi Akamatsu, Osamu Yoshida
    Abstract:

    Cytotoxic chemotherapy has shown little antitumor activity against renal cell carcinoma (RCC). It has been demonstrated that RCC cells secrete interleukin 6 (IL-6) and express IL-6 receptors (IL-6Rs). IL-6 inhibits apoptosis and enhances manganese superoxide dismutase expression. Several anticancer chemotherapeutic agents exert their cytotoxic activity in part through the induction of apoptosis and the production of free radicals. Thus, the resistance of RCC cells to the anticancer agents might correlate with IL-6 expression. The present study tested this hypothesis by examining the effect of Anti-IL-6 mAb and Anti-IL-6R mAb on the sensitivity of human RCC cells to anticancer chemotherapeutic agents. Treatment of Caki-1 cells with Anti-IL-6 mAb or Anti-IL-6R mAb in combination with cis-diamminedichloroplatinum(II) (CDDP) or mitomycin C overcame their resistance to CDDP or mitomycin C. However, treatment of Caki-1 cells with Anti-IL-6 mAb or Anti-IL-6R mAb in combination with Adriamycin, vinblastine or 5-fluorouracil did not overcome their resistance to these anticancer agents. Treatment of CDDP-resistant Caki-1 cells (Caki-1/DDP), two other RCC cell lines (ACHN and A704), and three freshly derived RCC cells with CDDP in combination with Anti-IL-6 mAb or Anti-IL-6R mAb reversed the resistance to CDDP in all these tumors. We then studied the effectiveness of other platinum derivatives. Treatment of Caki-1 cells with Anti-IL-6 mAb or Anti-IL-6R mAb enhanced their sensitivity to carboplatin, but not to trans-diamminedichloroplatinum(II). Several experiments investigated the mechanism of the antibody-mediated sensitization of RCC cells to CDDP. Incubation of Caki-1 cells with Anti-IL-6 mAb or Anti-IL-6R mAb did not change the intracellular accumulation of CDDP. The expressions of the multidrug resistant phenotype (gp170) and c-myc oncogene were not affected by the antibody-mediated sensitization. Treatment of Caki-1 cells with the Anti-IL-6 mAb or Anti-IL-6R mAb down-regulated the expression of glutathione S-transferase pi mRNA. This study demonstrates that treatment of RCC cells with CDDP in combination with Anti-IL-6 mAb or Anti-IL-6R mAb can overcome their CDDP-resistance and that the down-regulation of glutathione S-transferase pi expression by Anti-IL-6 mAb or Anti-IL-6R mAb might play a role in the enhanced cytotoxicity obtained.(ABSTRACT TRUNCATED AT 400 WORDS)

  • IL-6-Anti-IL-6 autoantibody complexes with IL-6 activity in sera from some patients with systemic sclerosis.
    Journal of immunology (Baltimore Md. : 1950), 1994
    Co-Authors: Hiroshi Suzuki, Tadamitsu Kishimoto, Kazuyuki Yoshizaki, H Takemura, Yasuo Koishihara, Yoshiyuki Ohsugi, Akira Okano, Yukio Akiyama, T Tojo, H Kashiwagi
    Abstract:

    Anti-IL-6 IgG autoantibodies, often found in sera from patients with systemic sclerosis, may increase to the level sufficient to bind significant amounts of IL-6 in serum. In our study of the role of Anti-IL-6 autoantibodies in serum, we found that some sera with the autoantibodies possessed considerably higher IL-6 levels (more than 100 pg/ml) compared with most of sera without the autoantibodies. Size-exclusion HPLC of the sera with these autoantibodies demonstrated that a significant part of the serum IL-6 activity was attributable to circulating IL-6-Anti-IL-6 autoantibody complexes. Gel filtration of IL-6-Anti-IL-6 IgG complexes made in vitro by incubation of rIL-6 and IgG purified from the autoantibody-positive sera demonstrated that the complexes at 200 to 250 kDa were dominant ones and that IL-6 bound to the autoantibodies retained more than 60% of the original IL-6 activity. Moreover, IL-6-Anti-IL-6 autoantibody complexes were shown to bind to recombinant soluble IL-6 receptors. Estimated affinity of Anti-IL-6 IgG autoantibodies from two patients was fairly high (4.2 x 10(9) to 3.3 x 10(10) L/M). Therefore, the retention of IL-6 activity by IL-6-Anti-IL-6 autoantibody complexes may be explained by intact receptor-binding sites on the autoantibody-bound IL-6 molecules. Taken together, these results suggest that the properties of Anti-IL-6 autoantibodies are consistent with a potential role as specific carriers for IL-6 in the circulation.

Masahiko Mihara - One of the best experts on this subject based on the ideXlab platform.

  • Anti-IL-6 receptor antibody suppressed T cell activation by inhibiting IL-2 production and inducing regulatory T cells.
    European journal of pharmacology, 2010
    Co-Authors: Hiroto Yoshida, Misato Hashizume, Miho Suzuki, Masahiko Mihara
    Abstract:

    T cell activation is crucial to the pathogenesis and progression of rheumatoid arthritis. Tumour necrosis factor-alpha (TNFalpha) and interleukin (IL)-6 inhibitors show marked efficacy in rheumatoid arthritis patients, but their impacts on T cell activation have remained unclear. To shed light on these impacts, we examined the effects of an Anti-IL-6 receptor antibody and an anti-TNFalpha antibody on T cell activation in two experimental systems: spleen cells stimulated by anti-CD3 antibody, and purified splenic CD4 T cells stimulated by both anti-CD3 and anti-CD28 antibodies. Anti-IL-6 receptor antibody significantly (but only partially) suppressed T cell activation (as indicated by [3H]-thymidine uptake and CD25 expression) and IL-2 production in both systems, and increased the frequency of regulatory T cells among spleen cells. Anti-TNFalpha antibody had no effects in either system. Neither antibody increased the expression of markers of apoptosis in CD4 T cells. In conclusion, our results show that Anti-IL-6 receptor antibody significantly (but only partially) suppressed the T cell receptor signalling-induced activation of CD4 T cells and also suggest that it achieved this partial suppression by the partial inhibition of IL-2 production and the induction of regulatory T cells. In stark contrast, anti-TNFalpha antibody had no impact on T cell activation. Extrapolating these results to the clinical treatment of rheumatoid arthritis, they suggest that IL-6 blockade inhibits T cell activation, whereas TNFalpha blockade does not.

  • Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production
    International immunopharmacology, 2008
    Co-Authors: Yasushi Uchiyama, Hiroto Yoshida, Nobuo Koike, Naohiko Hayakawa, Atsuko Sugita, Takashi Nishimura, Masahiko Mihara
    Abstract:

    We explored the mechanism for the increase of blood IL-6 level after Anti-IL-6 receptor (IL-6R) antibody injection. First, we examined whether Anti-IL-6R antibody stimulates IL-6 production. Single injection of tocilizumab (Anti-IL-6R antibody) in monkeys with collagen-induced arthritis (CIA) caused a marked increase in blood IL-6 and IL-6R levels, but did not increase IL-6 mRNA and IL-6R mRNA expression in liver, spleen, lymph nodes, synovium or whole blood 1, 3 and 7 days later. This suggests that tocilizumab did not induce IL-6 and IL-6R production. Second, we investigated whether Anti-IL-6R antibody releases IL-6 from IL-6 complexes in the blood. When plasma from CIA monkeys was incubated with tocilizumab, the IL-6 concentration was not affected. Finally, we studied whether Anti-IL-6R antibody affects the clearance of IL-6 from the blood. When MR16-1 (anti-mouse IL-6R antibody) was injected into IL-6-deficient mice continuously infused with human IL-6, blood human IL-6 levels significantly increased. These results suggest that the elevation of blood IL-6 after the administration of Anti-IL-6R antibody is the result of inhibition of the clearance of IL-6 due to IL-6R blockade, and that it is not the result of induction of IL-6 production or release of IL-6 from complexes.

  • crucial role of the interleukin 6 interleukin 17 cytokine axis in the induction of arthritis by glucose 6 phosphate isomerase
    Arthritis & Rheumatism, 2008
    Co-Authors: Keiichi Iwanami, Yoshiyuki Ohsugi, Masahiko Mihara, Isao Matsumoto, Yoko Tanakawatanabe, Asuka Inoue, Mizuko Mamura, Daisuke Goto, Satoshi Ito
    Abstract:

    Objective To clarify the glucose-6-phosphate isomerase (GPI)–specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti–interferon-γ (anti-IFNγ) monoclonal antibody (mAb), anti–interleukin-17 (anti–IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti–IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFNγ mAb exacerbated arthritis. Neither anti–IL-17 mAb nor anti-IFNγ mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti–IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.

  • blockage of interleukin 6 receptor ameliorates joint disease in murine collagen induced arthritis
    Arthritis & Rheumatism, 1998
    Co-Authors: Nobuhiro Takagi, Tadamitsu Kishimoto, Norihiro Nishimoto, Kazuyuki Yoshizaki, Masahiko Mihara, Yoichiro Moriya, Yasuhisa Takeda, Yoshiyuki Ohsugi
    Abstract:

    Objective To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). Methods CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (Anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. Results In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. Conclusion IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and Anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.