Abstract Takayasu arteritis (TA) is a chronic inflammatory disease that involves the aorta and its major branches. Since overproduction of interleukin‐6 (IL‐6) seems to play a pathogenic role in TA, we used the anti–IL‐6 receptor (IL‐6R) antibody tocilizumab to treat a 20‐year‐old woman with refractory active TA complicated by ulcerative colitis (UC). Treatment with tocilizumab improved the clinical manifestations of TA and the abnormal laboratory findings in this patient and ameliorated the activity of UC. These results indicate that IL‐6R inhibition with tocilizumab might be a future treatment option for TA.
Abstract Interleukin-6 (IL-6) is a key molecule involved in the pathogenesis of several inflammatory diseases and malignancies. Treatments that inhibit IL-6 mitigate the clinical conditions of such diseases. Here, we report on the development of a new receptor inhibitor of IL-6 (NRI) by genetically engineering tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody which specifically blocks IL-6 signaling. This NRI consists of VH and VL of tocilizumab in a single-chain fragment format dimerized by fusing to the Fc portion of human immunoglobulin G1. The binding activity to IL-6 receptor and the biological activity of the purified NRI were found to be similar to those of parental tocilizumab. Because NRI is encoded on a single gene, it is easily applicable to a gene delivery system using virus vehicles. We administered an adenovirus vector encoding NRI to mouse i.p. and monitored the serum NRI level and growth reduction property on S6B45, an IL-6–dependent multiple myeloma cell line, in vivo. Adequate amount of the serum NRI level to exert anti-IL-6 action could be obtained by the NRI gene introduction combined with adenovirus gene delivery, and this treatment inhibited the in vivo S6B45 cell growth significantly. These findings indicate that NRI is a promising agent applicable to the therapeutic gene delivery approach for IL-6–driven diseases. [Cancer Res 2007;67(3):871–5]
Journal Article A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years Get access Hideko Nakahara, Hideko Nakahara Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, JapanNTT West Osaka Hospital, 2-6-40 Karasugatsuji, Tennoji-ku, Osaka, Osaka 543-8922, Japan Search for other works by this author on: Oxford Academic Google Scholar Toru Mima, Toru Mima Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan Search for other works by this author on: Oxford Academic Google Scholar Naoko Yoshio-Hoshino, Naoko Yoshio-Hoshino Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan Search for other works by this author on: Oxford Academic Google Scholar Masato Matsushita, Masato Matsushita Division of Rheumatology, National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi-cho, Kawachinagano, Osaka 586-8521, Japan Search for other works by this author on: Oxford Academic Google Scholar Jun Hashimoto, Jun Hashimoto Department of Orthopaedics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan Search for other works by this author on: Oxford Academic Google Scholar Norihiro Nishimoto Norihiro Nishimoto Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan Correspondence to: Norihiro Nishimoto, Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan e-mail: norihiro@fbs.osaka-u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar Modern Rheumatology, Volume 19, Issue 1, 1 February 2009, Pages 69–72, https://doi.org/10.3109/s10165-008-0116-2 Published: 01 February 2009 Article history Received: 25 April 2008 Accepted: 22 July 2008 Published: 01 February 2009
Abstract Introduction Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various clinical manifestations. Several cytokines interact and play pathological roles in SLE, although the etiopathology is still obscure. In the present study we investigated the network of immune response-related molecules expressed in the peripheral blood of SLE patients, and the effects of cytokine interactions on the regulation of these molecules. Methods Gene expression profiles of peripheral blood from SLE patients and from healthy women were analyzed using DNA microarray analysis. Differentially expressed genes classified into the immune response category were selected and analyzed using bioinformatics tools. Since interactions among TNF, IFNγ, β-estradiol (E2), and IFNα may regulate the expression of interferon-inducible (IFI) genes, stimulating and co-stimulating experiments were carried out on peripheral blood mononuclear cells followed by analysis using quantitative RT-PCR. Results Thirty-eight downregulated genes and 68 upregulated genes were identified in the functional category of immune response. Overexpressed IFI genes were confirmed in SLE patient peripheral bloods. Using network-based analysis on these genes, several networks including cytokines – such as TNF and IFNγ – and E2 were constructed. TNF-regulated genes were dominant in these networks, but in vitro TNF stimulation on peripheral blood mononuclear cells showed no differences in the above gene expressions between SLE and healthy individuals. Co-stimulating with IFNα and one of TNF, IFNγ, or E2 revealed that TNF has repressive effects while IFNγ essentially has synergistic effects on IFI gene expressions in vitro . E2 showed variable effects on IFI gene expressions among three individuals. Conclusions TNF may repress the abnormal regulation by IFNα in SLE while IFNγ may have a synergistic effect. Interactions between IFNα and one of TNF, IFNγ, or E2 appear to be involved in the pathogenesis of SLE.
Prognosis of multiple myeloma (MM) remains insufficient despite the intervention of high dose chemotherapy with auto- or allo- hematopoietic stem cell transplantation and the advent of molecular target drugs such as thalidomide, lenalidomide, and bortezomib. Further development or new concepts of therapeutic approaches are still required for MM treatment. Current standard protocol for MM treatment does not include gene delivery method or oncolytic virus approaches. Since MM is a disorder originated from B cell lineage, it involves immunological aspects in both pathogenesis and clinical manifestations. Therefore, the comprehension of immunology as well as oncology is essential to exploit new therapeutic approaches. Recently, novel therapeutic concepts for MM have been emerging. In this review, we present current progress of gene therapy related to MM treatments as well as the overview of MM treatment history. Keywords: Gene therapy, myeloma cell, growth factor, IL-6, IL-6 receptor, tocilizumab, new receptor inhibitor of IL-6 (NRI)
After three decades from the development of the hybridoma technology, a monoclonal antibody-based therapy targeting the inflammatory cytokine has been established as an ultimate treatment for chronic inflammatory diseases. Interleukine-6 (IL-6) is one of the inflammatory cytokines playing a pivotal role in these conditions, and strategies targeting IL-6 signal show promise in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and Crohns disease. Although many groups have been exploring the approach to block the IL-6 signal, tocilizumab, a humanized monoclonal antibody of the IL-6 receptor, has been the most intensively studied agent for clinical use. Clinical trials regarding chronic inflammatory diseases described above have demonstrated efficacy of tocilizumab, however, this treatment has limitations in terms of economic costs and ease of administration, and further advances are necessary to expand the concept of IL-6-specific therapeutics. In this review, we discuss targeting IL-6 in a rational drug design and present the various strategies to achieve this. Keywords: Interleukin-6 (IL-6), IL-6 receptor, tocilizumab, adenovirus, rheumatoid arthritis, Castleman's disease
Background: Malignant mesotheliomas reportedly secrete interleukin-6 (IL-6) which augments production of vascular endothelial growth factor (VEGF) from mesothelioma cells. We previously reported the development of a new receptor inhibitor of IL-6 (NRI) by genetically engineering tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody. Since NRI is encoded on a single gene, it is easily applicable to a gene delivery system using virus vehicles. In this study, we report VEGF targeting through NRI expression based on adenovirus-mediated gene delivery in mesothelioma cells. Materials and Methods: We constructed an NRI expression vector in the context of a tropism-modified adenovirus vector that had enhanced infectivity in mesothelioma cells. Results: This virus effectively induced NRI secretion from mesothelioma cells. This virus infection also reduced the VEGF production in mesothelioma cells. Conclusion: These results indicate that NRI shows potential as an agent in the treatment of mesotheliomas.
Interleukin-6 overproduction is pathologically involved in adult onset Still's disease (AOSD). We successfully treated a man with refractory AOSD utilizing tocilizumab. Tocilizumab was discontinued after 15 doses due to intestinal bleeding, but the efficacy was sustained over 21 months. Tocilizumab was readministered safely upon recurrence and showed similar efficacy over 6 years. Corticosteroid and NSAIDs could be discontinued and intestinal bleeding was no more observed. Tocilizumab can be a therapeutic option for AOSD.
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