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Chen SY, Chu CT, Yang ML, Lin JD, Wang CT, Lee CH, Lin IC, Shiau AL, Ling P, Wu CL. Amelioration of Murine Colitis by Attenuated Salmonella choleraesuis Encoding Interleukin-19. Microorganisms 2023; 11:1530. [PMID: 37375032 DOI: 10.3390/microorganisms11061530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The imbalance of mucosal immunity in the lower gastrointestinal tract can lead to chronic inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis. IBD is a chronic inflammatory disorder that causes small and/or large intestines ulceration. According to previous studies, recombinant interleukin (IL)-10 protein and genetically modified bacteria secreting IL-10 ameliorate dextran sulfate sodium (DSS)-induced colitis in mice. IL-19 is a transcriptional activator of IL-10 and can alter the balance of T helper 1 (Th)1/Th2 cells in favor of Th2. In this study, we aimed to investigate whether the expression of the murine IL-19 gene carried by Salmonella choleraesuis (S. choleraesuis) could ameliorate murine IBD. Our results showed that the attenuated S. choleraesuis could carry and express the IL-19 gene-containing plasmid for IBD gene therapy by reducing the mortality and clinical signs in DSS-induced acute colitis mice as compared to the untreated ones. We also found that IL-10 expression was induced in IL-19-treated colitis mice and prevented inflammatory infiltrates and proinflammatory cytokine expression in these mice. We suggest that S. choleraesuis encoding IL-19 provides a new strategy for treating IBD in the future.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
| | - Chun-Ting Chu
- Division of Colorectal Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi City 60002, Taiwan
| | - Mei-Lin Yang
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Jian-Da Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei City 10617, Taiwan
| | - Chung-Teng Wang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Che-Hsin Lee
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - I-Chen Lin
- Division of Colorectal Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi City 60002, Taiwan
| | - Ai-Li Shiau
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Pin Ling
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chao-Liang Wu
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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Izco M, Schleef M, Schmeer M, Carlos E, Verona G, Alvarez-Erviti L. Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord. Pharmaceutics 2023; 15:pharmaceutics15041230. [PMID: 37111717 PMCID: PMC10145068 DOI: 10.3390/pharmaceutics15041230] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
The development of effective disease-modifying therapies to halt Parkinson's disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.
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Affiliation(s)
- Maria Izco
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | | | - Marco Schmeer
- PlasmidFactory GmbH & Co. KG, 33607 Bielefeld, Germany
| | - Estefania Carlos
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
| | - Guglielmo Verona
- Centre for Amyloidosis, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK
| | - Lydia Alvarez-Erviti
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3th Floor, 26006 Logroño, Spain
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Hartwig O, Shetab Boushehri MA, Shalaby KS, Loretz B, Lamprecht A, Lehr CM. Drug delivery to the inflamed intestinal mucosa - targeting technologies and human cell culture models for better therapies of IBD. Adv Drug Deliv Rev 2021; 175:113828. [PMID: 34157320 DOI: 10.1016/j.addr.2021.113828] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/19/2022]
Abstract
Current treatment strategies for inflammatory bowel disease (IBD) seek to alleviate the undesirable symptoms of the disorder. Despite the higher specificity of newer generation therapeutics, e.g. monoclonal antibodies, adverse effects still arise from their interference with non-specific systemic immune cascades. To circumvent such undesirable effects, both conventional and newer therapeutic options can benefit from various targeting strategies. Of course, both the development and the assessment of the efficiency of such targeted delivery systems necessitate the use of suitable in vivo and in vitro models representing relevant pathophysiological manifestations of the disorder. Accordingly, the current review seeks to provide a comprehensive discussion of the available preclinical models with emphasis on human in vitro models of IBD, along with their potentials and limitations. This is followed by an elaboration on the advancements in the field of biology- and nanotechnology-based targeted drug delivery systems and the potential rooms for improvement to facilitate their clinical translation.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | | | - Karim S Shalaby
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany; Department of Pharmaceutics and Industrial Pharmacy, Ain Shams University, Cairo, Egypt
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany
| | - Alf Lamprecht
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany.
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany.
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Mishra R, Dhawan P, Srivastava AS, Singh AB. Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy. World J Stem Cells 2020; 12:1050-1066. [PMID: 33178391 PMCID: PMC7596447 DOI: 10.4252/wjsc.v12.i10.1050] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), consisting primarily of ulcerative colitis and Crohn’s disease, is a group of debilitating auto-immune disorders, which also increases the risk of colitis-associated cancer. However, due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g., approximately 30% non-responders to anti-TNFα agents), and related serious side effects, about half of all IBD patients (in millions) turn to alternative treatment options. In this regard, mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis. However, despite the increasing clinical realization of the significance of the concept of mucosal healing, its regulation and means of therapeutic targeting remain largely unclear. Here, stem-cell therapy, which uses hematopoietic stem cells or mesenchymal stem cells, remains a promising option. Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells. The over-reaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process. Moreover, by differentiating into the mature intestinal epithelial cells, the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction, the root cause of the IBD. In this article, we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.
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Affiliation(s)
- Rangnath Mishra
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
| | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
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Jeong Y, Park JKH, Eun S. Viral Vector Mediated Interleukin-10 Gene Transfer in Skin Allograft. Transplant Proc 2020; 52:1864-1868. [PMID: 32446692 DOI: 10.1016/j.transproceed.2020.02.144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 02/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Expression of genes with immunoregulatory capacity can potentially decrease rejection of allograft. According to recent studies, viral interleukin (IL)-10 can reduce immune response during allotransplantation and is one of the most promising methods for the prevention of rejection. Our study aimed to analyze the immunosuppressive potential of recombinant adenovirus-mediated rat IL-10 in rat skin allograft. METHODS We performed skin graft surgery 1 hour after infecting the donated skin with adenovirus-mediated rat IL-10. On day 7 postoperatively, the skin allografts were harvested, and acute rejection was graded histologically. RESULTS Viral IL-10 gene transfer into rat skin allografts improved graft survival and reduced acute rejections. CONCLUSION The results of our study suggest that the therapeutic potential of graft viral IL-10 gene transfer is an effective immunosuppressive method for preventing skin allograft rejection.
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Affiliation(s)
- Yeonjin Jeong
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kangwon National University Hospital, Chuncheon, Korea
| | - Joseph Kyu-Hyung Park
- Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea
| | - Seokchan Eun
- Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea.
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Lee KH, Ahn BS, Cha D, Jang WW, Choi E, Park S, Park JH, Oh J, Jung DE, Park H, Park JH, Suh Y, Jin D, Lee S, Jang YH, Yoon T, Park MK, Seong Y, Pyo J, Yang S, Kwon Y, Jung H, Lim CK, Hong JB, Park Y, Choi E, Shin JI, Kronbichler A. Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review. Autoimmun Rev 2020; 19:102469. [PMID: 31918027 DOI: 10.1016/j.autrev.2020.102469] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 12/21/2022]
Abstract
Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.
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Affiliation(s)
- Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung Soo Ahn
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dohyeon Cha
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Woo Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eugene Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soohyun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyeong Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junseok Oh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Eun Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Heeryun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ju Ha Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngsong Suh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dongwan Jin
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Siyeon Lee
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Hwan Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tehwook Yoon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min-Kyu Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoonje Seong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jihoon Pyo
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sunmo Yang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngin Kwon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunjean Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chae Kwang Lim
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Beom Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeoeun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eunjin Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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Cao L, Xu H, Wang G, Liu M, Tian D, Yuan Z. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization. Int Immunopharmacol 2019; 72:264-274. [PMID: 31005036 DOI: 10.1016/j.intimp.2019.04.020] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) have shown repairing effects in tissue damage. However, their efficacy and mechanism in the treatment of ulcerative colitis (UC), a type of chronic inflammatory bowel disease, are unclear. To investigate the effects and possible mechanism of EVs in UC treatment, we established an in vitro model using lipopolysaccharide (LPS)-treated macrophages and an in vivo dextran sulfate sodium (DSS)-induced mouse model to mimic UC. In vitro, EVs promoted the proliferation and suppressed inflammatory response in LPS-induced macrophages, as demonstrated by the up-regulation of pro-inflammatory factors (TNF-α, IL-6, and IL-12) and down-regulation of the anti-inflammatory factor IL-10. In the in vivo model, EV administration ameliorated the symptoms of UC by reducing weight loss, disease activity index, and colon mucosa damage and severity while increasing colon length. This was additionally accompanied by the increase in IL-10 and TGF-β levels and the decline in VEGF-A, IFN-γ, IL-12, TNF-α, CCL-24, and CCL-17 levels. In terms of the mechanism, EVs promoted M2-like macrophage polarization, characterized by the increase in the M2 marker CD163. Furthermore, the positive effect of EVs on UC repair seemed to be related to the JAK1/STAT1/STAT6 signaling pathway. Collectively, BMSC-derived EVs exerted positive therapeutic effects against DSS-induced UC, which could be due to a negative inflammatory response.
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Affiliation(s)
- Li Cao
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Hanxin Xu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China
| | - Ge Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Mei Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Dean Tian
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Zhenglin Yuan
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China.
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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9
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Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat Commun 2018; 9:4493. [PMID: 30374059 PMCID: PMC6206083 DOI: 10.1038/s41467-018-06936-1] [Citation(s) in RCA: 199] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/02/2018] [Indexed: 12/18/2022] Open
Abstract
Therapeutic alteration of gene expression in vivo can be achieved by delivering nucleic acids (e.g., mRNA, siRNA) using nanoparticles. Recent progress in modified messenger RNA (mmRNA) synthesis facilitated the development of lipid nanoparticles (LNPs) loaded with mmRNA as a promising tool for in vivo protein expression. Although progress have been made with mmRNA-LNPs based protein expression in hepatocytes, cell specificity is still a major challenge. Moreover, selective protein expression is essential for an improved therapeutic effect, due to the heterogeneous nature of diseases. Here, we present a precision protein expression strategy in Ly6c+ inflammatory leukocytes in inflammatory bowel disease (IBD) induced mice. We demonstrate a therapeutic effect in an IBD model by targeted expression of the interleukin 10 in Ly6c+ inflammatory leukocytes. A selective mmRNA expression strategy has tremendous therapeutic potential in IBD and can ultimately become a novel therapeutic modality in many other diseases. Therapeutic alteration of protein expression using modified mRNA is limited by immunogenicity and instability in vivo. Here the authors use antibody-coated lipid nanoparticles to deliver mRNA to leukocytes and drive expression of anti-inflammatory cytokines in an inflammatory bowel disease mouse model.
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10
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Buckinx R, Timmermans JP. Targeting the gastrointestinal tract with viral vectors: state of the art and possible applications in research and therapy. Histochem Cell Biol 2016; 146:709-720. [PMID: 27665281 DOI: 10.1007/s00418-016-1496-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2016] [Indexed: 12/11/2022]
Abstract
While there is a large body of preclinical data on the use of viral vectors in gene transfer, relatively little is known about viral gene transfer in the gastrointestinal tract. Viral vector technology is especially underused in the field of neurogastroenterology when compared to brain research. This review provides an overview of the studies employing viral vectors-in particular retroviruses, adenoviruses and adeno-associated viruses-to transduce different cell types in the intestine. Early work mainly focused on mucosal transduction, but had limited success due to the harsh luminal conditions in the gastrointestinal tract and the high turnover rate of enterocytes. More recently, several studies have successfully employed viral gene transfer to target the enteric nervous system and its progenitors. Although several hurdles still need to be overcome, in particular on how to augment transduction efficiency and specific cell targeting, viral vector technology holds strong potential not only as a valid research tool in fundamental gastroenterological research but also as a therapeutic agent in translational (bio)medical research.
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Affiliation(s)
- Roeland Buckinx
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
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11
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Abstract
B-1 lymphocytes exhibit unique phenotypic, ontogenic, and functional characteristics that differ from the conventional B-2 cells. B-1 cells spontaneously secrete germline-like, repertoire-skewed polyreactive natural antibody, which acts as a first line of defense by neutralizing a wide range of pathogens before launching of the adaptive immune response. Immunomodulatory molecules such as interleukin-10, adenosine, granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-35 are also produced by B-1 cells in the presence or absence of stimulation, which regulate acute and chronic inflammatory diseases. Considerable progress has been made during the past three decades since the discovery of B-1 cells, which has improved not only our understanding of their phenotypic and ontogenic uniqueness but also their role in various inflammatory diseases including influenza, pneumonia, sepsis, atherosclerosis, inflammatory bowel disease, autoimmunity, obesity and diabetes mellitus. Recent identification of human B-1 cells widens the scope of this field, leading to novel innovations that can be implemented from bench to bedside. Among the vast number of studies on B-1 cells, we have carried out a literature review highlighting current trends in the study of B-1 cell involvement during inflammation, which may result in a paradigm shift toward sustainable therapeutics in various inflammatory diseases.
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Affiliation(s)
- Monowar Aziz
- Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA
| | - Nichol E Holodick
- Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA
| | - Thomas L Rothstein
- Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA
| | - Ping Wang
- Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. .,Department of Surgery, Hofstra North Shore-LIJ School of Medicine, 350 Community Dr., Manhasset, NY, 11030, USA.
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12
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Bermúdez-Humarán LG, Motta JP, Aubry C, Kharrat P, Rous-Martin L, Sallenave JM, Deraison C, Vergnolle N, Langella P. Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci. Microb Cell Fact 2015; 14:26. [PMID: 25889561 PMCID: PMC4371826 DOI: 10.1186/s12934-015-0198-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 01/23/2015] [Indexed: 12/18/2022] Open
Abstract
Background Different studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD). Methods In order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-β1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis. Results Our results show that oral administration of recombinant L. lactis strains expressing either IL-10 or TGF-β1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect. Conclusions Altogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLAB at the mucosal level for IBD treatment.
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Affiliation(s)
- Luis G Bermúdez-Humarán
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Jean-Paul Motta
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. .,Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
| | - Camille Aubry
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Pascale Kharrat
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
| | - Laurence Rous-Martin
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
| | - Jean-Michel Sallenave
- INSERM U874, Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France. .,INSERM U1152, Faculté de Médecine site Bichat, Université Paris Diderot, 16, rue Henri Huchard, 75018, Paris, France. .,Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France.
| | - Céline Deraison
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
| | - Nathalie Vergnolle
- Inserm, U1043, Toulouse, F-31300, France. .,CNRS, U5282, Toulouse, F-31300, France. .,Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. .,Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France.
| | - Philippe Langella
- INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. .,AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France.
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Matsumoto H, Haga K, Ohno I, Hiraoka K, Kimura T, Hermann K, Kasahara N, Anton P, McGowan I. Mucosal gene therapy using a pseudotyped lentivirus vector encoding murine interleukin-10 (mIL-10) suppresses the development and relapse of experimental murine colitis. BMC Gastroenterol 2014; 14:68. [PMID: 24712338 PMCID: PMC3991919 DOI: 10.1186/1471-230x-14-68] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 04/02/2014] [Indexed: 12/23/2022] Open
Abstract
Background Therapeutic gene transfer is currently being evaluated as a potential therapy for inflammatory bowel disease. This study investigates the safety and therapeutic benefit of a locally administered lentiviral vector encoding murine interleukin-10 in altering the onset and relapse of dextran sodium sulfate induced murine colitis. Methods Lentiviral vectors encoding the reporter genes firefly-luciferase and murine interleukin-10 were administered by intrarectal instillation, either once or twice following an ethanol enema to facilitate mucosal uptake, on Days 3 and 20 in Balb/c mice with acute and relapsing colitis induced with dextran sulfate sodium (DSS). DSS colitis was characterized using clinical disease activity, macroscopic, and microscopic scores. Bioluminescence optical imaging analysis was employed to examine mucosal lentiviral vector uptake and transgene expression. Levels of tumor necrosis factor-α and interleukin-6 in homogenates of rectal tissue were measured by ELISA. Biodistribution of the lentiviral vector to other organs was evaluated by real time quantitative PCR. Results Mucosal delivery of lentiviral vector resulted in significant transduction of colorectal mucosa, as shown by bioluminescence imaging analysis. Lentiviral vector-mediated local expression of interleukin-10 resulted in significantly increased levels of this cytokine, as well as reduced levels of tumor necrosis factor-α and interleukin-6, and significantly reduced the clinical disease activity, macroscopic, and microscopic scores of DSS colitis. Systemic biodistribution of locally instilled lentiviral vector to other organs was not detected. Conclusions Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ian McGowan
- Magee-Womens Research Institute, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Marel SVD, Majowicz A, Deventer SV, Petry H, Hommes DW, Ferreira V. Gene and cell therapy based treatment strategies for inflammatory bowel diseases. World J Gastrointest Pathophysiol 2011; 2:114-22. [PMID: 22180846 PMCID: PMC3240904 DOI: 10.4291/wjgp.v2.i6.114] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2011] [Revised: 08/12/2011] [Accepted: 08/19/2011] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders most commonly affecting young adults. Currently available therapies can result in induction and maintenance of remission, but are not curative and have sometimes important side effects. Advances in basic research in IBD have provided new therapeutic opportunities to target the inflammatory process involved. Gene and cell therapy approaches are suitable to prevent inflammation in the gastrointestinal tract and show therefore potential in the treatment of IBD. In this review, we present the current progress in the field of both gene and cell therapy and future prospects in the context of IBD. Regarding gene therapy, we focus on viral vectors and their applications in preclinical models. The focus for cell therapy is on regulatory T lymphocytes and mesenchymal stromal cells, their potential for the treatment of IBD and the progress made in both preclinical models and clinical trials.
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15
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Klampfer L. Cytokines, inflammation and colon cancer. Curr Cancer Drug Targets 2011; 11:451-64. [PMID: 21247378 DOI: 10.2174/156800911795538066] [Citation(s) in RCA: 213] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 08/03/2010] [Indexed: 02/07/2023]
Abstract
Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are at increased risk of developing colon cancer, confirming that chronic inflammation predisposes to development of tumors. Moreover, it appears that colon cancers that do not develop as a complication of inflammatory bowel disease are also driven by inflammation, because it has been shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the mortality from sporadic colon cancer and results in regression of adenomas in familial adenomatous polyposis (FAP) patients, who inherit a mutation in the Apc gene. Colorectal cancer therefore represents a paradigm for the link between inflammation and cancer. Inflammation is driven by soluble factors, cytokines and chemokines, which can be produced by tumor cells themselves or, more often, by the cells recruited to the tumor microenvironment. Inflammatory cytokines and chemokines promote growth of tumor cells, perturb their differentiation, and support the survival of cancer cells. Tumor cells become addicted to inflammatory stroma, suggesting that the tumor microenvironment represents an attractive target for preventive and therapeutic strategies. Proinflammatory cytokines, such as TNFα, IL-6 and IL-1β, or transcription factors that are required for signaling by these cytokines, including NF-κB and STATs, are indeed emerging as potential targets for anticancer therapy. TNFα antagonists are in phase I/II clinical trials and have been shown to be well tolerated in patients with solid tumors, and IL-1β antagonists that ameliorate several inflammatory disorders characterized by excessive IL-1β production, will likely follow. Therefore, development of drugs that normalize the tumor microenvironment or interrupt the crosstalk between the tumor and the tumor microenvironment is an important approach to the management of cancer.
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Affiliation(s)
- Lidija Klampfer
- Albert Einstein Cancer Center, Montefiore Medical Center, Department of Oncology, Bronx, NY 10467, USA.
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16
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Strisciuglio C, van Deventer S. Regulatory T cells as potential targets for immunotherapy in inflammatory bowel disease. Immunotherapy 2011; 2:749-52. [PMID: 21091105 DOI: 10.2217/imt.10.63] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Kim KO, Jang BI. Emerging Drugs in the Treatment of Inflammatory Bowel Disease: Beyond Anti-TNF-α. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:235-44. [DOI: 10.4166/kjg.2011.58.5.235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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Interleukin-10 repletion suppresses pro-inflammatory cytokines and decreases liver pathology without altering viral replication in murine cytomegalovirus (MCMV)-infected IL-10 knockout mice. Inflamm Res 2010; 60:233-43. [PMID: 20922456 PMCID: PMC3036806 DOI: 10.1007/s00011-010-0259-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 09/14/2010] [Accepted: 09/15/2010] [Indexed: 02/07/2023] Open
Abstract
Objective and design To determine the role of interleukin-10 (IL-10) in protecting against the deleterious pro-inflammatory cytokine response to murine cytomegalovirus (MCMV), we studied the impact of IL-10 repletion in MCMV-infected IL-10 knockout (KO) mice. Materials and methods IL-10 KO mice were infected with a sub-lethal dose of MCMV and treated daily with 5 μg of mouse recombinant IL-10 (mrIL-10). Cytokine transcription, viral load, cytokine expression and liver histopathology were assessed in IL-10 treated and untreated mice. Results mrIL-10 repletion suppressed the exaggerated pro-inflammatory cytokine response observed in IL-10 KO mice (vs. control) both systemically and at the organ level, without affecting viral load. Levels of IFN-γ and TNF-α mRNA in livers of treated mice were ~50–70-fold lower than in untreated mice at day 5 post-infection (p ≤ 0.05). In spleens and sera, levels of IFN-γ and IL-6 were significantly lower in treated mice than in untreated mice at day 5–7 post-infection (p ≤ 0.05). IL-10 blunting of cytokine responses was accompanied by attenuation of inflammation in livers of treated mice. Conclusions Repletion of IL-10 modulates the exaggerated pro-inflammatory cytokine responses that characterize IL-10 KO mice and protects against liver damage without altering viral load. IL-10 may be useful to control dysregulated pro-inflammatory cytokines responses during CMV infection.
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New pathophysiological insights and modern treatment of IBD. J Gastroenterol 2010; 45:571-83. [PMID: 20213337 DOI: 10.1007/s00535-010-0219-3] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Accepted: 02/03/2010] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn's disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today's differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.
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Jarry A, Bossard C, Bou-Hanna C, Masson D, Espaze E, Denis MG, Laboisse CL. Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants. J Clin Invest 2008; 118:1132-42. [PMID: 18259614 DOI: 10.1172/jci32140] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2007] [Accepted: 12/19/2007] [Indexed: 12/13/2022] Open
Abstract
IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10-inducible, immunosuppressive gene BCL3 and upregulation of IFN-gamma, TNF-alpha, and IL-17. Interestingly, TGF-beta blockade also strongly induced IFN-gamma production. In addition, the high levels of IFN-gamma produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-gamma production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-gamma secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-gamma-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-beta play crucial roles in maintaining human colonic mucosa homeostasis.
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21
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Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease. Gene Ther 2008; 15:1200-9. [DOI: 10.1038/gt.2008.67] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Kang H, Yang PY, Rui YC. Adenovirus viral interleukin-10 inhibits adhesion molecule expressions induced by hypoxia/reoxygenation in cerebrovascular endothelial cells. Acta Pharmacol Sin 2008; 29:50-6. [PMID: 18158865 DOI: 10.1111/j.1745-7254.2008.00718.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM To investigate the effects of recombinant adenovirus encoding viral interleukin-10 (vIL-10), a potent anti-inflammatory cytokine, on adhesion molecule expressions and the adhesion rates of leukocytes to endothelial cells in cerebrovascular endothelial cells injured by hypoxia/reoxygenation (H/R). METHODS A recombinant adenovirus expressing vIL-10 (Ad/vIL-10 (or the green fluorescent protein (Ad/GFP) gene was constructed. A cerebrovascular endothelial cell line bEnd.3 was pretreated with a different multiplicity of infection (MOI) of Ad/vIL-10 or Ad/GFP and then exposed to hypoxia for 9 h followed by reoxygenation for 12 h. The culture supernatants were tested for the expression of vIL-10 and endogenous murine IL-10 (mIL-10) by ELISA. The effects of Ad/vIL-10 on monocyte-endothelial cell adhesion were represented as the adhesion rate. Subsequently, the expressions of intercellular adhesion molecule 1(ICAM-1) and vascular cell adhesion molecule 1( VCAM-1) in the endothelial cells after treatment with Ad/vIL-10 and H/R were analyzed by Western blotting and real-time PCR. RESULTS vIL-10 was expressed in cultured bEnd.3 after Ad/vIL-10 transfection and was significantly increased by H/R. Ad/vIL-10 or Ad/GFP did not affect the mIL-10 level. H/R increased the mIL-10 expression, but insignificantly. Monocyte- endothelial cell adhesion induced by H/R was significantly inhibited by pretreatment with Ad/vIL-10(MOI:80). ICAM-1, and VCAM-1 in bEnd.3 and were significantly increased after H/R, while pretreatment with Ad/vIL-10 (MOI: 80) significantly inhibited their expressions. Ad/GFP did not markedly affect monocyte- endothelial adhesion and the expressions of ICAM-1 and VCAM-1 induced by H/R. CONCLUSION Ad/vIL-10 significantly inhibits the upregulation of endothelial adhesion molecule expressions and the increase of adhesion of monocytes- endothelial cells induced by H/R, indicating that vIL-10 gene transfer is of farreaching significance in the therapy of cerebrovascular inflammatory diseases, and anti-adhesion treatment may reduce H/R injury.
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Affiliation(s)
- Hui Kang
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
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Noguchi D, Wakita D, Tajima M, Ashino S, Iwakura Y, Zhang Y, Chamoto K, Kitamura H, Nishimura T. Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a Th17-independent manner. Int Immunol 2007; 19:1431-40. [DOI: 10.1093/intimm/dxm114] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Bolder U, Jeschke MG, Landmann L, Wolf F, de Sousa C, Schlitt HJ, Przkora R. Heat stress enhances recovery of hepatocyte bile acid and organic anion transporters in endotoxemic rats by multiple mechanisms. Cell Stress Chaperones 2006; 11:89-100. [PMID: 16572733 PMCID: PMC1400616 DOI: 10.1379/csc-143r.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Heat stress (HS) reduces the many sequelae of lipopolysaccharide (LPS)-induced endotoxemia. Without HS, endotoxins have been shown to induce a transcriptional down-regulation of hepatocyte transport proteins for bile acids and organic anions. We performed experiments in isolated perfused rat livers at various times after LPS administration with and without HS pretreatment to determine whether HS would correct deficient transport of bromosulfophthalein (BSP). Possible mechanisms involved were investigated in livers from intact animals. In isolated perfused livers, LPS injection reduced BSP excretion to 48% compared with saline-injected controls (P < 0.01). When HS was applied 2 hours prior to LPS, BSP excretion increased to 74% of controls (P < 0.05 vs LPS and controls). Expression of the basolateral (Oatp1a1) and canalicular (Mrp2) organic anion transporter involved in the transport of BSP recovered more rapidly when HS preceded LPS application. Recovery of mRNA levels of these transporters occurred also earlier. Coimmunoprecipitation experiments and immunoelectron microscopy using a double immunogold labeling of heat shock protein 70 (HSP70) and various hepatocyte transporters suggested colocalization with HSP70 for the canalicular bile acid transporter (Bsep) in the subcanalicular space. In contrast, no colocalization was shown for Ntcp and anion transporters. In conclusion, we could show that HS enhances recovery of organic anion transporters and bile acid transporters following endotoxemia. Faster recovery of mRNA seems to be a key mechanism for anion transporters, whereas physical interaction with HSP70 plays a role in preservation of bile acid transporters. This interaction of HSP70 and canalicular transporters occurs only in pericanalicular vesicles but not when the protein is integrated into the plasma membrane.
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Affiliation(s)
- Ulrich Bolder
- Department of Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
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Verhagen J, Taylor A, Blaser K, Akdis M, Akdis CA. T regulatory cells in allergen-specific immunotherapy. Int Rev Immunol 2006; 24:533-48. [PMID: 16318994 DOI: 10.1080/08830180500371173] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
A dramatic increase in the prevalence of allergy and asthma has occurred during the past few decades. Although the symptoms of many allergic disorders can be suppressed quite effectively by pharmacological interventions, these do not provide a curative solution and therefore involve lifelong use of medication. Allergen-specific immunotherapy (SIT) on the other hand provides a long-lasting effect on the immune response to common environmental antigens, therefore allowing cessation of the therapy after several years. The changes in the immune response brought about by allergen-SIT are slowly being unveiled and explained. Mechanisms underlying allergen-SIT and in particular the role of regulatory T cells will be discussed in this review, based on recent findings and current concepts.
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Affiliation(s)
- Johan Verhagen
- Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland
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Kang SS, Allen PM. Priming in the presence of IL-10 results in direct enhancement of CD8+ T cell primary responses and inhibition of secondary responses. THE JOURNAL OF IMMUNOLOGY 2005; 174:5382-9. [PMID: 15843536 DOI: 10.4049/jimmunol.174.9.5382] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although IL-10 acts as an inhibitory cytokine for APC and CD4(+) T cell function, its effects on CD8(+) T cells are unclear. Additionally, little is known about whether initial priming in the presence of IL-10 can have long-lasting effects and influence subsequent CD8(+) T cell responses that occur in the absence of the cytokine. In the present study, we clarified the role of IL-10 during primary responses and examined whether exposure to IL-10 during initial priming of CD8(+) T cells impacted secondary responses. To determine the effect of IL-10 on Ag-specific T cell responses, peptide-pulsed IL-10R2(-/-) splenic dendritic cells were used to prime T cells from OT-I CD8(+) TCR transgenic mice. During the primary response, the presence of IL-10 resulted in enhancement of CD8(+) T cell numbers without detectable alterations in the kinetics or percentage of cells that underwent proliferation. A modest increase in survival, not attributable to Bcl-2 or Bcl-x(L), was also observed with IL-10 treatment. Other parameters of CD8(+) T cell function, including IL-2, IFN-gamma, TNF-alpha, and granzyme production, were unaltered. In contrast, initial exposure to IL-10 during the primary response resulted in decreased OT-I expansion during secondary stimulation. This was accompanied by lowered IL-2 levels and reduced percentages of proliferating BrdU(+) cells and OT-I cells that were CD25(high). IFN-gamma, TNF-alpha, and granzyme production were unaltered. These data suggest that initial exposure of CD8(+) T cells to IL-10 may be temporarily stimulatory; however, programming of the cells may be altered, resulting in diminished overall responses.
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Affiliation(s)
- Silvia S Kang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Kesisoglou F, Zimmermann EM. Novel drug delivery strategies for the treatment of inflammatory bowel disease. Expert Opin Drug Deliv 2005; 2:451-63. [PMID: 16296767 DOI: 10.1517/17425247.2.3.451] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) encompasses two idiopathic inflammatory diseases of the intestinal tract: Crohn's disease and ulcerative colitis. Existing therapy for IBD consists mainly of orally or rectally administered small drug molecules, such as 5-aminosalicylates and corticosteroids, or potent systemic immune suppressants. IBD presents a challenging target for drug delivery, particularly by the oral route, as, contrary to most therapeutic regimens, minimal systemic absorption and maximal intestinal wall drug levels are desired. Several delivery strategies are employed to achieve this goal, including the chemical modification of the drug molecules, the use of controlled- and delayed-release formulations and the use of bioadhesive particles. The goal of this review is to summarise existing IBD therapy and examine novel approaches in intestinal drug delivery.
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Affiliation(s)
- Filippos Kesisoglou
- University of Michigan Department of Pharmaceutical Sciences, College of Pharmacy, Ann Arbor, MI 48109-1065, USA
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Abstract
Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.
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Affiliation(s)
- Sandro Ardizzone
- Chair of Gastroenterology, L. Sacco University Hospital, Milan, Italy
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Konrad A, Mähler M, Arni S, Flogerzi B, Klingelhöfer S, Seibold F. Ameliorative effect of IDS 30, a stinging nettle leaf extract, on chronic colitis. Int J Colorectal Dis 2005; 20:9-17. [PMID: 15338166 DOI: 10.1007/s00384-004-0619-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/25/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Anti-TNF-alpha antibodies are very effective in the treatment of acute Crohn's disease, but are limited by the decline of their effectiveness after repeated applications. The stinging nettle leaf extract, IDS 30, is an adjuvant remedy in rheumatic diseases dependent on a cytokine suppressive effect. We investigated the effect of IDS 30 on disease activity of murine colitis in different models. METHODS C3H.IL-10-/- and BALB/c mice with colitis induced by dextran sodium sulphate (DSS) were treated with either IDS 30 or water. Mice were monitored for clinical signs of colitis. Inflammation was scored histologically, and faecal IL-1beta and mucosal cytokines were measured by ELISA. Mononuclear cell proliferation of spleen and Peyer's patches were quantified by 3H-thymidine. RESULTS Mice with chronic DSS colitis or IL-10-/- mice treated with IDS 30 clinically and histologically revealed significantly (p < 0.05) fewer signs of colitis than untreated animals. Furthermore, faecal IL-1beta and mucosal TNF-alpha concentrations were significantly lower (p < 0.05) in treated mice. Mononuclear cell proliferation after stimulation with lipopolysaccharide was significantly (p < 0.001) reduced in mice treated with IDS 30. CONCLUSIONS The long-term use of IDS 30 is effective in the prevention of chronic murine colitis. This effect seems to be due to a decrease in the Th1 response and may be a new therapeutic option for prolonging remission in inflammatory bowel disease.
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Affiliation(s)
- Astrid Konrad
- Division of Gastroenterology, Inselspital, University Hospital, University of Bern, Freiburgstrasse, 3010 Berne, Switzerland.
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30
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Boles BR, Thoendel M, Singh PK. Self-generated diversity produces "insurance effects" in biofilm communities. Proc Natl Acad Sci U S A 2004; 101:16630-5. [PMID: 15546998 PMCID: PMC528905 DOI: 10.1073/pnas.0407460101] [Citation(s) in RCA: 425] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Diversity generally protects communities from unstable environmental conditions. This principle, known as the "insurance hypothesis," has been tested in many different ecosystems. Here we show that the opportunistic pathogen Pseudomonas aeruginosa undergoes extensive genetic diversification during short-term growth in biofilm communities. The induced genetic changes are produced by a recA-dependent mechanism and affect multiple traits, including the behavior of the bacteria in biofilms. Some biofilm-derived variants exhibit an increased ability to disseminate, whereas others manifest accelerated biofilm formation. Furthermore, the presence of these functionally diverse bacteria increases the ability of biofilms to resist an environmental stress. These findings suggest that self-generated diversity in biofilms provides a form of biological insurance that can safeguard the community in the face of adverse conditions.
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Affiliation(s)
- Blaise R Boles
- Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
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31
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Chen ZQ, Tang YQ, Zhang Y, Jiang ZH, Mao EQ, Zou WG, Lei RQ, Han TQ, Zhang SD. Adenoviral transfer of human interleukin-10 gene in lethal pancreatitis. World J Gastroenterol 2004; 10:3021-3025. [PMID: 15378786 PMCID: PMC4576265 DOI: 10.3748/wjg.v10.i20.3021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2004] [Revised: 01/23/2004] [Accepted: 02/24/2004] [Indexed: 12/15/2022] Open
Abstract
AIM To evaluate the therapeutic effect of adenoviral-vector-delivered human interleukin-10 (hIL-10) gene on severe acute pancreatitis (SAP) rats. METHODS Healthy Sprague-Dawley (SD) rats were intraperitoneally injected with adenoviral IL-10 gene (AdvhIL-10), empty vector (Adv0) or PBS solution. Blood, liver, pancreas and lung were harvested on the second day to examine hIL-10 level by ELISA and serum amylase by enzymatic assay. A SAP model was induced by retrograde injection of sodium taurocholate through pancreatic duct. SAP rats were then administered with AdvhIL-10, Adv0 and PBS solution by a single intraperitoneal injection 20 min after SAP induction. In addition to serum amylase assay, levels of hIL-10 and tumor necrosis factor-alpha (TNF-alpha) were detected by RT-PCR, ELISA and histological study. The mortality rate was studied and analyzed by Kaplan-Meier and log rank analysis. RESULTS The levels of hIL-10 in the pancreas, liver and lung of healthy rats increased significantly after AdvhIL-10 injection (1.42 ng/g in liver, 0.91 ng/g in pancreas); while there was no significant change of hIL-10 in the other two control groups. The concentration of hIL-10 was increased significantly in the SAP rats after AdvhIL-10 injection (1.68 ng/g in liver, 1.12 ng/g in pancreas) compared to the other two SAP groups with blank vector or PBS treatment (P<0.05). The serum amylase levels remained normal in the AdvhIL-10 transfected healthy rats. However, the serum amylase level was significantly elevated in the other two control SAP rats. In contrast, serum amylase was down-regulated in the AdvhIL-10 treated SAP groups. The TNF-alpha expression in the AdvhIL-10 treated SAP rats was significantly lower compared to the other two control SAP groups. The pathohistological changes in the AdvhIL-10 treated group were better than those in the other two control groups. Furthermore, the mortality of the AdvhIL-10 treated group was significantly reduced compared to the other two control groups (P<0.05). CONCLUSION Adenoviral hIL-10 gene can significantly attenuate the severity of SAP rats, and can be used in the treatment of acute inflammation process.
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Affiliation(s)
- Zi-Qian Chen
- Department of Surgery, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China
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32
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Baert F, Vermeire S, Noman M, Van Assche G, D'Haens G, Rutgeerts P. Management of ulcerative colitis and Crohn's disease. Acta Clin Belg 2004; 59:304-14. [PMID: 15641402 DOI: 10.1179/acb.2004.045] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The conventional medical treatment of IBD consists of aminosalicylates, corticosteroids, immunosuppressive drugs (azathioprine, 6-mercaptopurin, methotrexate, cyclosporin) and antibiotics. The only drugs able to modify the disease course are azathioprine, its metabolite 6-mercaptopurin and methotrexate. However, these drugs have a slow onset of action and are associated with important side-effects in some patients, necessitating the discontinuation of the drug. Moreover, up to 60% of patients do not respond to these drugs long-term. Fortunately, the management of IBD has entered a new era in the beginning of the 1990s with the development of new biological therapies, selectively blocking the inflammatory cascade. The novel molecules have arisen from the increasing knowledge about the disease pathogenesis and their production has been precipitated by the techniques of molecular biology. Infliximab, the first available biological for Crohn's disease has certainly revolutionised standard treatment. Because of its profound clinical, endoscopic and histological effects, the standard step up approach in the treatment of IBD has been challenged. A large array of new rationally designed biologicals, with a better safety profile and equally selectively acting is underway, and is likely to change our current practise even more dramatically in the next decade.
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Affiliation(s)
- F Baert
- Department of Gastroenterology, at the University Hospital Gasthuisberg, Leuven, Belgium
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Mizushima T, Ito T, Kishi D, Kai Y, Tamagawa H, Nezu R, Kiyono H, Matsuda H. Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis. Inflamm Bowel Dis 2004; 10:182-92. [PMID: 15290910 DOI: 10.1097/00054725-200405000-00002] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND FTY720 is a novel reagent that possesses potent immunosuppressive activity. The immunosuppression induced by FTY720 is mediated by completely different mechanisms from those of conventional immunosuppressants, that is, by altering the tissue distribution of lymphocytes rather than inhibiting activation. In this study, we examined the efficacy of FTY720 in the treatment of chronic colitis in an interleukin-10 gene-deficient (IL-0-/-) mouse model. METHODS FTY720 was administered orally for 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histologic appearance of the colon and the numbers, phenotype, cytokine production, and apoptosis of lymphocytes were compared with those characteristics in a control group. RESULTS Single-dose administration of FTY720 resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. Four-week administration resulted in a significant reduction of the CD4+ T lymphocytes subpopulation in the colonic lamina propria and IFN-gamma production of the colonic lymphocytes, accompanied by a significant decrease in the severity of colitis. CONCLUSIONS Treatment of established colitis in IL-10-/- mice with FTY720 ameliorated the colitis, probably as a result of decreasing the number of lymphocytes in the colonic mucosa and an associated reduction in IFN-gamma production.
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Affiliation(s)
- Tsunekazu Mizushima
- Department of Surgery (E1), Osaka University Graduate School of Medicine, Japan
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Affiliation(s)
- Severine Vermeire
- Department of Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
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Afuwape AO, Feldmann M, Paleolog EM. Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther 2003; 10:1950-60. [PMID: 14528319 DOI: 10.1038/sj.gt.3302104] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.
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Affiliation(s)
- A O Afuwape
- Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK
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Abstract
The pathogenesis of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease, involves a complex interplay between certain genetic, environmental and immunological factors. Considerable research progress in the last decade defined key inflammatory pathways in the inflamed gut and identified new potential therapeutic targets. Since the current medical treatment with corticosteroids and anti-inflammatory drugs is often associated with undesired side effects and cannot completely cure IBD, these current advances in our understanding of intestinal pathology may now allow the development of new biologic treatment strategies including gene therapy. In this review, we will give a brief overview of potential gene therapy target molecules related to chronic intestinal inflammation. Furthermore, we summarize the results of recent preclinical studies for intestinal gene transfer and discuss future perspectives.
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Affiliation(s)
- S Wirtz
- Laboratory of Immunology, I. Medical Clinic, University of Mainz, Germany
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Sanchez AL, Langdon CM, Akhtar M, Lu J, Richards CD, Bercik P, McKay DM. Adenoviral transfer of the murine oncostatin M gene suppresses dextran-sodium sulfate-induced colitis. J Interferon Cytokine Res 2003; 23:193-201. [PMID: 12856331 DOI: 10.1089/107999003765027393] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The use of biologics has promising potential in the treatment of inflammation. Studies with cultured cells and mouse models of disease have ascribed proinflammatory and anti-inflammatory functions to oncostatin M (OSM) and the related cytokine, interleukin-6 (IL-6). Here, we examined the effect of systemic administration of adenoviral (Ad) vectors encoding either murine OSM (AdMuOSM) or murine IL-6 (AdMuIL-6) in a mouse model of colitis. BALB/c mice were treated with a 5-day course of 4% dextran-sodium sulfate (DSS) water with or without administration of adenoviral vectors (i.p. or i.m. at 10(7) plaque-forming units [pfu]) given as a cotreatment or therapy. The deletion variant of the adenovirus served as a control for adenoviral infection. Colitis was assessed by (1) morphology (damage score, macrophage infiltration, apoptosis) and (2) function (myeloperoxidase activity and Ussing chamber analysis of epithelial ion transport). Infection with adenovirus alone did not affect colonic form or function. AdMuOSM (either i.p. or i.m.) significantly reduced the severity of the DSS-induced colitis. There was less damage, reduced macrophage infiltration, fewer apoptotic bodies, and a significant improvement in stimulated ion transport in colonic tissues from the treated mice. No benefit of AdMuIL-6 treatment was observed in this model system. Thus, systemic administration of AdMuOSM given as a cotreatment and to a lesser extent as a therapy was found to be of benefit in DSS-induced colitis, a murine model of inflammatory bowel disease (IBD).
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Affiliation(s)
- Ana L Sanchez
- Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada
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Lindsay J, Van Montfrans C, Brennan F, Van Deventer S, Drillenburg P, Hodgson H, Te Velde A, Sol Rodriguez Pena M. IL-10 gene therapy prevents TNBS-induced colitis. Gene Ther 2002; 9:1715-21. [PMID: 12457286 DOI: 10.1038/sj.gt.3301841] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2002] [Accepted: 06/25/2002] [Indexed: 12/11/2022]
Abstract
The transfer of genes encoding immunomodulatory proteins to the intestinal mucosa is a promising new approach to the treatment of Crohn's disease (CD). This study investigates the therapeutic efficacy of an adenoviral vector encoding IL-10 (AdvmuIL-10) in experimental colitis. BALB/c mice were treated with a single intravenous injection of AdvmuIL-10, empty cassette virus (Adv0) or PBS prior to the induction of trinitrobenzene sulphonic acid (TNBS) colitis. AdvmuIL-10 treatment prevented the severe loss of body weight associated with TNBS administration. In addition, AdvmuIL-10 therapy led to a significant reduction in both stool markers of inflammation (IL-1beta and TNFR-II) and acute phase response (serum amyloid protein). Finally, the histological scores of mice with TNBS colitis treated with AdvmuIL-10 were significantly lower than Adv0- or PBS-treated controls. The therapeutic efficacy of AdvmuIL-10 was associated with a decrease in the IFN-gamma and IL-6 levels detected in colonic homogenates from mice with TNBS colitis, whereas no effect was observed on cytokine release from stimulated systemic lymphocytes. Thus, AdvmuIL-10 is an effective therapy in the TNBS model of colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammatory conditions such as CD.
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Affiliation(s)
- J Lindsay
- The Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, UK
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Murakami Y, Akahoshi T, Kawai S, Inoue M, Kitasato H. Antiinflammatory effect of retrovirally transfected interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine air pouches. ARTHRITIS AND RHEUMATISM 2002; 46:2504-13. [PMID: 12355499 DOI: 10.1002/art.10468] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To investigate the role of interleukin-10 (IL-10) in the inflammatory response, the antiinflammatory effect of retrovirally transfected IL-10 was evaluated both in vitro and in vivo. METHODS A recombinant retrovirus containing the murine IL-10 gene was constructed using the pLXSN vector and was designated as LXSN-IL-10. Murine IL-10 was introduced into embryonic C57BL/6J fibroblast cells using LXSN-IL-10 to create C57-IL-10 cells. The effect of IL-10 in the culture supernatant of these cells was then evaluated by determining changes in the production of tumor necrosis factor alpha (TNFalpha), macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta by macrophages. The antiinflammatory effect of C57-IL-10 cells was also investigated using an in vivo model of monosodium urate monohydrate (MSU) crystal-induced acute inflammation. RESULTS The IL-10 gene transcript and its product were detected by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The level of IL-10 in the culture supernatant of C57-IL-10 cells was estimated to be 50 ng/ml. The culture supernatant of these cells exerted the biologic activity of IL-10, showing inhibition of TNFalpha, MIP-1alpha, and MIP-1beta production by macrophages. Injection of C57-IL-10 cells into murine air pouches significantly inhibited MSU crystal-induced cellular infiltration (P < 0.01) and production of the mouse CXC chemokine KC (P < 0.05). These findings were consistent with the results obtained by the injection of recombinant human IL-10 into air pouches. CONCLUSION In this murine air pouch model of MSU crystal-induced inflammation, IL-10 seemed to inhibit the recruitment of neutrophils at least partly by suppressing KC production. These findings seem to suggest that IL-10 gene therapy may be useful for inflammatory diseases.
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Affiliation(s)
- Yousuke Murakami
- Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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