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Setarehaseman A, Mohammadi A, Maitta RW. Thrombocytopenia in Sepsis. Life (Basel) 2025; 15:274. [PMID: 40003683 PMCID: PMC11857489 DOI: 10.3390/life15020274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Platelets, traditionally known for their role in hemostasis, have emerged as key players in immune response and inflammation. Sepsis, a life-threatening condition characterized by systemic inflammation, often presents with thrombocytopenia, which at times, can be significant. Platelets contribute to the inflammatory response by interacting with leukocytes, endothelial cells, and the innate immune system. However, excessive platelet activation and consumption can lead to thrombocytopenia and exacerbate the severity of sepsis. Understanding the multifaceted roles of platelets in sepsis is crucial for developing effective therapeutic strategies. Targeting platelet-mediated inflammatory responses and promoting platelet production may offer potential avenues for improving outcomes in septic patients with thrombocytopenia. Future research should focus on elucidating the mechanisms underlying platelet dysfunction in sepsis and exploring novel therapeutic approaches to optimize platelet function and mitigate inflammation. This review explores the intricate relationship between platelets, inflammation, and thrombosis in the context of sepsis.
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Affiliation(s)
- Alireza Setarehaseman
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;
| | - Abbas Mohammadi
- Department of Internal Medicine, Valley Health System, Las Vegas, NV 89119, USA;
| | - Robert W. Maitta
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;
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Li B, Yan YP, He YY, Liang C, Li MY, Wang Y, Yang ZM. IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice. Sci Signal 2023; 16:eadd0645. [PMID: 36853961 DOI: 10.1126/scisignal.add0645] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
The establishment of pregnancy depends on interactions between the epithelial and stromal cells of the endometrium that drive the decidual reaction that remodels the stroma and enables embryo implantation. Decidualization in mice also depends on ovarian hormones and the presence of a blastocyst. Hedgehog signaling is transduced by primary cilia in many tissues and is involved in epithelial-stromal cross-talk during decidualization. We found that primary cilia on mouse uterine stromal cells increased in number and length during early pregnancy and were required for decidualization. In vitro and in vivo, progesterone promoted stromal ciliogenesis and the production of Indian hedgehog (IHH) in the epithelium and Sonic hedgehog (SHH) in the stroma. Blastocyst-derived TNF-α also induced epithelial IHH, which stimulated the production of SHH in the stroma through a mechanism that may involve the release of arachidonic acid from epithelial cells. In the stroma, SHH activated canonical Hedgehog signaling through primary cilia and promoted decidualization through a mechanism that depended on interleukin-11 (IL-11) and primary cilia. Our findings identify a primary cilia-dependent network that controls endometrial decidualization and suggest primary cilia as a candidate therapeutic target for endometrial diseases.
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Affiliation(s)
- Bo Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China.,College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Ya-Ping Yan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yu-Ying He
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Chen Liang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Meng-Yuan Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Ying Wang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Zeng-Ming Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountain Region, College of Animal Science, Guizhou University, Guiyang 550025, China.,College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
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Lishchinskaya AA, Knyazev OV, Kagramanova AV, Dudina GA, Sabelnikova EA, Li IA, Noskova KK, Bodunova NA, Parfenov AI. Frequency and risk factors for thromboembolic complications in patients with inflammatory bowel diseases. TERAPEVT ARKH 2022; 94:172-179. [DOI: 10.26442/00403660.2022.02.201367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 11/22/2022]
Abstract
Background. Inflammatory bowel diseases (IBD) are characterized by chronic immune inflammation of the mucous membrane and/or the thickness of the intestinal wall, and are also accompanied by disorders of the blood clotting system and the development of a hypercoagulation state.
Aim. To identify the frequency of thromboembolic complications (TEC) in IBD patients and to determine the influence of acquired and inherited hypercoagulation factors that contribute to the development of TEС.
Materials and methods. The clinical status of 1,238 IBD patients who were treated in 2019 was evaluated. Of these, 748 patients with ulcerative colitis (UC) and 490 patients with Crohn's disease (CD). Among UC patients, there were 369 (49.3%) men and 379 (50.7%) women. In 10.1% of patients with UC, there were clinically significant feasibility studies. There were 227 (46.3%) men and 263 (53.7%) women among patients with CD; 7.3% of patients with CD had clinically significant feasibility studies.
Results. In general 112 (9.0%) of 1,238 IBD patients had clinically significant feasibility studies. Among patients with UC (n=748), 76 (10.2%) showed clinically significant feasibility studies. Among patients with CD (n=490), 36 (7.3%) had a feasibility study. Of 112 IBD patients with clinically significant TEC, 45 (40.2%) had genetic polymorphisms that increase affinity for fibrinogen, increase platelet aggregation, and contribute to a decrease in the activity of folate cycle enzymes, including methylenetetrahydrofolate reductase, which may be manifested by a moderate increase in homocysteine levels. Of the 45 IBD patients with clinically significant TEC due to inherited factors, 30 (66.6%) patients had UC, 15 (33.7%) patients had CD (hazard ratio 1.038, 95% confidence interval 0.7461.444; 2=0.049; p=0.83921); 67 (59.8%) patients with IBD who had clinically significant TEC did not have genetic polymorphisms leading to hypercoagulation.
Conclusion. Based on the analysis, we can conclude that such risk factors for the development of TEC as the status of a smoker, long bed rest, taking hormonal contraceptives, varicose veins of the lower extremities, high activity of the disease, glucocorticoids therapy, the extent of intestinal damage in patients with IBD, genetic factors, should be taken into account by gastroenterologists in the treatment of patients with UC and CD. The hereditary factor of hypercoagulation equally affects the development of TEC, both in patients with UC and CD.
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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol 2021; 18:787-803. [PMID: 34211157 DOI: 10.1038/s41575-021-00473-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2021] [Indexed: 02/06/2023]
Abstract
IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.
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5
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Metcalfe RD, Putoczki TL, Griffin MDW. Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Front Immunol 2020; 11:1424. [PMID: 32765502 PMCID: PMC7378365 DOI: 10.3389/fimmu.2020.01424] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.
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Affiliation(s)
- Riley D Metcalfe
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
| | - Tracy L Putoczki
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
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Ma C, Hussein IM, Al-Abbar YJ, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, Siegel CA, Peyrin-Biroulet L, Pai RK, Vande Casteele N, D'Haens GR, Sandborn WJ, Feagan BG, Jairath V. Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review. Clin Gastroenterol Hepatol 2018; 16:1407-1419.e22. [PMID: 29596987 DOI: 10.1016/j.cgh.2018.02.051] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/21/2018] [Accepted: 02/27/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. METHODS We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. RESULTS Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts' Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. CONCLUSIONS In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
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Affiliation(s)
- Christopher Ma
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada; Robarts Clinical Trials, Western University, London, Ontario, Canada
| | | | | | - Remo Panaccione
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Claire E Parker
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Tran M Nguyen
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Reena Khanna
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Corey A Siegel
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Rish K Pai
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Niels Vande Casteele
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Geert R D'Haens
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands
| | - William J Sandborn
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Brian G Feagan
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
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7
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Are Injection Site Reactions in Monoclonal Antibody Therapies Caused by Polysorbate Excipient Degradants? J Pharm Sci 2018; 107:2735-2741. [PMID: 30055223 DOI: 10.1016/j.xphs.2018.07.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/11/2018] [Accepted: 07/17/2018] [Indexed: 12/22/2022]
Abstract
Injection site reactions (ISRs) and other adverse side effects are commonly observed during therapy with biologics. These hypersensitivity-related side effects can vary from simple rash to life-threatening anaphylactic reaction and may be linked to the immunogenicity of the drug including formation of antidrug antibodies. Reactions can also occur as a consequence of excipients in the product. We report the case of a patient who developed erythematous ISRs to both commercial PCSK9i formulations and had to go off therapy even though efficacy was not impacted. Skin testing showed that the patient was reacting to the polysorbates. Polysorbates are added to stabilize the biotherapeutic. Polysorbates can also activate complement and lead to a range of acute hypersensitivity and systemic immunostimulation reactions. Oxidative degradation products can function as haptens by reacting with proteins at the injection site. Reactive degradation products may even form adducts with the biologic itself, creating a potential neoantigen. Further research is needed to understand the fundamental causes of ISRs. It is critical that only the highest quality raw material is used, and proper storage conditions are employed to minimize degradation of polysorbates in the product. Although complete elimination of ISRs is unlikely, all efforts must be made to minimize them.
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8
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Ma C, Dutton SJ, Cipriano LE, Singh S, Parker CE, Nguyen TM, Guizzetti L, Gregor JC, Chande N, Hindryckx P, Feagan BG, Jairath V. Systematic review with meta-analysis: prevalence, risk factors and costs of aminosalicylate use in Crohn's disease. Aliment Pharmacol Ther 2018; 48:114-126. [PMID: 29851091 DOI: 10.1111/apt.14821] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 04/13/2018] [Accepted: 05/02/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. AIMS To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. METHODS MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo-controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co-prescribed aminosalicylates in placebo arms was pooled using a random-effects model. Meta-regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. RESULTS Forty-two induction and 10 maintenance trials were included. The pooled proportion of patients co-prescribed aminosalicylates was 44% [95% CI: 39%-49%] in induction trials and 49% [95% CI: 35%-64%] in maintenance trials. There was substantial to considerable heterogeneity (I2 = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta-regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34-0.74] per 10-year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. CONCLUSIONS Over one-third of CD patients entering clinical trials are still co-prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy.
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Affiliation(s)
- C Ma
- Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Robarts Clinical Trials, Western University, London, ON, Canada
| | - S J Dutton
- Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - L E Cipriano
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Ivey Business School, Western University, London, ON, Canada
| | - S Singh
- Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA.,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - C E Parker
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - T M Nguyen
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - L Guizzetti
- Robarts Clinical Trials, Western University, London, ON, Canada
| | - J C Gregor
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - N Chande
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - P Hindryckx
- Department of Gastroenterology, University Hospital of Ghent, Ghent, Belgium
| | - B G Feagan
- Robarts Clinical Trials, Western University, London, ON, Canada.,Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
| | - V Jairath
- Robarts Clinical Trials, Western University, London, ON, Canada.,Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.,Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
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9
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Jairath V, Zou G, Parker CE, MacDonald JK, Mosli MH, AlAmeel T, Al Beshir M, AlMadi M, Al-Taweel T, Atkinson NSS, Biswas S, Chapman TP, Dulai PS, Glaire MA, Hoekman D, Kherad O, Koutsoumpas A, Minas E, Restellini S, Samaan MA, Khanna R, Levesque BG, D'Haens G, Sandborn WJ, Feagan BG. Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease. Aliment Pharmacol Ther 2017; 45:1021-1042. [PMID: 28164348 DOI: 10.1111/apt.13973] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 07/08/2016] [Accepted: 01/16/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Minimising placebo response is essential for drug development. AIM To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.
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Affiliation(s)
| | | | | | | | - M H Mosli
- London, ON, Canada.,Jeddah, Saudi Arabia
| | | | | | | | | | | | | | | | - P S Dulai
- London, ON, Canada.,La Jolla, CA, USA
| | | | | | | | | | | | | | | | | | | | - G D'Haens
- London, ON, Canada.,Amsterdam, The Netherlands
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10
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Wilhelm SM, Taylor JD, Osiecki LL, Kale-Pradhan PB. Novel Therapies for Crohn's Disease: Focus on Immunomodulators and Antibiotics. Ann Pharmacother 2016; 40:1804-13. [PMID: 16985094 DOI: 10.1345/aph.1h038] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Objective: To review the literature on novel immunomodulators such as tumor necrosis factor alpha (TNF-α)- and interleukin (IL)-related agents, 6-thioguanine (6-TG), tacrolimus, and leflunomide, and antibiotics such as ornidazole, rifaximin, and ciprofloxacin for the treatment of Crohn's disease. Data Sources: Literature was accessed through MEDLINE (1966–January 2006) using the terms Crohn's disease, novel therapies, immunomodulators, and antibiotics. Article references were hand-searched for additional relevant articles and abstracts. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated. Studies including greater than 5 patients with primarly adult populations were included in the review. Data Synthesis: There are a number of new TNF-α and IL-related agents that may be useful for management of Crohn's disease. They include CDP 571, CDP 870, etanercept, onercept, thalidomide, IL-10, and IL-11. Several studies have shown that CDP 571 decreases the Crohn's Disease Activity Index score and is promising, especially in patients with refractory disease. 6-TG, tacrolimus, and leflunomide are among other immunomodulators that appear to have a role in refractory/severe disease. Finally, ornidazole, rifaximin, and ciprofloxacin are antimicrobials that may be used in patients who have failed other therapies or as adjunctive therapies. Conclusions: A number of new treatment modalities are being investigated for Crohn's disease. Many of them are promising, and some of these agents may be considered in treatment-refractory patients in the future. However, some of the agents reviewed here are not available in the US. Future studies need to be double-blinded and placebo- or other treatment-controlled in a more homogeneous patient population.
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Affiliation(s)
- Sheila M Wilhelm
- Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
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11
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Reznikov LL, Puren AJ, Fantuzzi G, Hamner GR, Schwertschlag US, Ryan JL, Dinarello CA. Suppression of endotoxin-inducible cytokines in whole blood from human subjects following single dose of recombinant human interleukin-11. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519990050040601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
To determine whether a single injection of recombinant human interleukin-11 (rhIL-11) to human subjects would affect endotoxin-inducible cytokine production, 6 dialysis-dependent patients with renal failure and 4 healthy volunteers were subcutaneously injected with rhIL-11 (50 µg/kg). The circulating concentrations of rhIL-11 remained at a constant level of approximately 12 ng/ml for 0.25—6 h in healthy volunteers but were 2-fold higher in dialysis-dependent patients. Venous blood obtained before and after rhIL-11 was stimulated with 10 ng/ml of LPS for 24 h at 37°C and production of TNFα, IL-1β, and IL-8 determined. The maximum suppression of IL-1β, TNFα and IL-8 production (66%, 24% and 58%, respectively) was observed 1 h after rhIL-11 administration. After 24 h, when circulating concentration of rhIL-11 had decreased to near pre-injection levels, LPS-induced TNFα and IL-1β production remained suppressed (56 ± 17%, P < 0.05; 46 ± 4.7, P<0.01, respectively) but returned to baseline at 48 h. These findings suggest that there is a therapeutic benefit of single doses of rhIL-11 in reducing LPS-induced IL-1β and TNFα production.
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Affiliation(s)
- Leonid L. Reznikov
- Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | - Adrian J. Puren
- Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | - Giamila Fantuzzi
- Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | - Gary R. Hamner
- Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | | | - John L. Ryan
- Genetics Institute, Inc., Cambridge, Massachusetts, USA
| | - Charles A. Dinarello
- Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
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12
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Permyakov EA, Uversky VN, Permyakov SE. Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions. Cell Biochem Biophys 2016; 74:285-96. [DOI: 10.1007/s12013-016-0752-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 06/13/2016] [Indexed: 12/14/2022]
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13
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A panoramic review and in silico analysis of IL-11 structure and function. Cytokine Growth Factor Rev 2016; 32:41-61. [PMID: 27312790 DOI: 10.1016/j.cytogfr.2016.06.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 05/21/2016] [Accepted: 06/03/2016] [Indexed: 12/15/2022]
Abstract
Human Interleukin (IL)-11 is a multifunctional cytokine, recognized for its thrombopoietic effects for more than two decades; clinically, IL-11 is used in the treatment of thrombocytopenia. IL-11 shares structural and functional similarities with IL-6, a related family member. In recent years, there has been a renewed interest in IL-11, because its distinct biological activities associated with cancers of epithelial origin and inflammatory disorders have been revealed. Although the crystal structure of IL-11 was resolved more than two years, a better understanding of the mechanisms of IL-11 action is required to further extend the clinical use of IL-11. This review will discuss the available structural, functional, and bioinformatics knowledge concerning IL-11 and will summarize its relationship with several diseases.
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Abstract
IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers.
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Affiliation(s)
- Tracy L Putoczki
- The Walter & Eliza Hall Institute of Medical Research & Department of Medical Biology, University of Melbourne, Parkville Victoria 3052, Australia
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15
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Abstract
After a relatively long time of failed developments and negative clinical trials in pharmacological inflammatory bowel disease (IBD) therapy we now phase a time of a great number of successful studies and new therapy principles that will most likely make it into clinical practice. This will change the landscape of IBD therapy in future markedly. Many new therapeutic principles have been developed and old ones that seemed to have failed such as anti-sense technology suddenly now provide promising results. Some initially promising therapies will need further development or have failed such as Trichuris suis ova therapy (but not helminth therapy in general), CCR9 targeted therapies or recombinant IL-10. In contrast anti-leukocate trafficking therapies appear to be quite promising. Vedolizumab is the first in class anti-integrin antibody that was approved for the therapy of CD and UC recently. Other anti-integrin antibodies and small molecule adhesion inhibitors will most likely be approved in the next years for IBD therapy. Tofacitinib, a small molecule JAK inhibitor, is a promising candidate for the treatment of UC. Phosphatidylcholine may be a future option for patients with 5-ASA refractory UC or 5-ASA intolerance. The preliminary data for Mongersen, a Smad7 antisense oligonucleotide, are promising despite some concerns about long term effect of TGFβ induction. Anti IL6 strategies will hopefully be further evaluated keeping in mind the caveat of a lack of CRP induction in anti-IL6 treated patients. Stem cell transplantation will become an option for patients that have experienced failure of established medications. Fecal microbiota transplantation and also perhaps combined probiotic therapy is a field that will be evaluated in more detail in the near future especially for UC patients. Based on these new developments treatment algorithms need to be updated. This review will reflect these current developments and give a perspective for future IBD therapy.
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Auer K, Trachter R, Van den Bogaerde J, Bassaganya-Riera J, Sorrentino D. Translational research and efficacy of biologics in Crohn's disease: a cautionary tale. Expert Rev Clin Immunol 2014; 10:219-29. [PMID: 24410538 DOI: 10.1586/1744666x.2014.877839] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the last several years many biologic agents for Crohn's disease have been developed. Due to their unique molecular specificity biologics are de facto indicators of the ultimate significance of the molecule targeted by the biologic itself. Here, we have reviewed many clinical studies that have used biologics for Crohn's disease. Their results show that despite potentially sound theoretical mechanisms of action and some initially promising data, most biologics - with few notable exceptions - have failed. Pharmacologic, study design or patient-related issues might explain these findings in some studies. However in many cases clinical failure of biologics might highlight the complexity of in vivo events and the potential deficiencies of current experimental settings. Hence, these observations call for new and efficient ways of predicting drug efficacy in clinical trials based on bench research. Conceivably, computer-based pathogenetic models could be used to simulate and predict clinical studies results in vivo.
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Affiliation(s)
- Keil Auer
- Sunshine Coast Clinical School, Nambour, QLD 4560, Australia
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Bandzar S, Gupta S, Platt MO. Crohn's disease: a review of treatment options and current research. Cell Immunol 2013; 286:45-52. [PMID: 24321565 DOI: 10.1016/j.cellimm.2013.11.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 08/25/2013] [Accepted: 11/12/2013] [Indexed: 02/07/2023]
Abstract
Crohn's disease is an autoimmune disorder that affects nearly 1.4 million Americans. The etiology of Crohn's disease is not completely understood, however, research has suggested a genetic link. There is currently no known cure for Crohn's disease and, as a result, most government-funded research is being conducted to increase the quality of life of afflicted patients (i.e. reducing chronic inflammation and alleviating growth impairment in pediatric patients). A number of treatment options are available including an alpha-4 integrin inhibitor and several TNF-alpha inhibitors. Furthermore, research is being conducted on several alternative treatment options to help understand exactly which cellular mechanisms (i.e. inducing apoptosis in leukocytes) are required for clinical efficacy. This review seeks to chronicle the current available treatment options for patients affected by Crohn's disease to aid in understanding potential cellular mechanistic requirements for an efficacious drug, and shed light on potential options for future treatment.
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Affiliation(s)
- Sean Bandzar
- Georgia Regents University, Medical College of Georgia, Augusta, GA, United States.
| | - Shabnam Gupta
- Emory University School of Medicine, Atlanta, GA, United States
| | - Manu O Platt
- Georgia Institute of Technology, Coulter Department of Biomedical Engineering, Atlanta, GA, United States
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Kersting S, Behrendt V, Kersting J, Reinecke K, Hilgert C, Stricker I, Herdegen T, Janot MS, Uhl W, Chromik AM. The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium. J Inflamm Res 2013; 6:71-81. [PMID: 23667316 PMCID: PMC3650567 DOI: 10.2147/jir.s40092] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Indexed: 12/27/2022] Open
Abstract
Purpose: The c-Jun N-terminal kinases (JNK) are involved in the activation of T cells and the synthesis of proinflammatory cytokines. Several studies have established the relevance of the JNK pathway in inflammatory bowel diseases. The present study analyzed the therapeutic effect of D-JNKI-1, a specific JNK-inhibiting peptide, in a low-dose dextran sulfate sodium (DSS) model of chronic colitis. Methods: DSS colitis was induced in female C57/BL6 mice by cyclic administration using different concentrations of DSS (1.0% and 1.5%). Mice in the intervention groups received subcutaneous administration of 1 μg/kg D-JNKI-1 on days 2, 12, and 22. They were monitored daily to assess the severity of colitis, body weight, stool consistency, and the occurrence of occult blood or gross rectal bleeding using evaluation of the disease activity index. The animals were sacrificed after 30 days, and the inflamed intestine was histologically evaluated using a crypt damage score. Immunohistochemical quantification of CD4+ and CD8+ cells was also carried out. Results: Administration of 1 μg/kg D-JNKI-1 resulted in a significant decrease in the disease activity index (P = 0.013 for 1.0% DSS; P = 0.007 for 1.5% DSS). As a mild form of colitis was induced, histological examination did not show any distinct damage to the mucosa and crypts. However, expression of CD4+ and CD8+ cells was reduced in mice treated with D-JNKI-1 (not significant). Conclusion: Administration of D-JNKI-1 resulted in a clinical attenuation of chronic DSS colitis, and a therapeutic effect of D-JNKI-1 must therefore be assumed. The decrease in CD4+ and CD8+ cells may reflect the influence of D-JNKI-1 on T-cell activation, differentiation, and migration.
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Affiliation(s)
- Sabine Kersting
- Department of General and Visceral Surgery, St Josef Hospital, Ruhr University of Bochum, Bochum, Germany
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Bilsborough J, Viney JL. From model to mechanism: lessons of mice and men in the discovery of protein biologicals for the treatment of inflammatory bowel disease. Expert Opin Drug Discov 2013; 1:69-83. [PMID: 23506033 DOI: 10.1517/17460441.1.1.69] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Successful therapeutics for inflammatory bowel disease (IBD) must be able to reverse effectively the complex processes involved in the manifestation of inflammatory pathology in intact tissues. Although studies of human tissue samples are important to confirm the biological rationale for developing a particular therapeutic, in vivo rodent models of IBD provide a biological 'flask' in which therapeutics can be tested in a more representative setting. Moreover, gene targeting and transgenic technologies in rodents have exponentially increased the repertoire of available IBD models and provided insight into possible contributions that certain genes may have in the pathogenesis of disease. These models have been key in generating the current arsenal of biological therapeutics that are available, or are presently under investigation, for the treatment of IBD patients.
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Affiliation(s)
- Janine Bilsborough
- ZymoGenetics, Inc., Department of Autoimmunity and Inflammation, 1201 Eastlake Avenue East, Seattle, WA 98102, USA
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Tajdini M, Hosseini SMR, Mirbagheri SA, Modabbernia A. Interleukin-11 for induction of remission in Crohn's disease. Hippokratia 2012. [DOI: 10.1002/14651858.cd009822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Masih Tajdini
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
| | - Seyed Mohammad Reza Hosseini
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
| | - Seyed Amir Mirbagheri
- Faculty of Medicine, Tehran University of Medical Science; Department of Gastroenterology, Amira'lam Hospital; Digestive System Disorders Research Centre, Amira'lam Hospital, Tehran University of Medical Sciences Enghelab Street Tehran Iran 13337
| | - Amirhossein Modabbernia
- Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences; Department of Psychiatry; South Kargar Street Tehran Iran 13337
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Abstract
Inflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role in the pathogenesis of IBD, and thus biological therapies targeting key molecules such as cytokines have been designed. Several anti-TNF-α agents are currently being used to treat Crohn's disease and ulcerative colitis. Although these molecules dramatically improved the treatment of patients, side effects and the development of antidrug antibodies limits their application. There is thus an urgent need for alternative approaches to decrease inflammation and limit immunogenicity. Small neutralizing molecules, active immunization, gene silencing, selective transcription inhibitors and delivery of agents through the oral route are some of the currently developed strategies to meet these needs. In parallel, neutralizing antibodies targeting other pathways of the immune system have been developed and tested. Antibodies targeting IL-12/IL-23 pathways, and proinflammatory cytokines such as IFN-γ, IL-17A, IL-2 and IL-6 often showed an initial promising result, but for none of these agents efficacy has unequivocally been established. Administration of the regulatory cytokines IL-10 and IL-11 also failed to induce reproducible clinical effects. This article focuses on the anti-TNF therapies and the current challenges with monoclonal antibody therapies, discusses the innovative strategies targeting cytokine pathways to decrease inflammation in the bowel, and summarizes the recently developed agents neutralizing proinflammatory cytokines.
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Affiliation(s)
- Clémentine Perrier
- Division of Gastroenterology, University Hospital, Catholic University Leuven, Leuven, Belgium
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Abstract
IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.
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Abstract
Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn's disease ) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-alpha antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.
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Affiliation(s)
- Wojciech Blonski
- Center for Inflammatory Bowel Diseases, Hospital of the University of Pennsylvania, 3rd Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
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Kuhara T, Yamauchi K, Iwatsuki K. Bovine lactoferrin induces interleukin-11 production in a hepatitis mouse model and human intestinal myofibroblasts. Eur J Nutr 2011; 51:343-51. [PMID: 21688123 DOI: 10.1007/s00394-011-0219-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 06/07/2011] [Indexed: 12/24/2022]
Abstract
PURPOSE Orally administered bovine lactoferrin (bLF) exerts an anti-inflammatory effect on hepatitis and colitis animal models. To investigate the mechanism underlying the action of bLF, we explored the expression of inflammation-related factors in the intestine of a hepatitis mouse model after the oral administration of bLF and in several human intestinal cell lines treated with bLF. METHODS The effects of bLF on the expression of interleukin-11 (IL-11) and bone morphogenetic protein 2 (BMP2) in the intestinal mucosa of a hepatitis mouse model as well as in cell cultures of human intestinal epithelial cells, myofibroblasts, and monocytes were examined using the real-time reverse transcription polymerase chain reaction. Epithelial cells and myofibroblasts were also cocultured using transwells. bLF transport, and IL-11 and BMP2 induction, as well as the interactions between the two cell types, were then analyzed after bLF treatment. RESULTS In vivo, oral bLF administration increased the production of IL-11 and BMP2 in intestinal specimens. In vitro, bLF only stimulated the production of IL-11 in human intestinal myofibroblasts; i.e., it had no effect on BMP2 production in any cell type. In the transwell cocultures, bLF passed through the epithelium and directly stimulated IL-11 production in the myofibroblasts on the basolateral side. The IL-11 produced in the myofibroblasts subsequently acted protectively on the epithelial cells of the coculture. CONCLUSIONS bLF upregulated the activity of anti-inflammatory factors, such as IL-11, in the intestine of a hepatitis mouse model and human intestinal myofibroblasts.
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Affiliation(s)
- Tetsuya Kuhara
- Food Science & Technology Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa, 228-8583, Japan.
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Abstract
IMPORTANCE OF THE FIELD Increased understanding of the biological mechanisms of Crohn's disease has opened the door to a large number of new molecules; some of these are approved for clinical use, while others remain under evaluation. In this review, we examine the clinical efficacy of all the new drugs that have been evaluated in controlled trials in the last 12 years. AREAS COVERED IN THIS REVIEW Anti-TNF therapy has been reviewed briefly, given the many comprehensive reviews on this topic; attention is focused mainly on the other biological therapies. In assessing the clinical efficacy of these molecules, we consider only the remission rate, as this is considered the most meaningful end point in clinical practice. WHAT THE READER WILL GAIN We analyzed the main biological mechanisms of Crohn's disease and the new drugs whose use is based on insights into these mechanisms. We reviewed the following new drugs: probiotics, GM-CSF, IL-10, IL-11, anti-IL-6, anti-IL-12/-23, everolimus, anti-IFN-γ, IFN-β-I, co-stimulators, anti-integrins, anti-intercellular adhesion molecule 1, small molecules and mitogen-activated protein kinase inhibitors. TAKE HOME MESSAGE Anti-TNF therapies remain the best options, followed by anti-integrin drugs. The most promising new therapies are anti-IL-23, but further data are necessary. The disappointing results with other molecules may depend on the quality of trials and possibly on inadequate dosage of the drug.
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Affiliation(s)
- Mario Cottone
- Department of Internal Medicine, University of Palermo, Ospedale Villa Sofia-Cervello, via trabucco 180, 90146 Palermo, Italy
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Bouguen G, Chevaux JB, Peyrin-Biroulet L. Recent advances in cytokines: therapeutic implications for inflammatory bowel diseases. World J Gastroenterol 2011; 17:547-56. [PMID: 21350703 PMCID: PMC3040326 DOI: 10.3748/wjg.v17.i5.547] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 03/22/2010] [Accepted: 03/29/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mesenchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becoming a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of cytokines involved in IBD and new therapeutic opportunities for these diseases.
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Danese S, Angelucci E. New and emerging biologics in the treatment of inflammatory bowel disease: quo vadis? ACTA ACUST UNITED AC 2010; 33 Suppl 3:S217-27. [PMID: 20117345 DOI: 10.1016/s0399-8320(09)73157-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel diseases (IBD) are pathological conditions characterized by chronic inflammation that is primarily the consequence of dysregulation of the immune response. Over the last decade, the advances in the pathophysiology of IBD have paved the way for the development of a number of biological agents that selectively target specific molecules and/or pathways involved in gut inflammation. Although numerous, so far, the only biological therapeutics that are approved for the treatment for IBD are monoclonal antibodies against tumor necrosis factor alpha. This paper systematically reviews the mechanismof-action, efficacy, short-term and, where available, long-term safety of biological agents that target molecules other than tumor necrosis factor alpha, in IBD.
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Affiliation(s)
- S Danese
- Division of Gastroenterology, Istituto Clinico Humanitas, IRCCS in Gastroenterology, Rozzano, Milan, Italy.
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28
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Abstract
Implantation failure is the most important rate limiting factor in the success of assisted reproductive techniques like In vitro fertilization–embryo transfer (IVF-ET). Cytokines are multifunctional signaling molecules having an implicit role in the human implantation process. This review focuses on the redundant roles of cytokines during the various stages of implantation. It also indicates that levels of cytokines in biological fluids like serum and follicular fluid obtained during oocyte retrieval might act as determinants of implantation potential of the blastocyst. Thus a holistic, metabolomic approach of analyzing biological fluids may provide a simpler approach to study the hitherto enigmatic process rather than the proteomic and genomic approach.
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Affiliation(s)
- Natachandra Chimote
- Vaunshdhara Clinic and Assisted Conception Centre, 9, Dr. Munje Marg, Congress Nagar, Nagpur, India
| | - Meena Chimote
- Vaunshdhara Clinic and Assisted Conception Centre, 9, Dr. Munje Marg, Congress Nagar, Nagpur, India
| | - Bindu Mehta
- Vaunshdhara Clinic and Assisted Conception Centre, 9, Dr. Munje Marg, Congress Nagar, Nagpur, India
| | - Nirmalendu Nath
- Vaunshdhara Clinic and Assisted Conception Centre, 9, Dr. Munje Marg, Congress Nagar, Nagpur, India
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Gibson DL, Montero M, Ropeleski MJ, Bergstrom KSB, Ma C, Ghosh S, Merkens H, Huang J, Månsson LE, Sham HP, McNagny KM, Vallance BA. Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology 2010; 139:1277-88. [PMID: 20600022 DOI: 10.1053/j.gastro.2010.06.057] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Revised: 05/17/2010] [Accepted: 06/10/2010] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The roles of intestinal Toll-like receptors (TLR) in the pathogenesis of colitis are not known. TLR2 and TLR4 appear to protect against dextran sodium sulfate-induced colitis by promoting mucosal integrity, but it is not clear whether this method of protection occurs in other models of colitis. We investigated the roles of TLR2 and TLR4 and the cell types that express these receptors during infectious colitis. METHODS We generated chimeric mice with TLR2(-/-) or TLR4(-/-) bone marrow and infected them with the bacterial pathogen Citrobacter rodentium. We assessed their susceptibility to colitis and the mechanisms of TLR-mediated mucosal integrity. RESULTS TLR2-expressing tissue resident cells prevented lethal colitis, whereas TLR4-dependent inflammatory responses of hematopoietic cells mediated intestinal damage. TLR2 expression protected against intestinal damage by maintaining epithelial barrier function and inducing expression of interleukin (IL)-11 from tissue resident cells in the muscularis mucosae, concurrent with epithelial activation of the transcription factor STAT3. Addition of exogenous IL-11 protected against the lethal colitis in TLR2-deficient mice via STAT3 activation in intestinal epithelial cells. CONCLUSIONS TLR2-dependent cytoprotective responses from tissue resident cells maintain mucosal integrity against the ultimately lethal TLR4-dependent inflammatory responses of hematopoietic cells. Whereas TLR2 protects against various noxious agents, the role of TLR4 during colitis can be either protective or damaging, depending on the stimulus. Therefore, therapeutics that reduce innate immunity (TLR2 signaling in particular) may not be beneficial to patients with colitis; they could worsen symptoms. Therapies that stimulate cytoprotective responses, like IL-11, could have benefits for patients with colitis.
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Affiliation(s)
- Deanna L Gibson
- Division of Gastroenterology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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Abstract
Inflammatory bowel disease (IBD) is characterized by increasing morbidity and, if suboptimally treated, poor prognosis. Recent evidence strongly suggests that dysfunctional immune responses play an important role in the pathogenesis of IBD. Therefore, immunologically downregulating the overactivated innate and adaptive immune responses may be a better approach to treat IBD than currently used pharmaceutical therapies. In recent years, many new biological therapies have been developed. These therapies are shown to be effective for inducing remission, preventing complications, improving life quality of the patients, and reducing hospitalization and surgical rates. This article introduces and discusses these new biological agents that have been used effectively in clinic for IBD patients.
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Affiliation(s)
- Aiping Bai
- University of Manitoba, Winnipeg, Canada
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31
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MCNAMEE EÓINN, COLLINS COLMB, LEBSACK MATTHEWD, RIVERA–NIEVES JESÚS. Cell-specific inhibition of p38alpha as a therapeutic strategy for inflammatory bowel disease. Gastroenterology 2010; 138:1237-9. [PMID: 20184972 PMCID: PMC4414012 DOI: 10.1053/j.gastro.2010.02.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Wang L, Bai AP. Biological therapies for inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2010; 18:107-112. [DOI: 10.11569/wcjd.v18.i2.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, represents a heterogenic group of chronic diseases with a high morbidity and poor prognosis. The etiology of IBD is still unknown, and the pathogenesis of IBD has not been fully clarified. Consequently, the clinical outcome of IBD is unsatisfying. Fortunately, a variety of new biological therapies have being developed in recent years. These therapies are shown to be helpful in inducing remission, preventing complications, improving life quality of the patients, and reducing hospitalization rates and surgical rates. This article will review these new biological agents clinically used for IBD patients.
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Abstract
BACKGROUND Randomized, placebo controlled trials are used to assess the efficacy of therapies for Crohn's disease. The placebo response and remission rates vary among studies. AIM To analyse how the placebo response and remission rates in Crohn's trials have changed over time in the era of parenteral biologic therapies. METHODS A search for randomized, placebo-controlled trials of parenteral biologic therapies for active Crohn's disease was conducted using online databases. The placebo response and remission rates and study week of evaluation were recorded for each trial. The placebo response and remission rates were analysed as functions of publication date and study week of evaluation. RESULTS The odds of a placebo-induced remission and response significantly increased as the week of evaluation increased. The placebo remission rate increased significantly with year of publication. Adjusted for week of evaluation, this increase in placebo remission rate over time was no longer significant. The increase in the placebo response over this time period was not statistically significant. CONCLUSION The observed increase in placebo remission rates over time in trials of parenteral biologic therapies in Crohn's disease is explained by longer times to the primary endpoint in more recent trials.
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Affiliation(s)
- W C Gallahan
- Section of Gastroenterology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
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Ghosh N, Chaki R, Mandal V, Lin GD, Mandal SC. Mechanisms and efficacy of immunobiologic therapies for inflammatory bowel diseases. Int Rev Immunol 2010; 29:4-37. [PMID: 20100080 DOI: 10.3109/08830180903437212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Current advances in understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. Crohn's disease and ulcerative colitis, two common inflammatory bowel diseases likely result from interaction of multiple genetic and environmental risk and protective factors, deregulation of mucosal immunity in gut and breakdown of delicate balance of proinflammatory and anti-inflammatory cytokines. Immunobiologic agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-kappaB), and others are being assessed and will open exciting perspectives on development of therapies for inflammatory bowel disease.
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Affiliation(s)
- Nilanjan Ghosh
- Dr. B.C. Roy College of Pharmacy and Allied Health Sciences, Durgapur, India. bhu
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Guzeloglu-Kayisli O, Kayisli UA, Taylor HS. The role of growth factors and cytokines during implantation: endocrine and paracrine interactions. Semin Reprod Med 2009; 27:62-79. [PMID: 19197806 DOI: 10.1055/s-0028-1108011] [Citation(s) in RCA: 197] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Implantation, a critical step for establishing pregnancy, requires molecular and cellular events resulting in uterine growth and differentiation, blastocyst adhesion, invasion, and placental formation. Successful implantation requires a receptive endometrium, a normal and functional embryo at the blastocyst stage, and a synchronized dialogue between maternal and embryonic tissues. In addition to the well-characterized role of sex steroids, the complexity of embryo implantation and placentation is exemplified by the number of cytokines and growth factors with demonstrated roles in these processes. Disturbances in the normal expression and action of these cytokines result in an absolute or partial failure of implantation and abnormal placental formation in mice and human. Members of the gp130 cytokine family, interleukin-11 (IL-11) and leukemia inhibitory factor, the transforming growth factor beta superfamily, the colony-stimulating factors, and the IL-1 and IL-15 systems are crucial molecules for a successful implantation. Chemokines are also important, both in recruiting specific cohorts of leukocytes to the implantation site and in trophoblast trafficking and differentiation. This review provides discussion of the embryonic and uterine factors that are involved in the process of implantation in autocrine, paracrine, and/or juxtacrine manners at the hormonal, cellular, and molecular levels.
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Affiliation(s)
- Ozlem Guzeloglu-Kayisli
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA
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Rivera-Nieves J, Gorfu G, Ley K. Leukocyte adhesion molecules in animal models of inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:1715-35. [PMID: 18523998 PMCID: PMC2733908 DOI: 10.1002/ibd.20501] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The dysregulated recruitment of leukocytes into the intestine is required for the initiation and maintenance of inflammatory bowel disease (IBD). Several families of molecules regulate the influx of these cells into sites of inflammation. Interference with some of these molecules has already shown efficacy in the clinics and antibodies that target the molecules involved have been approved by the FDA for use in Crohn's disease (CD), multiple sclerosis (i.e., natalizumab), and psoriasis (i.e., efalizumab). Here, we discuss basic aspects of the different families of relevant molecules and compile a large body of preclinical studies that supported the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in colitis and in novel models of CD-like ileitis.
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Affiliation(s)
- Jesus Rivera-Nieves
- Mucosal Inflammation Program, Division of Gastroenterology, Department of Internal Medicine, University of Colorado Health Sciences Center, Denver Colorado 80206,Address correspondence and reprint requests to: Dr. Jesus Rivera-Nieves, Mucosal Inflammation Program, Division of Gastroenterology, Department of Internal Medicine, University of Colorado Health Sciences Center, Biochemistry Research Building Room 742A, 4200 E. 9th Ave SE, B146, Denver, CO 80206, e-mail address:
| | - Gezahegn Gorfu
- La Jolla Institute for Allergy and Immunology, Division of Inflammation Biology, La Jolla, CA 92037, USA
| | - Klaus Ley
- La Jolla Institute for Allergy and Immunology, Division of Inflammation Biology, La Jolla, CA 92037, USA
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Abstract
Signal transducers and activators of transcription 3 (STAT3) play an important role in various autoimmune disorders including inflammatory bowel disease (IBD). Recent studies have revealed that STAT3 activation plays distinctly different roles between innate immune responses and acquired immune responses in colitis. STAT3-mediated activation of acquired immune responses plays a pathogenic role in colitis by enhancing the survival of pathogenic T cells. In contrast, STAT3-mediated activation of innate responses contributes to the suppression of colitis. This review will summarize the current understanding of the roles of STAT3 in IBD and the potential of targeting STAT3 for the treatment of IBD, emphasizing recent observations.
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Abstract
In the past few years, antagonists of tumour necrosis factor have resulted in unforetold therapeutic benefits in Crohn's disease, but the magnitude and duration of responses are variable. New agents are therefore needed. Their development has benefited from advances in the understanding of the pathophysiology of this disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. With increasing evidence of an implication of the innate immune system and the intestinal epithelium, the therapeutic paradigm is also shifting from mere immunosuppression to the reinforcement of the intestinal barrier. We review mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials. We discuss future directions, including new strategies with optimum endpoints.
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Tinè F, Rossi F, Sferrazza A, Orlando A, Mocciaro F, Scimeca D, Olivo M, Cottone M. Meta-analysis: remission and response from control arms of randomized trials of biological therapies for active luminal Crohn's disease. Aliment Pharmacol Ther 2008; 27:1210-23. [PMID: 18346185 DOI: 10.1111/j.1365-2036.2008.03681.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Remission and response are the main outcomes to evaluate the efficacy of new treatments for Crohn's disease (CD). AIM To explain variation of remission and response rates in active luminal CD. METHODS We studied control patients from trials of biological therapies through articles retrieved by MEDLINE search (from 1997 to 2007) and by bibliography review. Thousand nine hundred and thirteen control patients from 28 trials were identified; data were extracted by three independent observers and pooled by DerSimonian and Laird random effect model; factors influencing remission and clinical response were explored by metaregression for aggregated data. RESULTS The pooled control rates of remission and response were 17% and 33%, respectively, both with significant heterogeneity among studies (P < 0.0001). At metaregression, the time of primary outcome evaluation was associated with remission, whereas the trial's criteria for defining response and publication year were predictors of response. CDAI score, CRP levels or other clinical variables related with disease activity or concomitant medications were not significant factors. CONCLUSIONS Populations used as 'add-on' treatment comparator in trials of biological therapies for active luminal CD are poorly characterized and outcomes are heterogeneous. Planning of future trials will require better description of patients and concomitant therapies, blinding of outcome assessors and homogeneous criteria of outcome definition.
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Affiliation(s)
- F Tinè
- Divisione di Gastroenterologia, Azienda Ospedaliera V. Cervello, Palermo, Italy.
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Abstract
Implantation, a critical step for establishing pregnancy, requires molecular and cellular events resulting in healthy uterine growth and differentiation, blastocyst adhesion, invasion and placental formation. Successful implantation requires a receptive endometrium, a normal and functional embryo at the blastocyst stage and a synchronized dialogue between maternal and embryonic tissues. In addition to the main role of sex steroids, the complexity of embryo implantation and placentation is exemplified by the number of cytokines and growth factors with demonstrated roles in these processes. Disturbances of the normal expression and action of these cytokines result in absolute or partial failure of implantation and abnormal placental formation in mice and humans. Members of the gp130 cytokine family, interleukin (IL)-11 and leukaemia inhibitory factor, the transforming growth factor-beta superfamily, colony-stimulating factors, and the IL-1 and IL-15 systems are all crucial for successful implantation. In addition, chemokines are important both in recruiting specific cohorts of leukocytes to the implantation site, and in trophoblast trafficking and differentiation. This review provides discussion on embryonic and uterine factors that are involved in the process of implantation in autocrine, paracrine and/or juxtacrine manners at hormonal, cellular, and molecular levels.
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Affiliation(s)
- Ozlem Guzeloglu-Kayisli
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA
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Flamant M, Bourreille A. Biothérapies et MICI: anti-TNF et nouvelles cibles thérapeutiques. Rev Med Interne 2007; 28:852-61. [PMID: 17628232 DOI: 10.1016/j.revmed.2007.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2007] [Accepted: 06/11/2007] [Indexed: 12/18/2022]
Abstract
PURPOSE Advances in the understanding of inflammatory bowel disease (IBD) pathophysiological mechanisms in the last few years have allowed the development of novel therapies such as biologic therapies. Theoretically, biologic therapies represent a more specific management of IBD with fewer effects. CURRENT KNOWLEDGE AND KEY POINTS Currently, infliximab is the only effective and widely accepted biologic therapy for the treatment of Crohn disease after the conventional therapies. Others anti-TNF therapies such as adalimumab or certolizumab will be soon an alternative treatment notably for patients with allergic reactions to infliximab and for those with lost of response because of anti-infliximab antibody development. Anti-integrin alpha4 therapies have been delayed by three progressive multifocal leukoencephalopathy cases. Immunostimulating therapy may be highly relevant in the future with granulocyte-monocyte colony-stimulating factor. PERSPECTIVES Efficacy of these new therapies will modify therapeutics of Crohn's disease and ulcerative colitis and in particular decrease the use of corticosteroids, which are not well tolerated by the patients.
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Affiliation(s)
- M Flamant
- Institut des maladies de l'appareil digestif (IMAD), CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 01, France
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Hoang B, Trinh A, Birnbaumer L, Edwards RA. Decreased MAPK- and PGE2-dependent IL-11 production in Gialpha2-/- colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1511-9. [PMID: 17332478 DOI: 10.1152/ajpgi.00307.2006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mice deficient in the G-protein alpha subunit G(i)alpha(2) spontaneously develop colitis and colon cancer. IL-11 is a pleiotropic cytokine known to protect the intestinal epithelium from injury in animal models of colitis and is produced by subepithelial myofibroblasts in response to inflammatory mediators including TGF-beta, IL-1beta, and PGE(2). Arachidonic acid release and subsequent PGE(2) production is significantly decreased in the colonic mucosa of G(i)alpha(2)-/- mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in G(i)alpha(2)-/- mice despite the presence of mild colitis. Primary cultures of G(i)alpha(2)-/- intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF-beta or IL-1beta-stimulated IL-11 mRNA and protein than wild-type cells. Inhibitors of ERK or p38 MAPK activation dose dependently inhibited IMF and CMF IL-11 production in response to TGF-beta stimulation, whereas 16,16 dimethyl-PGE(2) and prostanoid receptor subtype-selective agonists induced IL-11 production. Treatment of animals with the EP4-specific agonist ONO-AE1-329 resulted in enhanced mucosal levels of IL-11, and increased IL-11 production by ex vivo cultured CMF. Modulation of cAMP levels produced diverging results, with enhancement of TGF-beta-induced IL-11 release in IMF pretreated with 8-Br-cAMP and inhibition in cells treated either with pertussis toxin or the PKA inhibitor H-89. These data suggest a physiological role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.
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MESH Headings
- 16,16-Dimethylprostaglandin E2/pharmacology
- Alprostadil/analogs & derivatives
- Alprostadil/pharmacology
- Animals
- Cells, Cultured
- Colon/cytology
- Colon/drug effects
- Colon/enzymology
- Colon/metabolism
- Cyclic AMP/metabolism
- Dinoprostone/metabolism
- Dose-Response Relationship, Drug
- Enzyme Activation
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Fibroblasts/drug effects
- Fibroblasts/enzymology
- Fibroblasts/metabolism
- Flavonoids/pharmacology
- GTP-Binding Protein alpha Subunit, Gi2/deficiency
- GTP-Binding Protein alpha Subunit, Gi2/genetics
- GTP-Binding Protein alpha Subunit, Gi2/metabolism
- Imidazoles/pharmacology
- Interleukin-11/genetics
- Interleukin-11/metabolism
- Interleukin-1beta/metabolism
- Intestine, Small/cytology
- Intestine, Small/drug effects
- Intestine, Small/enzymology
- Intestine, Small/metabolism
- Methyl Ethers/pharmacology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitogen-Activated Protein Kinases/antagonists & inhibitors
- Mitogen-Activated Protein Kinases/metabolism
- Protein Kinase Inhibitors/pharmacology
- Pyridines/pharmacology
- RNA, Messenger/metabolism
- Receptors, Prostaglandin E/metabolism
- Receptors, Prostaglandin E, EP4 Subtype
- Signal Transduction/drug effects
- Transforming Growth Factor beta/metabolism
- p38 Mitogen-Activated Protein Kinases/metabolism
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Affiliation(s)
- Brian Hoang
- Dept. of Pathology, D449 Med Sci I, Univ. of California Irvine, Irvine, CA 92697-4800, USA
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Abstract
Several biologic agents have been assessed in patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC]). Until recently, only infliximab (humanized monoclonal anti-TNF-alpha antibody) had been approved by the Food and Drug Administration (FDA) to induce and maintain remission in patients with active mild to moderate and/or fistulizing Crohn's disease who are refractory to conventional therapy. Two recent trials, ACT 1 and ACT2, observed high efficacy of infliximab in inducing and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. This agent also was recently approved by the FDA for the treatment of ulcerative colitis to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa, and to eliminate the use of corticosteroids in patients with moderately to severely active UC who have had an inadequate response to conventional therapy. There have been many randomized, double-blind, controlled and open-label uncontrolled studies of large and small numbers of patients assessing the efficacy and safety of various biologic agents considered potentially useful in the treatment of IBD. Among all the biologic agents, infliximab has the most robust data on safety. This is because it has been evaluated in many more trials than has any other biologic agent. In addition, postmarketing experience provides very valuable information about adverse events occurring during treatment with this agent.
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Affiliation(s)
- Wojciech Blonski
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland
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Abstract
Crohn's disease (CD) and ulcerative colitis (UC), the two idiopathic inflammatory bowel diseases (IBDs), affect almost two million individuals in North America and several million worldwide. Cytokines are important in the pathogenesis of CD, and their manipulation has successfully reduced disease severity and maintained remission. Following the discovery of novel cytokines and the role they may play in gut mucosal immunity, as well as the emergence of new concepts and changing paradigms in CD pathogenesis, the roles of several cytokines have been elucidated and tested in both preclinical animal models and clinical trials of patients with IBD. Complementary to this, proof of concept for new cytokine targets is rapidly developing, with the possibility of future cytokine-based therapies that may offer greater specificity and decreased toxicity for the treatment of CD. This review discusses novel concepts in CD pathogenesis and the roles of cytokines in the initiation and perpetuation of disease. In addition, we review applications of cytokine-based therapies in human clinical trials and preclinical animal studies. Finally, we discuss novel cytokine targets not yet investigated in vivo and describe their potential contribution to CD pathogenesis.
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Affiliation(s)
- Theresa T Pizarro
- Division of Gastroenterology & Hepatology and the Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
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Hanauer SB. Review article: high-dose aminosalicylates to induce and maintain remissions in ulcerative colitis. Aliment Pharmacol Ther 2006; 24 Suppl 3:37-40. [PMID: 16961743 DOI: 10.1111/j.1365-2036.2006.03058.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Sulfasalazine was the first aminosalicylate to be used for induction and maintenance therapy of ulcerative colitis (UC). Initial trials demonstrated a dose response that was compromised by dose-related intolerance. Recognition that the 5-aminosalicylic acid moiety (5-ASA, mesalazine) is the active ingredient of sulfasalazine has allowed the development of sulpha-free formulations of mesalazine and alternative azo-bond derivatives (olsalazine, balsalazide) that substantially reduce the dose-related (and allergic) consequences of the sulfapyridine moiety of sulfasalazine. Dose-ranging studies of mesalazine formulations for induction of remission have demonstrated increased efficacy of oral mesalazine up to 4-4.8 g/day, particularly in patients with more moderate disease activity. Combination therapy with oral and rectal mesalazine provide additional efficacy for patients with both distal and extensive colitis. The mesalazine formulations have dose-related benefits without dose-related side effects. In contrast, the azo-bond formulations are compromised by secretory diarrhoea at doses providing greater than 2-2.4 g/day of mesalazine. There are less data regarding dose-related benefits of aminosalicylates to maintain remissions in UC greater than 1.6 g/day of mesalazine, although the absence of dose-related side effects allows continuation of the same inductive dose through maintenance treatment without dose-related toxicity.
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Affiliation(s)
- S B Hanauer
- Professor of Medicine and Clinical Pharmacology Chief, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637, USA.
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José León A, Garrote JA, Arranz E. [Cytokines in the pathogenesis of inflammatory bowel diseases]. Med Clin (Barc) 2006; 127:145-52. [PMID: 16831396 DOI: 10.1157/13090382] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is produced by an exaggerated response to bacterial flora within the intestinal mucous, in which both environmental and genetic factors are involved. T lymphocytes are involved during the genesis and maintenance of IBD, and their cytokine profile in Crohn's disease (mostly Th1 cytokines) is different from that in ulcerative colitis (mainly Th2 cytokines). After the inflammatory response has been established, the balance between proinflammatory and regulatory cytokines determines the degree of mucosal damage and the form of presentation. A deeper knowledge of the immunological mechanisms involved in IBD has opened new research lines aimed to the development of new therapies such as the neutralization of proinflammatory cytokines with antibodies and the administration of antiinflammatory cytokines, which are currently at different stages of research.
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Affiliation(s)
- Alberto José León
- Areas de Pediatría e Inmunología, Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid, Ramón y Cajal 7, 47005 Valladolid, Spain
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Deutscher N, Bataille F, Hausmann M, Kiessling S, Muller-Newen G, Leeb SN, Herfarth H, Heinrich PC, Schölmerich J, Rogler G. Functional expression of the interleukin-11 receptor alpha-chain in normal colonic epithelium and colon cancer. Int J Colorectal Dis 2006; 21:573-81. [PMID: 16292518 DOI: 10.1007/s00384-005-0055-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/22/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Interleukin-11 (IL-11) has been evaluated as an anti-inflammatory and mucosa-protective therapeutic agent in inflammatory bowel diseases (IBDs). Activity of IL-11 requires binding to the alpha receptor subunit (IL-11Ralpha) that provides ligand specificity. Recently, we showed that in the intestinal mucosa, IL-11Ralpha is mainly present on epithelial cells mediating antiapoptotic effects. The aim of this study was to investigate the expression profiling of IL-11Ralpha and its downstream signaling cascade in colonic adenoma and carcinoma. MATERIALS AND METHODS The expression of IL-11Ralpha in normal colonic mucosa, 11 colonic adenomas, and 10 carcinomas was analyzed by immunohistochemistry. In addition, IL-11Ralpha-expression and IL-11Ralpha-induced phosphorylation of signal transducer and activator of transcription (STAT)3 were investigated by Western blot analysis. RESULTS Immunohistochemistry revealed significant IL-11-Ralpha expression in epithelial cells of normal colonic mucosa. In contrast, the expression of IL-11-Ralpha in colon adenomas and carcinomas was either absent or only detectable in very few scattered epithelial cells. Densitometric analysis of Western blots confirmed these results, showing a decrease of IL-11Ralpha-protein in cells isolated from adenomas or carcinomas. Reduced STAT3-phosphorylation in carcinoma cells indicated functional consequences of decreased IL-11Ralpha-protein expression on signal transduction. CONCLUSION This study demonstrates a decrease of IL-11-Ralpha-protein expression in epithelial cells isolated from colon carcinomas and adenomas compared to normal colonic mucosa and a reduced STAT3 signaling. Because of reduced binding and signal transduction, it is unlikely that therapeutically administered IL-11 would contribute to colorectal carcinoma induction and growth.
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Affiliation(s)
- Nicole Deutscher
- Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany
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Herrlinger KR, Witthoeft T, Raedler A, Bokemeyer B, Krummenerl T, Schulzke JD, Boerner N, Kueppers B, Emmrich J, Mescheder A, Schwertschlag U, Shapiro M, Stange EF. Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease. Am J Gastroenterol 2006; 101:793-7. [PMID: 16635225 DOI: 10.1111/j.1572-0241.2005.00356.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset of patients with mild to moderate Crohn's disease (CD). The present study compared the efficacy of rhIL-11 versus prednisolone in remission induction in CD. METHODS Patients with active CD were randomly assigned to receive either subcutaneous rhIL-11 (1 mg once weekly) and prednisolone placebo tablets, or active prednisolone (60 mg/day) and rhIL-11 placebo, for 12 weeks. Prednisolone/placebo was tapered after week 1, and patients were assessed every second week. RESULTS Fifty-one patients received medication: 13/27 (rhIL-11) and 17/24 (prednisolone) completed 12 weeks of treatment. Remission rates (intent to treat) for rhIL-11 versus prednisolone were 4% versus 46% at week 4 (p < 0.001) and 19% versus 50% at week 6 (p < 0.05). Response to treatment (deltaCDAI > 100) was seen in 19% (rhIL-11) versus 63% (prednisolone) after 4 weeks (p < 0.002) and 37% versus 63% after 6 weeks (p = 0.1). After 12 weeks of treatment, it was observed that 22% (rhIL-11) versus 21% (prednisolone) had remained in remission. Frequent side effects of rhIL-11 included fever (n = 3), rash (4), arthralgia/arthritis (3), nausea/vomiting (3), and headache (6). CONCLUSION rhIL-11 is well tolerated but significantly inferior when compared to prednisolone in short-term remission induction in patients with active CD. In this patient cohort, both treatments appeared to be poor in maintaining remission over a period of 3 months.
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50
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Abstract
PURPOSE OF REVIEW The purpose of this review is to analyze the complications associated with treatment of inflammatory bowel disease with biologic agents. RECENT FINDINGS There have been various biologic agents evaluated in patients with inflammatory bowel disease; that is, Crohn's disease and ulcerative colitis. Thus far only infliximab has been approved by the US Food and Drug Administration as induction and maintenance treatment in patients with active Crohn's disease (moderate-to-severe and/or fistulizing) who are refractory to conventional therapy. Recent data from two large multicenter, multicountry, randomized controlled clinical trials have demonstrated that infliximab is efficacious also for the treatment of ulcerative colitis. Other biologics considered potentially efficacious are still undergoing evaluation in various clinical trials. SUMMARY The data concerning biologics' associated toxicity in patients with inflammatory bowel disease are the most robust in the case of infliximab. These data are derived from both prospective, randomized clinical trials and from post-marketing experience. In the case of the remaining agents the data concerning safety in inflammatory bowel disease are limited, as these agents were not evaluated in as many trials as infliximab; indeed, some of them included only several patients.
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Affiliation(s)
- Wojciech Blonski
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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