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Postlethwaite AE, Jiao Y, Yang C, Dong W, Aelion JA, Wang B, Postlethwaite BE, Sigal L, Kang AH, Myers LK, Wheller P, Ingels J, Gu W. Optimizing oral immune tolerance to Type II collagen in patients with rheumatoid arthritis: The importance of dose, interfering medication and genetics. Am J Med Sci 2024; 368:300-310. [PMID: 38897565 DOI: 10.1016/j.amjms.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/17/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024]
Abstract
OBJECTIVES Oral immune tolerance (OT) is a complex process with unknown genetic regulation. Our aim is to explore possible genetic control of OT in patients with rheumatoid arthritis (RA). METHODS RA patients with increased interferon γ production invitro when their isolated peripheral blood mononuclear cells (PBMC) were cultured with type II bovine collagen α1 chain [α1 (II)] were enrolled in this study and were randomly assigned to the "Low dose" type II collagen (CII) group (30 µg/day for 10 weeks, followed by 50 µg/day for 10 weeks, followed by 70 µg/day for 10 weeks) or "High dose" CII group (90 µg/day for 10 weeks, followed by 110 µg/day for 10 weeks, followed by 130 µg/day for 10 weeks). Heparinized blood was obtained at baseline and after each of the 10 weeks treatment for analysis of the invitro production of IFNγ by their PBMC stimulated by α1(II) . Single nucleotide polymorphism (SNP) analysis of the responders and non-responders to oral CII was conducted using GeneChip Mapping 10 K 2.0 Array. RESULTS The SNP A-15,737 was found to associate with the ability of CII to suppress IFNγ production by α1(CII)-stimulated RA PBMC. The potential for SNP A-15,737 to associate with the OT response for patients with another autoimmune disease [OT induced by oral type I bovine collagen (CI) in patients with diffuse cutaneous systemic sclersodid (dsSSc)] was also explored. CONCLUSIONS The ROT1 region plays a role in the control of IFNγ production after oral dosing of auto-antigens, thereby determining if oral tolerance to that antigen will develop.
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Affiliation(s)
- Arnold E Postlethwaite
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Veterans Affairs Medical Center, Memphis, Tennessee, 38104, USA.
| | - Yan Jiao
- Departments of Orthopaedic Surgery and BME-Campbell Clinic, and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA
| | - Chengyuan Yang
- Departments of Orthopaedic Surgery and BME-Campbell Clinic, and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA
| | - Wei Dong
- Departments of Orthopaedic Surgery and BME-Campbell Clinic, and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA
| | - Jacob A Aelion
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Benjamin Wang
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | | | - Leonard Sigal
- Gateway Immunosciences, LLC, Stockbridge MA. 01262, USA
| | - Andrew H Kang
- Department of Veterans Affairs Medical Center, Memphis, Tennessee, 38104, USA
| | - Linda K Myers
- Department of Pediatrics University of Tennessee Health Science Center, Memphis, TN, USA
| | - Patricia Wheller
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jesse Ingels
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Weikuan Gu
- Departments of Orthopaedic Surgery and BME-Campbell Clinic, and Pathology, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; Department of Veterans Affairs Medical Center, Memphis, Tennessee, 38104, USA
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Chen X, Elson CO, Dunkin D. Epicutaneous Immunotherapy with CBir1 Alleviates Intestinal Inflammation. Inflamm Bowel Dis 2023; 29:798-807. [PMID: 36651798 PMCID: PMC10152294 DOI: 10.1093/ibd/izac261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND Inflammatory bowel disease may be due to failed tolerance to normal gut bacteria. We demonstrate that epicutaneous immunotherapy (ET) to ovalbumin can alleviate colitis in murine models. However, most people are tolerant to or have anergy to ovalbumin. Half of Crohn's disease (CD) patients have CBir1 antibodies that can be elevated years before CD development. We determined whether ET with a CBir1 multi-epitope peptide (MEP1) could alleviate colitis. METHODS Wild type mice (C57BL/6) were transferred with CBir1 T cell receptor (TCR) T cells followed by epicutaneous application of MEP1. Proliferating Foxp3+ T cells were measured in mesenteric lymph nodes (LNs), spleen, small intestine, and colon by flow cytometry. Lymphocytes from MEP1 epicutaneously exposed and immunized C57BL/6 mice were cultured with MEP1. Interferon (IFN)-γ production was measured. Colitis was induced by transferring CD4+CD45Rbhi T cells from CBIR1 TCR or C57BL/6 mice into RAG1-/- mice. Mice were treated with ET. Body weight, colon length, colonic cytokine production, histological inflammation, inflammatory genes, and regulatory T cells (Tregs) from lamina propria were measured. RESULTS ET with 10 μg of MEP1 induced CBir1-specific Tregs that migrated to the small intestine and colon and suppressed MEP1-specific IFN-γ production. ET alleviated colitis when the model utilized CBir1 TCR T cells in mice colonized with CBir1 or A4Fla2 positive bacteria. Treated mice had improved colon length and histological inflammation and reduced colonic IFN-γ production. CONCLUSION Epicutaneous immunotherapy with MEP1 induced Tregs that migrate to intestines and suppress inflammation in mice with CBir1 or A4Fla2-positive bacterial colonization. This could be a potential strategy to treat CD and warrants further study.
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Affiliation(s)
- Xin Chen
- Division of Pediatric Gastroenterology and the Mindich Child Health and Development Institute (MCHDI), The Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA
| | - Charles O Elson
- Department of Medicine, Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - David Dunkin
- Division of Pediatric Gastroenterology and the Mindich Child Health and Development Institute (MCHDI), The Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA
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Drennan PG, Karponis D, Richards D, Coles M, Fullerton JN. In vivo human keyhole limpet hemocyanin challenge in early phase drug development: A systematic review. Clin Transl Sci 2023; 16:357-382. [PMID: 36420645 PMCID: PMC10014697 DOI: 10.1111/cts.13457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/18/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Experimental exposure of healthy volunteers to the T-cell dependent neoantigen keyhole limpet hemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to survey the published literature where KLH was used as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies using KLH challenge in humans between January 1, 1994, and April 1, 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co-administered IMPs, and end points. Of 2421 titles and abstracts screened, 46 met the inclusion criteria, including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this end point. Two early phase IMP studies (14%) described the response to intradermal re-challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25-fold variation: 100-2500 mcg), KLH formulation, and co-administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue-level mechanism-relevant end points afforded by KLH challenge has impaired the translational utility of this paradigm to date. Future standardization, characterization, and methodological development is required to permit tailored, appropriately powered, mechanism-dependent study design to optimize drug development decisions.
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Affiliation(s)
- Philip G Drennan
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Medicine, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Duncan Richards
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Medicine, University of Oxford, Oxford, UK
| | - Mark Coles
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Medicine, University of Oxford, Oxford, UK
| | - James N Fullerton
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK.,Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Medicine, University of Oxford, Oxford, UK
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Huldani H, Margiana R, Ahmad F, Opulencia MJC, Ansari MJ, Bokov DO, Abdullaeva NN, Siahmansouri H. Immunotherapy of inflammatory bowel disease (IBD) through mesenchymal stem cells. Int Immunopharmacol 2022; 107:108698. [PMID: 35306284 DOI: 10.1016/j.intimp.2022.108698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023]
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Rezende RM, Weiner HL. Oral tolerance: an updated review. Immunol Lett 2022; 245:29-37. [PMID: 35395272 DOI: 10.1016/j.imlet.2022.03.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/27/2022] [Accepted: 03/31/2022] [Indexed: 12/18/2022]
Abstract
Oral tolerance (OT) has classically been defined as the specific suppression of cellular and/or humoral immune responses to an antigen by prior administration of the antigen through the oral route. Multiple mechanisms have been proposed to explain the induction of OT including T cell clonal depletion and anergy when high doses of antigens are fed, and regulatory T (Treg) cell generation following oral administration of low and repeated doses of antigens. Oral antigen administration suppresses the immune response in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis, uveitis, thyroiditis, myasthenia, arthritis and diabetes, but also non-autoimmune inflammatory conditions such as asthma, atherosclerosis, graft rejection, allergy and stroke. However, human trials have given mixed results and a great deal remains to be learned about the mechanisms of OT before it can be successfully applied to people. One of the possible mechanisms relates to the gut microbiota and in this review, we will explore the cellular components involved in the induction of OT and the role of the gut microbiota in contributing to OT development.
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Affiliation(s)
- Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
| | - Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Dai C, Huang YH, Jiang M, Sun MJ. Nonclostridium difficile enteric infection and the risk of developing inflammatory bowel disease: A systematic review and meta-analysis. Saudi J Gastroenterol 2020; 26:299495. [PMID: 33154203 PMCID: PMC8019142 DOI: 10.4103/sjg.sjg_231_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/22/2020] [Accepted: 08/05/2020] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder. Some studies have investigated the association between non-Clostridium difficile infection (CDI) enteric infection and the risk of developing IBD with conflicting conclusions. The objective of our study was to perform a meta-analysis of available studies evaluating the possible association between non-CDI enteric infection and the risk of developing IBD. METHODS We performed a systematic literature search of multiple online electronic databases. Inclusion criteria entailed studies about non-CDI enteric infection and IBD; A meta-analysis was conducted to evaluate relative risk (RR) and 95% confidence intervals (CIs) of combined studies for the association between non-CDI enteric infection and the risk of developing IBD. Publication bias was assessed by funnel plot analysis. RESULTS Eight studies comprising 345,490 enteric infected patients, 3223 ulcerative colitis (UC) patients, and 2133 CD patients were included in the meta-analysis. Meta-analysis showed a significantly higher risk of UC in patients with enteric infection compared with noninfected patients (RR, 2.28; 95% CI, 1.85-2.8) (I2 = 91.3%, P < 0.001). It also showed a significantly higher risk of CD in patients with enteric infection compared with noninfected patients (RR, 1.88; 95% CI, 1.66-2.14) (I2 = 49%, P = 0.024). CONCLUSION Our meta-analysis has found that patients with non-CDI enteric infection were associated with an increased risk of IBD. Future studies are needed to determine the association between non-CDI enteric infection and the risk of developing IBD and elucidate the potential underlying mechanisms.
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Affiliation(s)
- Cong Dai
- Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Yu-Hong Huang
- Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Ming-Jun Sun
- Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
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Dunkin D, Berin MC, Mondoulet L, Tobar S, Yeretssian G, Tordesillas L, Iuga A, Larcher T, Gillespie V, Benhamou PH, Colombel JF, Sampson HA. Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice. Inflamm Bowel Dis 2017; 23:1972-1982. [PMID: 29019858 PMCID: PMC5659741 DOI: 10.1097/mib.0000000000001273] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation. METHODS Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-β, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed. RESULTS Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-β-dependent, but IL-10 and iFoxp3 Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP and Foxp3 Tregs in the colon. CONCLUSIONS This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.
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Affiliation(s)
- David Dunkin
- *Division of Pediatric Gastroenterology, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; †Division of Pediatric Allergy and Immunology, Precision Immunology Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; ‡DBV Technologies, Bagneux, France; §Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; ‖Department of Pathology, Columbia University Medical School, New York, New York; ¶National Veterinary School, Nantes, France; **Department of Comparative Pathology, Icahn School of Medicine at Mount Sinai, New York, New York; and ††Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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Ino S, Kohda C, Takeshima K, Ishikawa H, Norose T, Yamochi T, Takimoto M, Takahashi H, Tanaka K. Oral tolerance is inducible during active dextran sulfate sodium-induced colitis. World J Gastrointest Pharmacol Ther 2016; 7:242-253. [PMID: 27158540 PMCID: PMC4848247 DOI: 10.4292/wjgpt.v7.i2.242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 01/20/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis.
METHODS: Colitis was induced in 6- to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-)] were intragastrically (i.g.) administered ovalbumin (OVA) as a tolerogen before systemic challenge with OVA. Following this, serum levels of OVA-specific IgE antibodies were measured. In mice with active colitis, CD4+CD25+Foxp3+ cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction.
RESULTS: Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS [DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4+CD25+Foxp3+ cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change.
CONCLUSION: Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correlate with these results.
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Katsanos KH, Torres J, Roda G, Brygo A, Delaporte E, Colombel JF. Review article: non-malignant oral manifestations in inflammatory bowel diseases. Aliment Pharmacol Ther 2015; 42:40-60. [PMID: 25917394 DOI: 10.1111/apt.13217] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/04/2015] [Accepted: 04/08/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND Patients with inflammatory bowel diseases (IBD) may present with lesions in their oral cavity. Lesions may be associated with the disease itself representing an extraintestinal manifestation, with nutritional deficiencies or with complications from therapy. AIM To review and describe the spectrum of oral nonmalignant manifestations in patients with inflammatory bowel diseases [ulcerative colitis (UC), Crohn's disease (CD)] and to critically review all relevant data. METHODS A literature search using the terms and variants of all nonmalignant oral manifestations of inflammatory bowel diseases (UC, CD) was performed in November 2014 within Pubmed, Embase and Scopus and restricted to human studies. RESULTS Oral lesions in IBD can be divided into three categories: (i) lesions highly specific for IBD, (ii) lesions highly suspicious of IBD and (iii) nonspecific lesions. Oral lesions are more common in CD compared to UC, and more prevalent in children. In adult CD patients, the prevalence rate of oral lesions is higher in CD patients with proximal gastrointestinal tract and/or perianal involvement, and estimated to range between 20% and 50%. Oral lesions can also occur in UC, with aphthous ulcers being the most frequent type. Oral manifestations in paediatric UC may be present in up to one-third of patients and are usually nonspecific. CONCLUSIONS Oral manifestations in IBD can be a diagnostic challenge. Treatment generally involves managing the underlying intestinal disease. In cases presenting with local disabling symptoms and impaired quality of life, local and systemic medical therapy must be considered and/or oral surgery may be required.
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Affiliation(s)
- K H Katsanos
- The Henry D. Janowitz Division of Gastroenterology, The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - J Torres
- The Henry D. Janowitz Division of Gastroenterology, The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - G Roda
- The Henry D. Janowitz Division of Gastroenterology, The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - A Brygo
- Department of Stomatology, Centre Hospitalier Régional Universitaire de Lille 2, Lille Cedex, France
| | - E Delaporte
- Department of Dermatology, Centre Hospitalier Régional Universitaire de Lille 2, Lille Cedex, France
| | - J-F Colombel
- The Henry D. Janowitz Division of Gastroenterology, The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Abstract
The therapeutic landscape of IBD has undergone a dramatic transformation since the advent of biologic therapies, especially TNF inhibitors. However, 30% of patients are primary nonresponders to biologic therapy and secondary failures are frequent. Due to substantial progress in our understanding of the biology of regulatory T cells (Tregs) and in the pathways of homing to the gastrointestinal tract, novel cell-based therapies for IBD have become possible. For example, although a reductionist view, one could envisage IBD as an imbalance between the proinflammatory effectors (such as Th17 cells) and the anti-inflammatory regulators (like Tregs). Here we focus on the development of ex vivo and in vivo approaches to enhance Tregs in the gastrointestinal tract. Specifically, herein we highlight a recently concluded phase 1/2a clinical trial that investigated the safety and efficacy of a single injection of escalating doses of autologous ovalbumin-specific Tregs in patients with active Crohn's disease refractory to conventional therapy. This therapy was well tolerated and demonstrated dose-related efficacy. We also discuss the potential of directing Tregs derived through intranasal as well as epicutaneous immunization to the gastrointestinal tract by enhancing their gut homing signature and their potential to decrease gastrointestinal inflammation. Finally, the strengths and pitfalls of these new therapeutic approaches are discussed as we move forward in this largely uncharted territory.
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Affiliation(s)
- David Dunkin
- Division of Gastroenterology and Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
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Hedin CR, McCarthy NE, Louis P, Farquharson FM, McCartney S, Taylor K, Prescott NJ, Murrells T, Stagg AJ, Whelan K, Lindsay JO. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings. Gut 2014; 63:1578-86. [PMID: 24398881 DOI: 10.1136/gutjnl-2013-306226] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. DESIGN Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip. RESULTS Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. CONCLUSIONS Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.
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Affiliation(s)
- Charlotte R Hedin
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK
| | - Neil E McCarthy
- Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK
| | - Petra Louis
- Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK
| | - Freda M Farquharson
- Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK
| | - Sara McCartney
- Department for Gastroenterology and Clinical Nutrition, University College Hospitals NHS Foundation Trust, London, UK
| | - Kirstin Taylor
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Natalie J Prescott
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Trevor Murrells
- National Nursing Research Unit, Florence Nightingale School of Nursing and Midwifery, King's College London, London, UK
| | - Andrew J Stagg
- Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London, London, UK
| | - Kevin Whelan
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
| | - James O Lindsay
- Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK Gastroenterology Division, Barts Health NHS Trust, London, UK
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13
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Can we produce true tolerance in patients with food allergy? J Allergy Clin Immunol 2013; 131:14-22. [PMID: 23265693 DOI: 10.1016/j.jaci.2012.10.058] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 10/05/2012] [Accepted: 10/05/2012] [Indexed: 11/23/2022]
Abstract
Immune tolerance is defined as nonresponsiveness of the adaptive immune system to antigens. Immune mechanisms preventing inappropriate immune reactivity to innocuous antigens include deletion of reactive lymphocytes and generation of regulatory T (Treg) cells. The normal response to food antigens is the generation of antigen-specific Treg cells. In patients with food allergy, the dominant immune response is a T(H)2-skewed T-cell response and the generation of food-specific IgE antibodies from B cells. It is not known whether a failure of the Treg cell response is behind this inappropriate immune response, but interventions that boost the Treg cell response, such as mucosal immunotherapy, might lead to a restoration of immune tolerance to foods. Tolerance has been notoriously difficult to restore in animal disease models, but limited data from human trials suggest that tolerance (sustained nonresponsiveness) can be re-established in a subset of patients. Furthermore, studies on the natural history of food allergy indicate that spontaneous development of tolerance to foods over time is not uncommon. The current challenge is to understand the mechanisms responsible for restoration of natural or induced tolerance so that interventions can be developed to more successfully induce tolerance in the majority of patients with food allergy.
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Meyer T, Ullrich R, Zeitz M. Oral tolerance induction in humans. Exp Mol Pathol 2012; 93:449-54. [DOI: 10.1016/j.yexmp.2012.10.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Accepted: 10/01/2012] [Indexed: 01/03/2023]
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15
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Cassani B, Villablanca EJ, De Calisto J, Wang S, Mora JR. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med 2011; 33:63-76. [PMID: 22120429 DOI: 10.1016/j.mam.2011.11.001] [Citation(s) in RCA: 144] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 11/01/2011] [Accepted: 11/10/2011] [Indexed: 01/27/2023]
Abstract
The vitamin A (VA) metabolite all-trans retinoic acid (RA) plays a key role in mucosal immune responses. RA is produced by gut-associated dendritic cells (DC) and is required for generating gut-tropic lymphocytes and IgA-antibody-secreting cells (IgA-ASC). Moreover, RA modulates Foxp3(+) regulatory T cell (T(REG)) and Th17 effector T cell differentiation. Thus, although RA could be used as an effective "mucosal adjuvant" in vaccines, it also appears to be required for establishing intestinal immune tolerance. Here we discuss the roles proposed for RA in shaping intestinal immune responses and tolerance at the gut mucosal interface. We also focus on recent data exploring the mechanisms by which gut-associated DC acquire RA-producing capacity.
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Affiliation(s)
- Barbara Cassani
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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16
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Abstract
The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103(+) retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3(+) iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP(+) Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal.
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Affiliation(s)
- Howard L Weiner
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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17
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Brandtzaeg P. The gut as communicator between environment and host: immunological consequences. Eur J Pharmacol 2011; 668 Suppl 1:S16-32. [PMID: 21816150 DOI: 10.1016/j.ejphar.2011.07.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 07/01/2011] [Accepted: 07/07/2011] [Indexed: 12/18/2022]
Abstract
During human evolution, the mucosal immune system developed two anti-inflammatory mechanisms: immune exclusion by secretory antibodies (SIgA and SIgM) to control epithelial colonization of microorganisms and inhibit penetration of harmful substances; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens such as food proteins. The latter function is referred to as oral tolerance when induced via the gut. Similar mechanisms also control immunity to commensal bacteria. The development of immune homeostasis depends on "windows of opportunity" where adaptive and innate immunities are coordinated by antigen-presenting cells; their function is not only influenced by microbial products but also by dietary constituents, including vitamin A and lipids like polyunsaturated omega-3 fatty acids. These factors can in several ways exert beneficial effects on the immunophenotype of the infant. Also breast milk provides immune-modulating factors and SIgA antibodies - reinforcing the gut barrier. Mucosal immunity is most abundantly expressed in the gut, and the intestinal mucosa of an adult contains at least 80% of the body's activated B cells - terminally differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric IgA which is exported by secretory epithelia expressing the polymeric Ig receptor (pIgR), also called membrane secretory component (SC). Immune exclusion is therefore performed mainly by SIgA. Notably, pIgR knockout mice which lack SIgs show increased uptake of food and microbial antigens and they have a hyper-reactive immune system with disposition for anaphylaxis; but this untoward development is counteracted by cognate oral tolerance induction as a homeostatic back-up mechanism.
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Affiliation(s)
- Per Brandtzaeg
- Laboratory for Immunohistochemistry and Immunopathology, Centre for Immune Regulation, University of Oslo, and Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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18
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Kumamoto CA. Inflammation and gastrointestinal Candida colonization. Curr Opin Microbiol 2011; 14:386-91. [PMID: 21802979 DOI: 10.1016/j.mib.2011.07.015] [Citation(s) in RCA: 169] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Accepted: 07/06/2011] [Indexed: 02/06/2023]
Abstract
Candida organisms commonly colonize the human gastrointestinal tract as a component of the resident microbiota. Their presence is generally benign. Recent studies, however, show that high level Candida colonization is associated with several diseases of the gastrointestinal tract. Further, results from animal models argue that Candida colonization delays healing of inflammatory lesions and that inflammation promotes colonization. These effects may create a vicious cycle in which low-level inflammation promotes fungal colonization and fungal colonization promotes further inflammation. Both inflammatory bowel disease and gastrointestinal Candida colonization are associated with elevated levels of the pro-inflammatory cytokine IL-17. Therefore, effects on IL-17 levels may underlie the ability of Candida colonization to enhance inflammation. Because Candida is a frequent colonizer, these effects have the potential to impact many people.
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Affiliation(s)
- Carol A Kumamoto
- Department of Molecular Biology and Microbiology, Tufts University, 136 Harrison Ave., Boston, MA 02111, USA.
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19
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Jiang XL, Cui HF. New treatments for refractory ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2011; 19:1871-1873. [DOI: 10.11569/wcjd.v19.i18.1871] [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
Traditional therapies have poor efficacy for hormone-dependent or -resistant ulcerative colitis. However, treatment with non-myeloablative cord blood stem cells and infliximab shows promising results in patients with refractory ulcerative colitis and represents a safe and effective approach to the management of refractory ulcerative colitis.
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20
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Brandtzaeg P. Homeostatic impact of indigenous microbiota and secretory immunity. Benef Microbes 2010; 1:211-27. [DOI: 10.3920/bm2010.0009] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In the process of evolution, the mucosal immune system has generated two layers of anti-inflammatory defence: (1) immune exclusion performed by secretory IgA (and secretory IgM) antibodies to modulate or inhibit surface colonisation of microorganisms and dampen penetration of potentially dangerous antigens; and (2) suppressive mechanisms to avoid local and peripheral hypersensitivity to innocuous antigens, particularly food proteins and components of commensal bacteria. When induced via the gut, the latter phenomenon is called 'oral tolerance', which mainly depends on the development of regulatory T (Treg) cells in mesenteric lymph nodes to which mucosal dendritic cells (DCs) carry exogenous antigens and become conditioned for induction of Treg cells. Mucosally induced tolerance appears to be a rather robust adaptive immune function in view of the fact that large amounts of food proteins pass through the gut, while overt and persistent food allergy is not so common. DCs are 'decision makers' in the immune system when they perform their antigen-presenting function, thus linking innate and adaptive immunity by sensing the exogenous mucosal impact (e.g. conserved microbial molecular patterns). A balanced indigenous microbiota is required to drive the normal development of both mucosa-associated lymphoid tissue, the epithelial barrier with its secretory IgA (and IgM) system, and mucosally induced tolerance mechanisms including the generation of Treg cells. Notably, polymeric Ig receptor (pIgR/SC) knock-out mice that lack secretory IgA and IgM antibodies show reduced epithelial barrier function and increased uptake of antigens from food and commensal bacteria. They therefore have a hyper-reactive immune system and show predisposition for systemic anaphylaxis after sensitisation; but this development is counteracted by enhanced oral tolerance induction as a homeostatic back-up mechanism.
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Affiliation(s)
- P. Brandtzaeg
- Department and Institute of Pathology, Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), University of Oslo, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway
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21
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Abstract
Numerous genes are involved in innate and adaptive immunity and these have been modified over millions of years. During this evolution, the mucosal immune system has developed two anti-inflammatory strategies: immune exclusion by the use of secretory antibodies to control epithelial colonization of microorganisms and to inhibit the penetration of potentially harmful agents; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens, such as food proteins. The latter strategy is called oral tolerance when induced via the gut. Homeostatic mechanisms also dampen immune responses to commensal bacteria. The mucosal epithelial barrier and immunoregulatory network are poorly developed in newborns. The perinatal period is, therefore, critical with regard to the induction of food allergy. The development of immune homeostasis depends on windows of opportunity during which innate and adaptive immunity are coordinated by antigen-presenting cells. The function of these cells is not only orchestrated by microbial products but also by dietary constituents, including vitamin A and lipids, such as polyunsaturated omega-3 fatty acids. These factors may in various ways exert beneficial effects on the immunophenotype of the infant. The same is true for breast milk, which provides immune-inducing factors and secretory immunoglobulin A, which reinforces the gut epithelial barrier. It is not easy to dissect the immunoregulatory network and identify variables that lead to food allergy. This Review discusses efforts to this end and outlines the scientific basis for future food allergy prevention.
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Affiliation(s)
- Per Brandtzaeg
- Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), University of Oslo and Department and Institute of Pathology, Oslo University Hospital, Rikshospitalet, N-0027 Oslo, Norway.
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22
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Silva MF, Kamphorst AO, Hayashi EA, Bellio M, Carvalho CR, Faria AMC, Sabino KCC, Coelho MGP, Nobrega A, Tavares D, Silva AC. Innate profiles of cytokines implicated on oral tolerance correlate with low- or high-suppression of humoral response. Immunology 2010; 130:447-57. [PMID: 20331474 DOI: 10.1111/j.1365-2567.2010.03248.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
SUMMARY Oral tolerance (OT) is being studied with great interest because of its therapeutic potential in allergy and autoimmunity. In the present study, two mouse strains with extreme phenotypes of OT susceptibility (TS) or resistance (TR) to ovalbumin (OVA) were used to demonstrate whether the tr and ts genes, cumulated during 18 generations of bi-directional genetic selection, influence expression of immunobiological traits in naive or antigen-gavaged TR/TS mice. The difference in anti-OVA titres was 2048-fold between OVA-gavaged TS and TR mice. Tolerance susceptibility to OVA gavage in individuals from a (TS x TR)F(2) population was 24% high-susceptibility, 62% low-susceptibility and 14% non-tolerant. Different antigens, unrelated to OVA, were tested by gavage and TS mice were generally susceptible while TR mice were resistant. The stability of TS and TR phenotypes was not affected by the use of strict protocols of intraperitoneal immunization or feeding over 30 consecutive days. The levels of interleukin-2 (IL-2), IL-4, interferon-gamma and IL-10 cytokines evaluated in concanavalin A-stimulated spleen cells from naive mice and in OVA-stimulated spleen cells from OVA-gavaged mice were higher in TS mice. Interleukin-10 was up-regulated in OVA-gavaged TS mice and down-regulated in TR mice. In naive mice, the percentage of CD4(+) CD25(+) and CD4(+) Foxp3(+) spleen cells and IL-10 expression by CD4(+) cells was significantly higher in TS mice. These results indicate that regulation of IL-10 expression could be an important factor contributing to the mechanisms controlling OT susceptibility, and that the OT responses of TR and TS individuals strongly correlate with their innate potential to secrete this cytokine.
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Affiliation(s)
- Maria F Silva
- Universidade Estadual do Norte Fluminense, Rio de Janeiro, Brazil.
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23
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Abstract
Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.
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Affiliation(s)
- Jerrold R Turner
- Department of Pathology, The University of Chicago, 5841 South Maryland, MC 1089, Chicago, Illinois 60637, USA.
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24
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Abstract
Regulatory T cells help maintain intestinal homeostasis by preventing inappropriate innate and adaptive immune responses. CD4(+) T cells that express Foxp3 and Tr1-like cells that produce IL-10 comprise the major regulatory populations in the intestine. CD4(+)Foxp3(+) T cells play an important functional role in promoting tolerance of the flora and dietary proteins. Tr1-like cells can be generated in conditions that also promote effector T cell responses and may serve a similar function. In this review, we discuss the signals specific to the gastrointestinal tract that support both regulatory cell types and their distinct modes of action in the mesenteric lymph nodes and intestinal tissues. Dysregulation of intestinal immune homeostasis occurs in inflammatory bowel disease and can also be observed in graft-versus-host disease, tumor immunotherapy regimens, and acute HIV infection.
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Affiliation(s)
- Michael J Barnes
- Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK
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25
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Fields SW, Baiocco PJ, Korelitz BI. Influenza vaccinations: should they really be encouraged for IBD patients being treated with immunosuppressives? Inflamm Bowel Dis 2009; 15:649-51; author reply 651-2. [PMID: 18831525 DOI: 10.1002/ibd.20731] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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26
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Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol 2008; 29:532-40. [DOI: 10.1016/j.it.2008.09.002] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 08/26/2008] [Accepted: 09/01/2008] [Indexed: 01/27/2023]
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Sartor RB, Muehlbauer M. Microbial host interactions in IBD: implications for pathogenesis and therapy. Curr Gastroenterol Rep 2008; 9:497-507. [PMID: 18377803 DOI: 10.1007/s11894-007-0066-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Crohn's disease (CD), ulcerative colitis (UC), and pouchitis appear to be caused by pathogenic T-cell responses to discrete antigens from the complex luminal microbiota, with susceptibility conferred by genetic polymorphisms that regulate bacterial killing, mucosal barrier function, or immune responses. Environmental triggers initiate or reactivate inflammation and modulate genetic susceptibility. New pathogenesis concepts include defective bacterial killing by innate immune cells in CD, colonization of the ileum in CD with functionally abnormal Escherichia coli that adhere to and invade epithelial cells and resist bacterial killing, and alterations in enteric microbiota composition in CD, UC, and pouchitis detected by molecular probes. The considerable therapeutic potential of manipulating the enteric microbiota in inflammatory bowel disease patients has not been realized, probably due to failure to recognize heterogenic disease mechanisms that require individualized use of antibiotics, probiotics, prebiotics, combination therapies, and genetically engineered bacteria to restore mucosal homeostasis.
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Affiliation(s)
- R Balfour Sartor
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, CB #7032, Room 7309, Medical Biomolecular Research Building, Chapel Hill, NC 27599, USA.
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28
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Abstract
Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
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Affiliation(s)
- Howard L. Weiner
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andre Pires da Cunha
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Francisco Quintana
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Henry Wu
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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