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Huang T, Xu X, Chen S, Liu Z, Huang Y, Huo X, Chen G. Down-regulation of serum SIRT6 levels is associated with an increased risk of chronic intestinal inflammation in children exposed to airborne particulate matter and polycyclic aromatic hydrocarbons from e-waste. ENVIRONMENT INTERNATIONAL 2025; 201:109549. [PMID: 40449062 DOI: 10.1016/j.envint.2025.109549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 04/09/2025] [Accepted: 05/21/2025] [Indexed: 06/02/2025]
Abstract
Informal e-waste recycling releases airborne particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs), which are linked to intestinal barrier dysfunction and chronic inflammation. SIRT6, a histone deacetylase, modulates inflammation by suppressing NF-κB signaling, but its role in mitigating e-waste pollutant-induced childhood enteritis remains unclear. This cross-sectional study evaluated associations between e-waste exposure, intestinal inflammation, and SIRT6 levels in 217 preschool children from Guiyu (e-waste-exposed, n = 109) and Haojiang (non-exposed control, n = 108), China. Airborne pollutant exposure was quantified via the Air Quality Composite Index (AQCI) and average daily dose (ADD) for PM2.5, PM10, NO2, and SO2. Urinary PAH metabolites, serum SIRT6, inflammatory markers (GM-CSF, IL-10), and intestinal barrier biomarkers (IFABP, endotoxins) were measured using GC/MS, ELISA, and automated hematology analyzers. Dietary patterns, residential proximity to e-waste sites, and gastrointestinal symptoms were assessed via questionnaires. Statistical analyses included Spearman correlations, multivariate regression, and Bayesian kernel machine regression (BKMR) to evaluate pollutant effects on SIRT6 and inflammation. Children residing in Guiyu demonstrated significantly elevated urinary PAH metabolites and higher ADD of PM2.5, PM10, NO2, and SO2 compared to reference populations. Concurrently, this cohort exhibited biomarker patterns indicative of intestinal barrier compromise, including elevated IFABP and systemic endotoxin levels. Serum analyses revealed quantifiable reductions in SIRT6 and GM-CSF concentrations, accompanied by increased circulating monocytes and lymphocytes. Notably, BKMR modeling identified non-linear U-shaped associations between mixed PM/PAH exposures and progressive SIRT6 suppression. Proximity to e-waste sites, lower parental education, and poor household ventilation correlated with heightened pollutant exposure and gastrointestinal morbidity. Chronic e-waste exposure was associated with decreased serum SIRT6 levels and concurrent elevation of intestinal inflammatory biomarkers in children. Our cross-sectional analysis revealed significant correlations between SIRT6 downregulation, altered GM-CSF/IL-10 signaling profiles, and disrupted macrophage-Treg homeostasis. These observational findings suggest SIRT6 may serve as a potential protective mediator in environmental enteritis.
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Affiliation(s)
- Tengyang Huang
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China; Department of Digestive Surgery, the First Affiliated Hospital of Shantou University Medical College, Shantou 515000 Guangdong, PR China
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China; Department of Cell Biology and Genetics, Shantou University Medical College, 515041 Shantou, Guangdong, PR China
| | - Shuqin Chen
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China
| | - Zhiping Liu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China
| | - Yu Huang
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment and Climate, Jinan University, Guangzhou 511443 Guangdong, PR China
| | - Guangcan Chen
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou 515041 Guangdong, PR China; Department of Digestive Surgery, the First Affiliated Hospital of Shantou University Medical College, Shantou 515000 Guangdong, PR China.
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de Carvalho JC, Pascoal-Xavier MA, Araújo MG, Teixeira-Carvalho A, Martins-Filho OA, Peruhype-Magalhães V, Coelho-dos-Reis JGA, Araújo MSS. Different profiles of chemokines, cytokines and cell growth factors in plasma samples from patients with leprosy, leprosy reactions and households contacts. Mem Inst Oswaldo Cruz 2024; 119:e230129. [PMID: 38381878 PMCID: PMC10876044 DOI: 10.1590/0074-02760230129] [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: 07/24/2023] [Accepted: 01/10/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1β), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.
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Affiliation(s)
- Jairo Campos de Carvalho
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
- Fundação Hospitalar do Estado de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Marcelo Antônio Pascoal-Xavier
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia Patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| | - Marcelo Grossi Araújo
- Serviço de Dermatologia do Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Andrea Teixeira-Carvalho
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
| | - Olindo Assis Martins-Filho
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
| | - Vanessa Peruhype-Magalhães
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
| | - Jordana Grazziela Alves Coelho-dos-Reis
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Microbiologia, Laboratório de Virologia Básica e Aplicada, Belo Horizonte, MG, Brasil
| | - Márcio Sobreira Silva Araújo
- Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo Integrado de Pesquisas em Biomarcadores, Belo Horizonte, MG, Brasil
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Zysk W, Gleń J, Trzeciak M. Current Insight into the Role of IL-35 and Its Potential Involvement in the Pathogenesis and Therapy of Atopic Dermatitis. Int J Mol Sci 2022; 23:ijms232415709. [PMID: 36555351 PMCID: PMC9779445 DOI: 10.3390/ijms232415709] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Interleukin 35 (IL-35), a new member of the IL-12 family of heterodimeric cytokines, could induce two different types of regulatory cells including regulatory T and B cells such as IL-35-induced regulatory T cells and IL-10-producing regulatory B cells (IL-10+Bregs), and IL-35-producing regulatory B cells (IL-35+Bregs). These cells appear to play an important role in modulating the immune system in numerous diseases. Several findings suggested that the expression of IL-35 is dysregulated in many autoimmune, inflammatory, and allergic diseases. Due to the functions of IL-35, it seems that this cytokine may act as an efficient therapeutic strategy for numerous conditions including atopic dermatitis (AD). We aimed to provide a comprehensive overview of the role of IL-35 in modulating the immune system. Additionally, we highlight IL-35 as a specific immunological target, discuss its possible involvement in the pathogenesis of AD, and hypothesize that IL-35 may become a novel target for the treatment of AD. However, further studies are required to evaluate this hypothesis.
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Affiliation(s)
- Weronika Zysk
- Dermatological Students Scientific Association, Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdańsk, Poland
| | - Jolanta Gleń
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdańsk, Poland
| | - Magdalena Trzeciak
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdańsk, Poland
- Correspondence: ; Tel.: +48-58-584-40-10
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Li X, Xu H, Huang J, Luo D, Lv S, Lu X, Xiao C. Dysfunctions, Molecular Mechanisms, and Therapeutic Strategies of Regulatory T Cells in Rheumatoid Arthritis. Front Pharmacol 2021; 12:716081. [PMID: 34512345 PMCID: PMC8428974 DOI: 10.3389/fphar.2021.716081] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Regulatory T cells (Tregs) represent a distinct subpopulation of CD4+ T lymphocytes that promote immune tolerance and maintain immune system homeostasis. The dysfunction of Tregs is tightly associated with rheumatoid arthritis (RA). Although the complex pathogenic processes of RA remain unclear, studies on Tregs in RA have achieved substantial progress not only in fundamental research but also in clinical application. This review discusses the current knowledge of the characterizations, functions, and molecular mechanisms of Tregs in the pathogenesis of RA, and potential therapies for these disorders are also involved.
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Affiliation(s)
- Xiaoya Li
- The Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.,Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Huihui Xu
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Huang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Luo
- Department of Ophthalmology, Traditional Chinese Medicine Hospital of Changping District, Beijing, China
| | - Shuang Lv
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xiangchen Lu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Cheng Xiao
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Department of Emergency, China-Japan Friendship Hospital, Beijing, China
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Figliuolo VR, Dos Santos LM, Abalo A, Nanini H, Santos A, Brittes NM, Bernardazzi C, de Souza HSP, Vieira LQ, Coutinho-Silva R, Coutinho CMLM. Sulfate-reducing bacteria stimulate gut immune responses and contribute to inflammation in experimental colitis. Life Sci 2017; 189:29-38. [PMID: 28912045 DOI: 10.1016/j.lfs.2017.09.014] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 09/01/2017] [Accepted: 09/11/2017] [Indexed: 12/14/2022]
Abstract
The intestinal microbiota is critical for mammalian immune system development and homeostasis. Sulfate-reducing bacteria (SRB) are part of the normal gut microbiota, but their increased levels may contribute to colitis development, likely in association with hydrogen sulfide (H2S) production. Here, we investigated the effects of SRB in the gut immune response in germ-free mice, and in experimental colitis. After 7days of colonization with Desulfovibrio indonesiensis or with a human SRB consortium (from patients with colitis), germ-free mice exhibited alterations in the colonic architecture, with increased cell infiltration in the lamina propria. SRB colonization upregulated the Th17 and Treg profiles of cytokine production/cell activation, in T cells from mesenteric lymph nodes. These alterations were more pronounced in mice colonized with the human SRB consortium, although D. indonesiensis colonization produced higher levels of H2S. Importantly, the colon of C57BL/6 mice with colitis induced by TNBS or oxazolone had increased SRB colonization, and the administration of D. indonesiensis to mice with TNBS-induced colitis clearly exacerbated the alterations in colonic architecture observed in the established disease, and also increased mouse weight loss. We conclude that SRB contribute to immune response activation in the gut and play an important role in colitis development.
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Affiliation(s)
- Vanessa Ribeiro Figliuolo
- Instituto de Biofísica Carlos Chagas Filho - IBCCF, Universidade Federal do Rio de Janeiro, RJ, Brazil; Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Liliane Martins Dos Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alessandra Abalo
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Hayandra Nanini
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | - Angela Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Nilda M Brittes
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Claudio Bernardazzi
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | | | - Leda Quercia Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Robson Coutinho-Silva
- Instituto de Biofísica Carlos Chagas Filho - IBCCF, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | - Claudia Mara Lara Melo Coutinho
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos - LITEB, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil.
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Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol 2015; 21:11236-45. [PMID: 26523099 PMCID: PMC4616201 DOI: 10.3748/wjg.v21.i40.11236] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 06/02/2015] [Accepted: 08/28/2015] [Indexed: 02/06/2023] Open
Abstract
Since their discovery two decades ago, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) have become the subject of intense investigation by immunologists. Unlike other T cells, which promote an immune response, Tregs actively inhibit inflammation when activated by their cognate antigen, thus raising hope that these cells could be engineered into a highly targeted, antigen-specific, immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4(+)T cells, they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular, spontaneous intestinal inflammation has been shown to occur in the absence of Tregs, suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease (IBD). However, over the past decade, multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn's disease and ulcerative colitis. In this review, we will discuss the history of Tregs, what is known about them in IBD, and what progress and obstacles have been seen with efforts to employ them for therapeutic benefit.
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Scaparrotta A, Di Pillo S, Consilvio NP, Attanasi M, Cingolani A, Rapino D, Cerasa M, Pucci N, Di Gioacchino M, Chiarelli F. Usefulness of Atopy Patch Test on a child with milk protein-induced enterocolitis syndrome: a case report. Int J Immunopathol Pharmacol 2014; 26:795-800. [PMID: 24067480 DOI: 10.1177/039463201302600327] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
We describe the case of a child affected by milk-protein induced enterocolitis, in which oral challenge with corn was performed without symptoms after a negative specific Atopy Patch Test. Food protein-induced enterocolitis syndrome (FPIES) is an uncommon nonIgE-mediated gastrointestinal food hypersensitivity of infancy, characterized by severe vomiting and diarrhea arising within 1 to 3 hours after ingestion of the causative food. Little is known about the pathophysiology of FPIES. The absence of food-specific IgE as demonstrated by negative skin prick tests suggests that the disease is not caused by an early onset IgE-mediated reaction. Atopy Patch Test has been described as sensitive and predictive in this syndrome. The hypothesis on the immunological pathogenesis has been discussed on the basis of literature data.
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Affiliation(s)
- A Scaparrotta
- Allergy and Respiratory Unit, Department of Pediatrics, University of Chieti, Italy
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Collins CB, Aherne CM, Yeckes A, Pound K, Eltzschig HK, Jedlicka P, de Zoeten EF. Inhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function. Mucosal Immunol 2013; 6:960-71. [PMID: 23321985 PMCID: PMC3748235 DOI: 10.1038/mi.2012.134] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 11/26/2012] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition thought to reflect a failure of the enteral immune system to adequately regulate itself. Inflammatory stress drives upregulation of heat-shock proteins (HSPs), including the pro-inflammatory chaperone, HSP90. This protein sequesters the transcription factor, heat-shock factor 1 (HSF1) in the cytoplasm preventing transcription of a number of anti-inflammatory proteins. We hypothesized that inhibition of HSP90 would exert an anti-inflammatory effect and thereby attenuate intestinal inflammation in murine models of IBD. Inhibition of HSP90 with 17-allylaminogeldanamycin (17-AAG) reduced inflammation in acute dextran sodium sulfate and chronic CD45RB(High) colitis models coinciding with increased interleukin (IL)-10 production in the colon. Regulatory T cells (Tregs) from mice treated with 17-AAG demonstrated significantly greater suppressive capacity in vitro abolished in HSF1-/- or IL-10-/- cells. Finally, Tregs treated with 17-AAG exhibited increased nuclear localization of HSF1 with resultant upregulation of HSF1 response genes, including HSP70, HSP90 and IL-10.
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Affiliation(s)
- Colm B. Collins
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Carol M. Aherne
- University of Colorado School of Medicine, Department of Anesthesiology, Colorado 80045
| | - Alyson Yeckes
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Kayla Pound
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
| | - Holger K. Eltzschig
- University of Colorado School of Medicine, Department of Anesthesiology, Colorado 80045
| | - Paul Jedlicka
- University of Colorado School of Medicine, Department of Pathology, Colorado 80045
| | - Edwin F. de Zoeten
- Mucosal Inflammation Program, University of Colorado School of Medicine, Department of Pediatrics, Children's Hospital Colorado, Digestive Health Institute, Colorado 80045
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Duncan FJ, Silva KA, Johnson C, King B, Szatkiewicz JP, Kamdar S, Ong DE, Napoli JL, Wang J, King LE, Whiting DA, McElwee KJ, Sundberg JP, Everts HB. Endogenous retinoids in the pathogenesis of alopecia areata. J Invest Dermatol 2013; 133:334-43. [PMID: 23014334 PMCID: PMC3546144 DOI: 10.1038/jid.2012.344] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of the four levels of dietary vitamin A or an unpurified diet 2 weeks before grafting and disease progression followed. High vitamin A accelerated AA, whereas mice that were not fed vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B-positive cells were altered by vitamin A. IFNγ was also the lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA.
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Affiliation(s)
- F. Jason Duncan
- Department of Nutrition, The Ohio State University, Columbus, OH
| | | | - Charles Johnson
- Department of Nutrition, The Ohio State University, Columbus, OH
| | | | | | | | - David E. Ong
- Vanderbilt University Medical Center, Nashville, TN
| | | | | | | | | | | | - John P. Sundberg
- The Jackson Laboratory, Bar Harbor, ME
- Vanderbilt University Medical Center, Nashville, TN
| | - Helen B. Everts
- Department of Nutrition, The Ohio State University, Columbus, OH
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Dighe AS, Yang S, Madhu V, Balian G, Cui Q, Orthopaedic Research Laboratories. Interferon gamma and T cells inhibit osteogenesis induced by allogeneic mesenchymal stromal cells. J Orthop Res 2013; 31:227-34. [PMID: 22886855 PMCID: PMC3510319 DOI: 10.1002/jor.22212] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Accepted: 07/23/2012] [Indexed: 02/04/2023]
Abstract
The mesenchymal stromal cells (MSCs) are reported to be immunoprivileged and osteogenic. We hypothesized that the use of allogeneic MSCs for bone repair was possible if they displayed an ability to induce similar osteogenesis in syngeneic as well as in allogeneic hosts. To test this hypothesis we used a cloned bone marrow derived cell, termed D1, isolated from Balb/c mice. The D1 cells were subcutaneously injected in syngeneic Balb/c, allogeneic immunocompetent B6, allogeneic T-cell deficient NCr nude, and allogeneic B6 Pfp-/- Rag2-/- mice that lack matured T and B cells as well as NK-cell cytolytic functions. D1 cells formed ectopic bones only in syngeneic or allogeneic immunocompromised hosts but not in allogeneic B6 hosts. The lack of T cells alone in allogeneic NCr mice was sufficient to promote osteogenesis in allogeneic environment. We observed a significantly higher number of T cells, B cells, macrophages and significantly higher expression of interferon gamma (IFN-γ) in B6 allogeneic implants as compared to the syngeneic implants. These factors correlated with severe inhibition of expression of alkaline phosphatase, osteocalcin, and runx2 genes in the implants from B6 mice. Our data suggest that strategies to inhibit T cells and IFN-γ functions will be useful for bone repair mediated by allogeneic MSCs.
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Affiliation(s)
- Abhijit S. Dighe
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Scott Yang
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Vedavathi Madhu
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Gary Balian
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA,Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA
| | - Quanjun Cui
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA,Corresponding author: Quanjun Cui, Department of Orthopaedic Surgery, P.O. Box 800159, University of Virginia, Charlottesville, VA 22908. Phone: 1-434-243-0236, Fax: 1-434-243-0242,
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Oomizu S, Arikawa T, Niki T, Kadowaki T, Ueno M, Nishi N, Yamauchi A, Hattori T, Masaki T, Hirashima M. Cell surface galectin-9 expressing Th cells regulate Th17 and Foxp3+ Treg development by galectin-9 secretion. PLoS One 2012; 7:e48574. [PMID: 23144904 PMCID: PMC3492452 DOI: 10.1371/journal.pone.0048574] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 09/26/2012] [Indexed: 12/18/2022] Open
Abstract
Galectin-9 (Gal-9), a β-galactoside binding mammalian lectin, regulates immune responses by reducing pro-inflammatory IL-17-producing Th cells (Th17) and increasing anti-inflammatory Foxp3(+) regulatory T cells (Treg) in vitro and in vivo. These functions of Gal-9 are thought to be exerted by binding to receptor molecules on the cell surface. However, Gal-9 lacks a signal peptide for secretion and is predominantly located in the cytoplasm, which raises questions regarding how and which cells secrete Gal-9 in vivo. Since Gal-9 expression does not necessarily correlate with its secretion, Gal-9-secreting cells in vivo have been elusive. We report here that CD4 T cells expressing Gal-9 on the cell surface (Gal-9(+) Th cells) secrete Gal-9 upon T cell receptor (TCR) stimulation, but other CD4 T cells do not, although they express an equivalent amount of intracellular Gal-9. Gal-9(+) Th cells expressed interleukin (IL)-10 and transforming growth factor (TGF)-β but did not express Foxp3. In a co-culture experiment, Gal-9(+) Th cells regulated Th17/Treg development in a manner similar to that by exogenous Gal-9, during which the regulation by Gal-9(+) Th cells was shown to be sensitive to a Gal-9 antagonist but insensitive to IL-10 and TGF-β blockades. Further elucidation of Gal-9(+) Th cells in humans indicates a conserved role of these cells through evolution and implies the possible utility of these cells for diagnosis or treatment of immunological diseases.
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Affiliation(s)
- Souichi Oomizu
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tomohiro Arikawa
- Department of Biology, Kanazawa Medical University, Ishikawa, Japan
| | - Toshiro Niki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- GalPharma Co., Ltd., Kagawa, Japan
| | - Takeshi Kadowaki
- Department of Holistic Immunology, Kagawa University, Kagawa, Japan
| | - Masaki Ueno
- Department of Inflammation Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Nozomu Nishi
- Life Science Research Center, Kagawa University, Kagawa, Japan
| | - Akira Yamauchi
- Department of Breast Surgery, Kitano Hospital, Osaka, Japan
| | - Toshio Hattori
- Laboratory of Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Mitsuomi Hirashima
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- GalPharma Co., Ltd., Kagawa, Japan
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12
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Dhingra S, Huang XP, Li RK. Challenges in allogeneic mesenchymal stem cell-mediated cardiac repair. Trends Cardiovasc Med 2012; 20:263-8. [PMID: 22433652 DOI: 10.1016/j.tcm.2011.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Autologous mesenchymal stem cells (MSCs) have been proven safe in phase I and II clinical trials in patients who have suffered a myocardial infarction. However, their potential for proliferation and differentiation decreases with age, which limits their efficacy in elderly patients. Allogeneic MSCs offer several key advantages over autologous MSCs, including a high regenerative potential and availability for clinical use without the delay required for expansion. It was believed that allogeneic MSCs were immune privileged and thus able to escape the recipient's immune system. In several preclinical studies, allogeneic MSCs were successful in regenerating the myocardium, and the transplanted MSCs improved heart function early after implantation. However, the long-term ability of allogeneic MSCs to preserve heart function is limited because of a transition from an immune privileged to an immunogenic phenotype after the cells differentiate. The initial phase I/II clinical study using allogeneic MSCs in patients with acute myocardial infarction was safe, and no side effects were observed. However, the long-term safety and efficacy of allogeneic MSCs remain to be established. In this review, we discuss the challenges of using allogeneic MSCs for cardiac repair and present strategies to prevent the immune rejection of allogeneic MSCs to increase their potential for use in cardiac patients.
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Affiliation(s)
- Sanjiv Dhingra
- Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7
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13
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Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH. Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev Rep 2011; 7:181-94. [PMID: 20532836 DOI: 10.1007/s12015-010-9163-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.
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Affiliation(s)
- Dong-Hyuk Park
- Department of Neurosurgery, Korea University Medical Center, Anam Hospital, Korea University College of Medicine, #126, 5-GA, Anam-Dong, Sungbuk-Ku, Seoul 136-705, Korea.
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14
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Kreisman LSC, Cobb BA. Glycoantigens induce human peripheral Tr1 cell differentiation with gut-homing specialization. J Biol Chem 2011; 286:8810-8. [PMID: 21228275 PMCID: PMC3059040 DOI: 10.1074/jbc.m110.206011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 01/11/2011] [Indexed: 11/06/2022] Open
Abstract
The carbohydrate antigen (glycoantigen) PSA from an intestinal commensal bacteria is able to down-regulate inflammatory bowel disease in model mice, suggesting that stimulation with PSA results in regulatory T cell (Treg) generation. However, mechanisms of how peripheral human T cells respond and home in response to commensal antigens are still not understood. Here, we demonstrate that a single exposure to PSA induces differentiation of human peripheral CD4(+) T cells into type-Tr1 Tregs. This is in contrast to mouse models where PSA induced the production of Foxp3(+) iTregs. The human PSA-induced Tr1 cells are profoundly anergic and exhibit nonspecific bystander suppression mediated by IL-10 secretion. Most surprisingly, glycoantigen exposure provoked expression of gut homing receptors on their surface. These findings reveal a mechanism for immune homeostasis in the gut whereby exposure to commensal glycoantigens provides the requisite information to responding T cells for proper tissue localization (gut) and function (anti-inflammatory/regulatory).
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Affiliation(s)
- Lori S. C. Kreisman
- From the Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Brian A. Cobb
- From the Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
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15
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Cytokine expression in CD3+ cells in an infant with food protein-induced enterocolitis syndrome (FPIES): case report. Clin Dev Immunol 2010; 2009:679381. [PMID: 20011655 PMCID: PMC2786190 DOI: 10.1155/2009/679381] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 07/10/2009] [Accepted: 09/01/2009] [Indexed: 11/17/2022]
Abstract
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by severe vomiting, diarrhea, and often failure to thrive in infants. Symptoms typically resolve after the triggering food-derived protein is removed from the diet and recur within few hours after the re-exposure to the causal protein. The diagnosis is based on clinical symptoms and a positive food challenge. In this study, we report a case of FPIES to rice in an 8-month-old boy. We performed a double-blind placebo-controlled food challenge (DBPCFC) to rice and we measured the intracellular T cell expression of interleukin-4 (IL-4); IL-10, and interferon γ (IFN-γ) pre-and post-challenge during an acute FPIES reaction and when tolerance to rice had been achieved. For the first time we describe an increase in T cell IL-4 and decrease in IFN-γ expression after a positive challenge with rice (i.e. rice triggered a FPIES attack) and an increase in T cell IL-10 expression after rice challenge 6 months later after a negative challenge (i.e., the child had acquired tolerance to rice) in an 8 month old with documented FPIES to rice. A Th2 activation associated with high IL-4 levels may contribute to the pathophysiology of the disease. On the other hand, T cell-derived IL-10 may play a role in the acquisition of immunotolerance by regulating the Th1 and Th2 responses.
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16
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Noh J, Lee JH, Noh G, Bang SY, Kim HS, Choi WS, Cho S, Lee SS. Characterisation of allergen-specific responses of IL-10-producing regulatory B cells (Br1) in Cow Milk Allergy. Cell Immunol 2010; 264:143-9. [PMID: 20646682 DOI: 10.1016/j.cellimm.2010.05.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 05/10/2010] [Accepted: 05/22/2010] [Indexed: 01/04/2023]
Abstract
CD19+CD5+ regulatory B cells regulate immune responses by producing IL-10. IL-10-producing regulatory B cell (Br1) responses by allergen stimulation were investigated in human food allergy. Six milk allergy patients and eight milk-tolerant subjects were selected according to DBPCFC. PBMCs were stimulated by casein in vitro and stained for intracellular IL-10 and apoptosis. In response to allergen stimulation, Br1 decreased from 26.2+/-18.3 to 15.5+/-8.9% (p=0.031, n=6) in the milk allergy group and increased from 15.4+/-9.0 to 23.7+/-11.2% (p=0.023, n=8) in the milk-tolerant group. Apoptotic non-IL-10-producing regulatory B cells increased from 21.8+/-9.3 to 38.0+/-16.1% (p=0.031, n=6) in the milk allergy group and unchanged from 28.8+/-13.8 to 28.0+/-15.0% (p=0.844, n=8) in the milk-tolerant group. Br1 may be involved in the immune tolerance of food allergies by producing IL-10 and simultaneously undergoing apoptosis in humans. The exact roles for Br1 in immune tolerance needs to be further investigated.
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Affiliation(s)
- Joonyong Noh
- Department of Animal Biotechnology, College of Animal Bioscience and Technology, Konkuk University, Seoul, Republic of Korea
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17
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Tolosa JN, Park DH, Eve DJ, Klasko SK, Borlongan CV, Sanberg PR. Mankind's first natural stem cell transplant. J Cell Mol Med 2010; 14:488-95. [PMID: 20141549 PMCID: PMC3823451 DOI: 10.1111/j.1582-4934.2010.01029.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Accepted: 02/03/2010] [Indexed: 11/26/2022] Open
Abstract
The timing of the umbilical cord clamping at birth is still controversial. In the modern era of medicine, the cord has been clamped early to facilitate resuscitation and stabilization of infants. However, recently delayed cord clamping has been supported by physicians because it allows for the physiological transfer of blood from the placenta to the infant. Many clinical studies have revealed that the delayed cord clamping elevates blood volume and haemoglobin and prevents anaemia in infants. Moreover, since it was known that umbilical cord blood contains various valuable stem cells such as haematopoietic stem cells, endothelial cell precursors, mesenchymal progenitors and multipotent/pluripotent lineage stem cells, the merit of delayed cord clamping has been magnified. In this review, we discuss the advantages and disadvantages of delayed cord clamping at birth. We highlight the importance of delayed cord clamping in realizing mankind's first stem cell transfer and propose that it should be encouraged in normal births.
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Affiliation(s)
- Jose N Tolosa
- Department of Pediatrics, Division Neonatology, University of South Florida, College of MedicineTampa, FL, USA
| | - Dong-Hyuk Park
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, College of MedicineTampa, FL, USA
- Department of Neurosurgery, Korea University Medical Center, Korea University College of MedicineSeoul, South Korea
| | - David J Eve
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, College of MedicineTampa, FL, USA
| | - Stephen K Klasko
- Department of Obstetrics and Gynecology, University of South Florida, College of MedicineTampa, FL, USA
| | - Cesario V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, College of MedicineTampa, FL, USA
| | - Paul R Sanberg
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, College of MedicineTampa, FL, USA
- Office of Research and Innovation, University of South FloridaTampa, FL, USA
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18
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Analysis of Intestinal T Cell Populations and Cytokine Productions. METHODS IN MICROBIOLOGY 2010. [DOI: 10.1016/s0580-9517(10)37009-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register]
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19
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20
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Park DH, Borlongan CV, Willing AE, Eve DJ, Cruz LE, Sanberg CD, Chung YG, Sanberg PR. Human Umbilical Cord Blood Cell Grafts for Brain Ischemia. Cell Transplant 2009; 18:985-98. [DOI: 10.3727/096368909x471279] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Irreversible and permanent damage develop immediately adjacent to the region of reduced cerebral blood perfusion in stroke patients. Currently, the proven thrombolytic treatment for stroke, tissue plasminogen activator, is only effective when administered within 3 h after stroke. These disease characteristics should be taken under consideration in developing any therapeutic intervention designed to widen the narrow therapeutic range, especially cell-based therapy. Over the past several years, our group and others have characterized the therapeutic potential of human umbilical cord blood cells for stroke and other neurological disorders using in vitro and vivo models focusing on the cells' ability to differentiate into nonhematopoietic cells including neural lineage, as well as their ability to produce several neurotrophic factors and modulate immune and inflammatory reaction. Rather than the conventional cell replacement mechanism, we advance alternative pathways of graft-mediated brain repair involving neurotrophic effects resulting from release of various growth factors that afford cell survival, angiogenesis, and anti-inflammation. Eventually, these multiple protective and restorative effects from umbilical cord blood cell grafts may be interdependent and act in harmony in promoting therapeutic benefits for stroke.
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Affiliation(s)
- Dong-Hyuk Park
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
- Department of Neurosurgery, Korea University Medical Center, Korea University College of Medicine, Seoul, Korea
| | - Cesar V. Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Alison E. Willing
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - David J. Eve
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - L. Eduardo Cruz
- Cryopraxis and Silvestre Laboratory, Cryopraxis, BioRio, Pólo de Biotechnologia do Rio de Janeiro, Rio di Janiero, Brazil
| | | | - Yong-Gu Chung
- Cryopraxis and Silvestre Laboratory, Cryopraxis, BioRio, Pólo de Biotechnologia do Rio de Janeiro, Rio di Janiero, Brazil
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
- Office of Research and Innovation, University of South Florida, Tampa, FL, USA
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21
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Franceschi DSA, Mazini PS, Rudnick CCC, Sell AM, Tsuneto LT, Ribas ML, Peixoto PR, Visentainer JEL. Influence of TNF and IL10 gene polymorphisms in the immunopathogenesis of leprosy in the south of Brazil. Int J Infect Dis 2008; 13:493-8. [PMID: 19058987 DOI: 10.1016/j.ijid.2008.08.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2008] [Revised: 08/15/2008] [Accepted: 08/18/2008] [Indexed: 10/21/2022] Open
Abstract
OBJECTIVE To determine whether cytokine polymorphisms are associated with leprosy and/or their subtypes in a Brazilian population. METHODS Genotyping using polymerase chain reaction with sequence-specific primers (PCR-SSP) was performed for: TNF(-308/-238), IL2(-330/+166), IL6(-174), IFNG(+874), TGFB1(+869/+915), and IL10(-592/-819/-1082) in 240 healthy controls and 167 patients with leprosy. RESULTS For TNF(-308), a higher frequency of GG genotype (85.5% vs. 74.1% in healthy controls, p = 0.009), along with a decreased frequency of GA/AA genotypes was observed among leprosy patients as compared to the control group (14.5% vs. 25.9%, p = 0.009). The GG genotype was particularly higher in patients with tuberculoid (TT) and borderline (BB) leprosy (90.5% and 89.8%, respectively). Analysis of IL10 genotypes revealed a lower frequency of GCC/GCC haplotype in lepromatous leprosy (LL) patients (6.2%) in comparison to controls (15.4%). CONCLUSION It is suggested that the G-->A substitution at position -308 in the TNF promoter region plays an important role in leprosy patients.
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Affiliation(s)
- Danilo Santana Alessio Franceschi
- Laboratório de Imunogenética, Departamento de Análises Clínicas, Universidade Estadual de Maringá, Av. Colombo, 5790, Maringá, PR, CEP 87020-900, Brazil
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22
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Campos Alberto EJ, Shimojo N, Suzuki Y, Mashimo Y, Arima T, Matsuura T, Inoue Y, Yamaide A, Tomiita M, Fujii K, Hata A, Kohno Y. IL-10 gene polymorphism, but not TGF-beta1 gene polymorphisms, is associated with food allergy in a Japanese population. Pediatr Allergy Immunol 2008; 19:716-21. [PMID: 18208460 DOI: 10.1111/j.1399-3038.2007.00709.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The regulatory IL-10 and TGF-beta1 cytokine gene polymorphisms have been associated with allergic diseases in different populations, like Caucasian, Chinese and Indians. We investigated the association between the polymorphisms IL-10 A-1082G, C-819T, C-627A and TGF-beta1 T+869C, G+915C, C-509T and food allergy in Japanese children. One hundred and eleven children with food allergy and 115 atopic control children without food allergy were recruited. DNA samples from these subjects were genotyped by using PCR. The odds ratio of IL-10 -1082 AA genotype was 2.5 (95% CI, 1.0-6.4) for food allergy risk when compared with atopic control subjects (p = 0.03). There were no significative differences in the frequency of TGF-beta1 gene polymorphisms between both groups. Our results indicate that IL-10 A-1082G gene polymorphism is associated with food allergy susceptibility in atopic Japanese children.
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Alford SK, Longmore GD, Stenson WF, Kemper C. CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:2544-55. [PMID: 18684945 PMCID: PMC2597161 DOI: 10.4049/jimmunol.181.4.2544] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Tissue homing of activated T cells is typically mediated through their specific integrin and chemokine receptor repertoire. Activation of human primary CD4(+) T cells in the presence of CD46 cross-linking induces the development of a distinct immunomodulatory T cell population characterized by high IL-10/granzyme B production. How these regulatory T cells (Tregs) migrate/home to specific tissue sites is not understood. In this study, we determined the adhesion protein and chemokine receptor expression pattern on human CD3/CD46-activated peripheral blood CD4(+) T cells. CD3/CD46-activated, but not CD3/CD28-activated, T cells up-regulate the integrin alpha(4)beta(7). The interaction of alpha(4)beta(7) with its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) mediates homing or retention of T cells to the intestine. CD3/CD46-activated Tregs adhere to/roll on MAdCAM-1-expressing HeLa cells, similar to T cells isolated from the human lamina propria (LP). This interaction is inhibited by silencing MAdCAM-1 expression in HeLa cells or by the addition of blocking Abs to beta(7). CD46 activation of T cells also induced the expression of the surface-bound cytokine LIGHT and the chemokine receptor CCR9, both marker constitutively expressed by gut LP-resident T cells. In addition, we found that approximately 10% of the CD4(+) T lymphocytes isolated from the LP of patients undergoing bariatric surgery contain T cells that spontaneously secrete a cytokine pattern consistent with that from CD46-activated T cells. These data suggest that CD46-induced Tregs might play a role in intestinal immune homeostasis where they could dampen unwanted effector T cell responses through local IL-10/granzyme B production.
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Affiliation(s)
- Shannon K. Alford
- Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Gregory D. Longmore
- Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - William F. Stenson
- Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Claudia Kemper
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
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24
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Huang X, Moore DJ, Ketchum RJ, Nunemaker CS, Kovatchev B, McCall AL, Brayman KL. Resolving the conundrum of islet transplantation by linking metabolic dysregulation, inflammation, and immune regulation. Endocr Rev 2008; 29:603-30. [PMID: 18664617 PMCID: PMC2819735 DOI: 10.1210/er.2008-0006] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Accepted: 05/29/2008] [Indexed: 02/08/2023]
Abstract
Although type 1 diabetes cannot be prevented or reversed, replacement of insulin production by transplantation of the pancreas or pancreatic islets represents a definitive solution. At present, transplantation can restore euglycemia, but this restoration is short-lived, requires islets from multiple donors, and necessitates lifelong immunosuppression. An emerging paradigm in transplantation and autoimmunity indicates that systemic inflammation contributes to tissue injury while disrupting immune tolerance. We identify multiple barriers to successful islet transplantation, each of which either contributes to the inflammatory state or is augmented by it. To optimize islet transplantation for diabetes reversal, we suggest that targeting these interacting barriers and the accompanying inflammation may represent an improved approach to achieve successful clinical islet transplantation by enhancing islet survival, regeneration or neogenesis potential, and tolerance induction. Overall, we consider the proinflammatory effects of important technical, immunological, and metabolic barriers including: 1) islet isolation and transplantation, including selection of implantation site; 2) recurrent autoimmunity, alloimmune rejection, and unique features of the autoimmune-prone immune system; and 3) the deranged metabolism of the islet transplant recipient. Consideration of these themes reveals that each is interrelated to and exacerbated by the other and that this connection is mediated by a systemic inflammatory state. This inflammatory state may form the central barrier to successful islet transplantation. Overall, there remains substantial promise in islet transplantation with several avenues of ongoing promising research. This review focuses on interactions between the technical, immunological, and metabolic barriers that must be overcome to optimize the success of this important therapeutic approach.
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Affiliation(s)
- Xiaolun Huang
- Department of Surgery, University of Virginia, Charlottesville, Virginia 22908, USA
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25
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Bachy V, Williams D, Ibrahim M. Altered dendritic cell function in normal pregnancy. J Reprod Immunol 2008; 78:11-21. [DOI: 10.1016/j.jri.2007.09.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2007] [Revised: 08/15/2007] [Accepted: 09/28/2007] [Indexed: 10/22/2022]
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26
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Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, Qin FXF, Gilliet M, Liu YJ. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 2008; 28:870-80. [PMID: 18513999 PMCID: PMC2709453 DOI: 10.1016/j.immuni.2008.03.018] [Citation(s) in RCA: 427] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2007] [Revised: 02/27/2008] [Accepted: 03/20/2008] [Indexed: 12/16/2022]
Abstract
Previous studies suggest that thymus produces a homogenous population of natural regulatory T (Treg) cells that express a transcriptional factor FOXP3 and control autoimmunity through a cell-contact-dependent mechanism. We found two subsets of FOXP3+ natural Treg cells defined by the expression of the costimulatory molecule ICOS in the human thymus and periphery. Whereas the ICOS+FOXP3+ Treg cells used interleukin-10 to suppress dendritic cell function and transforming growth factor (TGF)-beta to suppress T cell function, the ICOS-FOXP3+ Treg cells used TGF-beta only. The survival and proliferation of the two subsets of Treg cells were differentially regulated by signaling through ICOS or CD28, respectively. We suggest that the selection of natural Treg cells in thymus is coupled with Treg cell differentiation into two subsets imprinted with different cytokine expression potentials and use both cell-contact-dependent and independent mechanisms for immunosuppression in periphery.
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Affiliation(s)
| | | | - Yi-Hong Wang
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Woong Ryeon Park
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Kazuhiko Arima
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Laura Bover
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - F. Xiao-Feng Qin
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Michel Gilliet
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Yong-Jun Liu
- Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston Texas 77030, USA
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27
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Guichelaar T, ten Brink CB, van Kooten PJ, Berlo SE, Broeren CP, van Eden W, Broere F. Autoantigen-Specific IL-10-Transduced T Cells Suppress Chronic Arthritis by Promoting the Endogenous Regulatory IL-10 Response. THE JOURNAL OF IMMUNOLOGY 2008; 180:1373-81. [DOI: 10.4049/jimmunol.180.3.1373] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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28
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Willing AE, Eve DJ, Sanberg PR. Umbilical cord blood transfusions for prevention of progressive brain injury and induction of neural recovery: an immunological perspective. Regen Med 2007; 2:457-64. [PMID: 17635052 DOI: 10.2217/17460751.2.4.457] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
One of the most promising treatments for neurodegenerative diseases appears to be human umbilical cord blood cell transplantation. A variety of studies demonstrate some benefit of this method of treatment in a number of different animal models and case studies. However, before the methodologies and results of these animal studies and case studies can be translated into successful widespread treatments, aspects relating to the immunological properties of the transplanted cells must be considered. In this perspective, we discuss the benefit of the cellular immaturity of these cells with respect to the immune response, and compare cord blood transplantation to blood transfusions, as well as discussing what future studies should entail.
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Affiliation(s)
- Alison E Willing
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA.
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29
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Spadafora-Ferreira M, Caldas C, Faé KC, Marrero I, Monteiro SM, Lin-Wang HT, Socorro-Silva A, Fonseca SG, Fonseca JA, Kalil J, Coelho V. CD4+CD25+Foxp3+ indirect alloreactive T cells from renal transplant patients suppress both the direct and indirect pathways of allorecognition. Scand J Immunol 2007; 66:352-61. [PMID: 17635813 DOI: 10.1111/j.1365-3083.2007.01976.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Alloreactive T cells recognize donor antigens by two routes: direct and indirect pathways of allorecognition. Although the direct pathway is reported to be dominant in allograft rejection, indirect allorecognition also plays an important role. Indirect alloreactivity is also observed in renal transplant patients irrespective of rejection. Previously we showed a predominance of interleukin (IL)-10 induced by indirect allorecognition of donor human leucocyte antigen (HLA)-DR peptides, suggesting the existence of indirect alloreactive T cells displaying regulatory activity. In the present work, our objective was to characterize these regulatory T cells. We detected indirect alloproliferation of peripheral blood mononuclear cells (PBMC) from renal transplant patients, induced by donor HLA-DR peptides, dependent on IL-4 or IL-10, suggesting regulatory activity as part of the alloreactive T-cell repertoire. PBMC-derived indirect alloreactive T-cell lines were established and produced both inflammatory and regulatory cytokines. We showed that two of these T-cell lines which were able to inhibit both direct and indirect alloproliferation of another T-cell line from the same patient presented a CD4(+)CD25(+)Foxp3(+) T-cell population. These data support the idea that indirect alloreactive T cells may also have regulatory activity and may contribute to the maintenance of the human renal allograft.
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Affiliation(s)
- M Spadafora-Ferreira
- Heart Institute (InCor), Medical School, University of São Paulo, São Paulo, Brazil
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30
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Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007; 149:353-63. [PMID: 17521318 PMCID: PMC1941956 DOI: 10.1111/j.1365-2249.2007.03422.x] [Citation(s) in RCA: 484] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The ability of mesenchymal stem cells (MSC) to suppress alloresponsiveness is poorly understood. Herein, an allogeneic mixed lymphocyte response was used as a model to investigate the mechanisms of MSC-mediated immunomodulation. Human MSC are demonstrated to express the immunosuppressive cytokines hepatocyte growth factor (HGF), interleukin (IL)-10 and transforming growth factor (TGF)-beta1 at concentrations that suppress alloresponses in vitro. MSC also express cyclooxygenase 1 and 2 and produce prostaglandin E2 constitutively. Blocking studies with indomethacin confirmed that prostaglandins contribute to MSC-mediated allosuppression. The proinflammatory cytokine interferon (IFN)-gamma did not ablate MSC inhibition of alloantigen-driven proliferation but up-regulated HGF and TGF-beta1. IFN-gamma also induced expression of indoleamine 2,3, dioxygenase (IDO), involved in tryptophan catabolism. Use of an antagonist, 1-methyl-L-tryptophan, restored alloresponsiveness and confirmed an IDO contribution to IFN-gamma-induced immunomodulation by MSC. Addition of the tryptophan catabolite kynurenine to mixed lymphocyte reactions (MLR), blocked alloproliferation. These findings support a model where IDO exerts its effect through the local accumulation of tryptophan metabolites rather than through tryptophan depletion. Taken together, these data demonstrate that soluble factors, or products derived from MSC, modulate immune responses and suggest that MSC create an immunosuppressive microenvironment capable of modulating alloresponsiveness even in the presence of IFN-gamma.
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Affiliation(s)
- J M Ryan
- Institute of Immunology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland
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31
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Beilharz MW, Cummins JM, Bennett AL. Protection from lethal influenza virus challenge by oral type 1 interferon. Biochem Biophys Res Commun 2007; 355:740-4. [PMID: 17316562 DOI: 10.1016/j.bbrc.2007.02.019] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Accepted: 02/05/2007] [Indexed: 11/28/2022]
Abstract
The persistence of highly pathogenic avian influenza within wild bird populations has forged interest in control measures to limit a possible human pandemic. We therefore investigated the efficacy of low dose oral administration of IFN-alpha as a potential therapy against influenza infection in a murine model. We have identified an optimal low oral dose of IFN-alpha that when delivered daily as prophylactic therapy protects C57BL/6J mice from a lethal challenge with mouse adapted human influenza virus A/PR/8/34 (H1N1). These results provide strong support for the application of low dose type 1 IFN pretreatment to human influenza control.
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Affiliation(s)
- Manfred W Beilharz
- Discipline of Microbiology and Immunology, M502 School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, Perth, WA 6009, Australia.
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32
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McTaggart SJ, Atkinson K. Mesenchymal stem cells: Immunobiology and therapeutic potential in kidney disease (Review Article). Nephrology (Carlton) 2007; 12:44-52. [PMID: 17295660 DOI: 10.1111/j.1440-1797.2006.00753.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cells (MSC) are non-haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non-immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non-mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease.
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Affiliation(s)
- Steven J McTaggart
- Queensland Child & Adolescent Renal Service, Royal Children's Hospital, Australia.
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33
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Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 2006; 212:256-71. [PMID: 16903919 DOI: 10.1111/j.0105-2896.2006.00423.x] [Citation(s) in RCA: 371] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way.
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Affiliation(s)
- Ana Izcue
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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34
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Ito T, Wang YH, Duramad O, Hanabuchi S, Perng OA, Gilliet M, Qin FXF, Liu YJ. OX40 ligand shuts down IL-10-producing regulatory T cells. Proc Natl Acad Sci U S A 2006; 103:13138-43. [PMID: 16924108 PMCID: PMC1559766 DOI: 10.1073/pnas.0603107103] [Citation(s) in RCA: 151] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
IL-10-producing CD4(+) type 1 regulatory T (Tr1) cells play a critical role in the maintenance of peripheral tolerance. Although immunosuppressive drugs, cytokines, costimulatory molecules, and immature dendritic cells are implicated in the induction of Tr1 cells, the signals that negatively regulate the generation and function of Tr1 cells have been elusive. We report that OX40 ligand (OX40L) completely inhibited the generation of IL-10-producing Tr1 cells from naïve and memory CD4(+) T cells induced by the immunosuppressive drugs dexamethasone and vitamin D3. This unique function of OX40L was not shared by two costimulatory TNF family members, GITR ligand and 4-1BB ligand. OX40L strongly inhibited the generation of IL-10-producing Tr1 cells induced by two physiologic stimuli, the inducible costimulatory ligand and immature dendritic cells. In addition, OX40L strongly inhibited IL-10 production and suppressive function of differentiated IL-10-producing Tr1 cells. These two novel functions of OX40L shed light on the mechanism by which OX40/OX40L regulates immunity and tolerance.
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Affiliation(s)
- Tomoki Ito
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Yui-Hsi Wang
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Omar Duramad
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Shino Hanabuchi
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Olivia A. Perng
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Michel Gilliet
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - F. Xiao-Feng Qin
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
| | - Yong-Jun Liu
- Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-1903
- *To whom correspondence should be addressed at:
Department of Immunology and Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, 7455 Fannin, Unit 901, Houston, TX 77030-1903. E-mail:
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35
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Barchet W, Price JD, Cella M, Colonna M, MacMillan SK, Cobb JP, Thompson PA, Murphy KM, Atkinson JP, Kemper C. Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation. Blood 2005; 107:1497-504. [PMID: 16239430 PMCID: PMC1895395 DOI: 10.1182/blood-2005-07-2951] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Concurrent activation of the T-cell receptor (TCR) and complement regulator CD46 on human CD4+ T lymphocytes induces Tr1-like regulatory T cells that suppress through IL-10 secretion bystander T-cell proliferation. Here we show that, despite their IL-10 production, CD46-induced T-regulatory T cells (Tregs) do not suppress the activation/maturation of dendritic cells (DCs). DC maturation by complement/CD46-induced Tregs is mediated through simultaneous secretion of GM-CSF and soluble CD40L, factors favoring DC differentiation and reversing inhibitory effects of IL-10. Thus, CD46-induced Tregs produce a distinct cytokine profile that inhibits T-cell responses but leaves DC activation unimpaired. Such "DC-sparing" Tregs could be desirable at host/environment interfaces such as the gastrointestinal tract where their specific cytokine profile provides a mechanism that ensures unresponsiveness to commensal bacteria while maintaining reactivity to invading pathogens.
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Affiliation(s)
- Winfried Barchet
- Washington University School of Medicine, Department of Pathology and Immunology, St Louis, MO 63110, USA
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36
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Barry FP, Murphy JM, English K, Mahon BP. Immunogenicity of adult mesenchymal stem cells: lessons from the fetal allograft. Stem Cells Dev 2005; 14:252-65. [PMID: 15969620 DOI: 10.1089/scd.2005.14.252] [Citation(s) in RCA: 141] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Herein we review recent data that support host tolerance of allogeneic adult mesenchymal stem cells (MSC). Evidence is emerging that donor MSC deploy a very powerful array of mechanisms that allow escape from host allogeneic responses. These mechanisms include limited expression of alloantigen by the stem cell and cell contact-dependent and -independent mechanisms. MSC modulate host dendritic cell and T cell function, promoting induction of suppressor or regulatory T cells. These effects are complemented by the induction of divisional arrest anergy in T cells and by stem cell production of soluble immunomodulatory factors, including interleukin-10, transforming growth factor-beta, prostaglandin E2, and hepatocyte growth factor. In addition, MSC express the enzyme indoleamine 2,3-dioxygenase, which creates a tryptophan-depleted milieu that promotes immunosuppression. We propose that these observations show striking similarity to emerging data on the maternal acceptance of the fetal allograft. This comparison suggests new approaches to determine the contribution of different mechanisms to the successful use of MSC in regenerative medicine.
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Affiliation(s)
- Frank P Barry
- Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland
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37
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Park BL, Han IK, Lee HS, Kim LH, Kim SJ, Shin JS, Kim SY, Shin HD. Association of interleukin 10 haplotype with low bone mineral density in Korean postmenopausal women. BMB Rep 2005; 37:691-9. [PMID: 15607028 DOI: 10.5483/bmbrep.2004.37.6.691] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Osteoporosis is a disease characterized by exaggerated loss of bone mass, with as much as 50 to 85% of the variation in bone mineral density (BMD) commonly accepted as being genetically determined. Although intensive studies have attempted to elucidate the genetic effects of polymorphisms on BMD and/or osteoporosis in several genes, the genes involved are still largely unknown. The possible associations of genetic variants in five-candidate genes (IL10, CCR3, MCP1, MCP2 and GC) with spinal BMD were investigated in Korean postmenopausal women (n = 370). Fourteen SNPs in five candidate genes were genotyped, and the haplotypes of each gene constructed. The associations of adjusted spinal BMD by age, year since menopause (YSM) and body mass index (BMI), with genetic polymorphisms, were analyzed using multiple regression models. Genetic association analysis of Korean postmenopausal women revealed that IL10 -592A > C and/or IL10 ht2 were associated with decreased bone mass, whereas no significant associations were observed with all polymorphisms in other genes. The levels of spinal BMD in individuals bearing the IL10 -592CC genotype were lower (0.78 +/- 0.16) than those in others (0.85 +/- 0.17) (P = 0.02), and the BMD of IL10 ht2 bearing individuals were also lower (0.82 +/- 0.15) than those in others (0.85 +/- 0.17) (P = 0.04). Our results suggest that variants of IL10 might play a role in the decreased BMD, although additional study might need to be followed-up in a more powerful cohort.
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Affiliation(s)
- Byung Lae Park
- Department of Genetic Epidemiology, SNP Genetics, Inc., 11th Floor, Maehun B/D, 13 Chongro 4 Ga, Chongro Gu, Seoul 110-834, Korea
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38
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Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. JOURNAL OF INFLAMMATION-LONDON 2005; 2:8. [PMID: 16045800 PMCID: PMC1215510 DOI: 10.1186/1476-9255-2-8] [Citation(s) in RCA: 641] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2005] [Accepted: 07/26/2005] [Indexed: 02/07/2023]
Abstract
Adult bone marrow derived mesenchymal stem cells offer the potential to open a new frontier in medicine. Regenerative medicine aims to replace effete cells in a broad range of conditions associated with damaged cartilage, bone, muscle, tendon and ligament. However the normal process of immune rejection of mismatched allogeneic tissue would appear to prevent the realisation of such ambitions. In fact mesenchymal stem cells avoid allogeneic rejection in humans and in animal models. These finding are supported by in vitro co-culture studies. Three broad mechanisms contribute to this effect. Firstly, mesenchymal stem cells are hypoimmunogenic, often lacking MHC-II and costimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting NK as well as CD8+ and CD4+ T cell function. Thirdly, mesenchymal stem cells induce a suppressive local microenvironment through the production of prostaglandins and interleukin-10 as well as by the expression of indoleamine 2,3,-dioxygenase, which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft, and contrasted with the immune evasion mechanisms of tumor cells. Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection.
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Affiliation(s)
- Jennifer M Ryan
- Institute of Immunology, National University of Ireland, Maynooth, Co. Kildare Ireland
| | - Frank P Barry
- Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland
| | - J Mary Murphy
- Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland
| | - Bernard P Mahon
- Institute of Immunology, National University of Ireland, Maynooth, Co. Kildare Ireland
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Ina K, Kusugami K, Kawano Y, Nishiwaki T, Wen Z, Musso A, West GA, Ohta M, Goto H, Fiocchi C. Intestinal Fibroblast-Derived IL-10 Increases Survival of Mucosal T Cells by Inhibiting Growth Factor Deprivation- and Fas-Mediated Apoptosis. THE JOURNAL OF IMMUNOLOGY 2005; 175:2000-9. [PMID: 16034145 DOI: 10.4049/jimmunol.175.3.2000] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Mucosal T cells are essential to immune tolerance in the intestine, an organ constantly exposed to large amounts of dietary and bacterial Ags. We investigated whether local fibroblasts affect mucosal T cell survival, which is critical for maintenance of immune tolerance. Coculture with autologous fibroblasts significantly increased viability of mucosal T cells by inhibiting IL-2 deprivation- and Fas-mediated apoptosis, an effect that was both contact- and secreted product-dependent. Investigation of anti-apoptotic factors in the fibroblast-conditioned medium (FCM) revealed the presence of IL-10 and PGE2, but not IFN-beta, IL-2, or IL-15. Although recombinant IFN-beta, but not PGE2, effectively prevented T cell apoptosis, neutralizing Ab studies showed that only IL-10 blockade significantly increased T cells apoptosis, whereas neutralizing IFN-beta or IFN-alpha failed to inhibit the anti-apoptotic effect of FCM. To confirm that fibroblast-derived IL-10 was responsible for preserving mucosal T cell viability, IL-10 mRNA was demonstrated in fibroblasts by Southern blotting and RT-PCR. When FCM was submitted to HPLC fractionation, only the peak matching rIL-10 contained the anti-apoptotic activity, and this was eliminated by treatment with an IL-10-neutralizing Ab. Finally, when fibroblasts were transiently transfected with IL-10 antisense oligonucleotides, the conditioned medium lost its T cell anti-apoptotic effect, whereas medium from fibroblasts transfected with IFN-beta antisense oligonucleotides displayed the same anti-apoptotic activity of medium from untransfected fibroblasts. These results indicate that local fibroblast-derived IL-10 is critically involved in the survival of mucosal T cells, underscoring the crucial importance of studying organ-specific cells and products to define the mechanisms of immune homeostasis in specialized tissue microenvironments like the intestinal mucosa.
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Affiliation(s)
- Kenji Ina
- Division of Medical Oncology, Nagoya Memorial Hospital, Nagoya University School of Medicine, Nagoya, Japan
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40
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Abstract
Regulatory T cells are now recognized as important mediators of self-tolerance and may mediate responses to immune therapy. The mechanisms of action of these cells are diverse, and some studies suggest that there may be defects in regulatory cells in patients with type 1 diabetes. These cells may be expanded by immune therapy, suggesting the possible development of adoptive immune therapy to transfer regulation with the cells.
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Affiliation(s)
- Brygida C Bisikirska
- Division of Endocrinology, Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons, Columbia University, Room 10-105, 630 W. 168th Street, New York, NY 10032, USA
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41
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Abstract
Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4+CD25+ T cells are a major subset. Recent evidence suggests that CD4+CD25+ T cells have a role in controlling the development of autoimmune diseases in animals and in humans. The precise delineation of the function of CD4+CD25+ T cells in autoimmune inflammation is therefore of great importance for the understanding of the pathogenesis of autoimmune diseases. Moreover, the ability to control such regulatory mechanisms might provide novel therapeutic opportunities in autoimmune disorders such as rheumatoid arthritis. Here we review existing knowledge of CD4+CD25+ T cells and discuss their role in the pathogenesis of rheumatic diseases.
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Affiliation(s)
- Jan Leipe
- Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alla Skapenko
- Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Peter E Lipsky
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hendrik Schulze-Koops
- Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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42
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Abstract
Two distinct, but rapidly converging, areas of research (the hygiene hypothesis and the study of probiotic/prebiotic effects) have emphasised the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. The story began with allergic disorders but now inflammatory bowel disease is increasingly involved.
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Affiliation(s)
- G A W Rook
- Centre for Infectious Diseases and International Health, Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, 46 Cleveland St, London W1T 4JF, UK.
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43
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Herold KC, Taylor L. Treatment of Type 1 diabetes with anti-CD3 monoclonal antibody: induction of immune regulation? Immunol Res 2004; 28:141-50. [PMID: 14610290 DOI: 10.1385/ir:28:2:141] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Anti-CD3 monoclonal antibodies (MAbs) were developed as a way of inducing immune suppression of T cells. More recent studies have indicated that anti-CD3 MAbs can affect immune responses by inducing immune regulation. We recently reported that a single course of treatment with a non-FcR binding anti-CD3 MAb, hOKT3gamma1(Ala-Ala), can lead to preservation of insulin production in patients with new-onset Type 1 diabetes for even beyond 1 yr after treatment. The sustained insulin production was accompanied by improvement in glucose control and reduced use of insulin. Our studies of the mechanism of the non-FcR binding anti-CD3 MAb indicate that the MAb delivers an activation signal to T cells resulting in disproportionate production of interleukin-10 (IL-10) relative to interferon-gamma(IFN-gamma) in vitro compared with FcR binding anti-CD3 MAb, and detectable levels of IL-10, IL-5, but rarely IFN-gamma or IL-2 in the serum after treatment. In addition, the drug induces a population of CD4+IL-10+ CCR4+ cells in vivo. Preclinical data suggest that anti-CD3 MAb induces a population of regulatory T cells that can prevent or lead to reversal of Type 1 diabetes. The induction of cells with a regulatory phenotype may account for the ability of anti-CD3 MAb to induce immune regulation.
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Affiliation(s)
- Kevan C Herold
- Department of Medicine, the Naomi Berrie Diabetes Center, and the Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
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44
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Abstract
The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism. This dilemma imposed by the gut environment has probably contributed significantly to the evolutionary drive that has led to sophisticated mechanisms and diversification of the immune system to allow for protection while maintaining the integrity of the mucosal barrier. The immense expansion and specialization of the immune system is particularly mirrored in the phylogeny, ontogeny, organization, and regulation of the adaptive intraepithelial lymphocytes, or IEL, which are key players in the unique intestinal defense mechanisms that have evolved in mammals.
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Affiliation(s)
- Hilde Cheroutre
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
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45
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Ten Hove T, The Olle F, Berkhout M, Bruggeman JP, Vyth-Dreese FA, Slors JFM, Van Deventer SJH, Te Velde AA. Expression of CD45RB functionally distinguishes intestinal T lymphocytes in inflammatory bowel disease. J Leukoc Biol 2004; 75:1010-5. [PMID: 15020649 DOI: 10.1189/jlb.0803400] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The importance of CD45RB expression on T cells was already shown in mice where CD45RB(high) expression determines pathogenic potential. In this study, we analyzed the expression of CD45RA, CD45RB, and CD45RO on CD4(+) T lymphocytes in the intestinal mucosa and in the circulation of patients with inflammatory bowel disease (IBD). In addition, we studied the cytokine profile of these cells. In the circulation, virtually all CD4(+)CD45RB(high) T cells expressed the naive marker CD45RA, and circulating CD4(+)CD45RB(low) cells expressed the memory marker CD45RO in IBD patients and a control patient population. In contrast, the intestinal CD4(+) CD45RB(high) T cells are in normal controls for 90% CD45RO(+). However, in IBD, 27.7% [Crohn's disease (CD)] and 49% [ulcerative colitis (UC)] of the intestinal CD4(+) CD45RB(high) T cells are CD45RA(+). This special CD4CD45RA(+) T cell in IBD can be found in the lamina propria as well as in lymphoid follicles (confocal laser-scanning microscopy). The CD4(+)CD45RB(high) T lymphocytes produce significantly less interleukin (IL)-10 and IL-4 and produce more tumor necrosis factor alpha than CD45RB(low) T lymphocytes in control patients. CD4(+)CD45RB(low) T cells from IBD patients produced less IL-10 than CD4(+)CD45RB(low) T lymphocytes of controls, and interferon-gamma production by both T lymphocyte subsets was decreased in IBD. These data indicate that CD and UC are characterized by an influx of CD4(+)CD45RB(high) T lymphocytes. These CD4(+)CD45RB(high) T lymphocytes seem to be important in the pathogenesis of IBD, as they produce more proinflammatory cytokines and less anti-inflammatory cytokines compared with CD4(+)CD45RB(low) T lymphocytes.
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Affiliation(s)
- Tessa Ten Hove
- H2-256, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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White CA, Johansson M, Roberts CT, Ramsay AJ, Robertson SA. Effect of Interleukin-10 Null Mutation on Maternal Immune Response and Reproductive Outcome in Mice1. Biol Reprod 2004; 70:123-31. [PMID: 13679317 DOI: 10.1095/biolreprod.103.018754] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Interleukin-10 (IL-10) is an anti-inflammatory and immune-deviating cytokine expressed in the endometrium and placenta. IL-10 null mutant (IL-10-/-) mice have been employed to examine the role of IL-10 in regulating immune events in early pregnancy and its significance in implantation and pregnancy success. The inflammatory response elicited in endometrial tissue by insemination was amplified in IL-10-/- mice, with a 66% increase in leukocytes in the endometrial stroma on Day 3 of pregnancy. Despite this, no evidence of abnormal type 1/type 2 skewing was seen in T-lymphocytes from lymph nodes draining the uterus. On Day 18 of gestation, IL-10-/- females mated with IL-10-/- males had 15% more implantation sites and 27% more viable fetuses than pregnant wild-type (IL-10+/+) mice. Placental weight was unaffected, but fetal weight and the fetal:placental weight ratio were higher in IL-10-/- pregnancies. Similar data were obtained in allogeneic pregnancies when IL-10-/- females were mated with major-histocompatibility complex (MHC) disparate IL-10-/- males. Pups delivered by IL-10-/- mothers had increased birth weight and followed an altered growth trajectory, with growth impairment evident from early postnatal life into adulthood, which was reflected in alterations in body composition at 14 wk of age. This study shows that although IL-10 is not essential for maternal immune tolerance or successful pregnancy irrespective of MHC disparity in the fetus, maternal IL-10 is a determinant of growth trajectory in progeny in utero and after birth.
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Affiliation(s)
- Christine A White
- Department of Obstetrics and Gynaecology and Reproductive Medicine Unit, University of Adelaide, Adelaide 5005, Australia
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47
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Strobel S. Understanding primary oral tolerance induction: the end of the beginning. Monatsschr Kinderheilkd 2003. [DOI: 10.1007/s00112-003-0801-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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48
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Braat H, Peppelenbosch MP, Hommes DW. Interleukin-10-based therapy for inflammatory bowel disease. Expert Opin Biol Ther 2003; 3:725-31. [PMID: 12880373 DOI: 10.1517/14712598.3.5.725] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD. This review will discuss the characteristics of IL-10, its immunoregulatory properties in mice and humans, and the use of IL-10 as a treatment for CD. The review will summarise the clinical studies that have taken place and discuss the lessons learned from these trials. Finally, the advantages and disadvantages of promising new strategies of IL-10 treatment, including gene therapy and the use of genetically modified bacteria, will be discussed. Both novel therapies have been shown to be successful in animal models of disease, and clinical testing is currently underway. The future goal of IL-10 treatment should be focused on mucosal delivery and remission maintenance instead of remission induction. In conclusion, it can be said that despite the disappointing results of IL-10 therapy so far, there is still enough rationale for the use of IL-10 as an anti-inflammatory biological treatment in chronic IBD.
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Affiliation(s)
- Henri Braat
- Department of Experimental Internal Medicine, Academic Medical Center, Meiberdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Chen Y, Chen Y. Cytokines, lymphocyte homeostasis and self tolerance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 520:66-72. [PMID: 12613572 DOI: 10.1007/978-1-4615-0171-8_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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50
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Meagher C, Sharif S, Hussain S, Cameron MJ, Arreaza GA, Delovitch TL. Cytokines and chemokines in the pathogenesis of murine type 1 diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 520:133-58. [PMID: 12613577 DOI: 10.1007/978-1-4615-0171-8_9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Affiliation(s)
- C Meagher
- The Robarts Research Institute and University of Western Ontario, Department of Microbiology and Immunology, and Medicine, London, Ontario, Canada
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