Regulatory CD4+ T cells and the control of autoimmune disease

Wraith, David C.; Nicolson, Kirsty; Whitley, Nat

doi:10.1016/j.coi.2004.09.015

Cited by 108 publications

(99 citation statements)

References 65 publications

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“…Defects in CD4 + CD25 + Tregs have been observed in RA patients 16, and Treg plays a pivotal role in the regulation of auto‐reactive T‐cell activation in CIA 29. Our previous study demonstrated that SJMHE1 treatment increases CD4 + CD25 + Tregs in vivo and in vitro 11, as well as generates CD4 + CD25 + Tregs to suppress DTH responses 12.…”

Section: Resultsmentioning

confidence: 97%

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Wang

et al. 2016

J Cellular Molecular Medi

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Helminth‐derived products have recently been shown to prevent the development of inflammatory diseases in mouse models. However, most identified immunomodulators from helminthes are mixtures or macromolecules with potentially immunogenic side effects. We previously identified an immunomodulatory peptide called SJMHE1 from the HSP60 protein of Schistosoma japonicum. In this study, we assessed the ability of SJMHE1 to affect murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated by toll‐like receptor (TLR) ligands in vitro and its treatment effect on mice with collagen‐induced arthritis (CIA). We show that SJMHE1 not only modulates the cytokine production of murine macrophage (MΦ) and dendritic cell but also affects cytokine production upon coculturing with allogeneic CD4+ T cell. SJMHE1 potently inhibits the cytokine response to TLR ligands lipopolysaccharide (LPS), CpG oligodeoxynucleotides (CpG) or resiquimod (R848) from mouse splenocytes, and human PBMCs stimulated by LPS. Furthermore, SJMHE1 suppressed clinical signs of CIA in mice and blocked joint erosion progression. This effect was mediated by downregulation of key cytokines involved in the pathogenesis of CIA, such as interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐17, and IL‐22 and up‐regulation of the inhibitory cytokine IL‐10, Tgf‐β1 mRNA, and CD4+ CD25+Foxp3+ Tregs. This study provides new evidence that the peptide from S. japonicum, which is the ‘safe’ selective generation of small molecule peptide that has evolved during host–parasite interactions, is of great value in the search for novel anti‐inflammatory agents and therapeutic targets for autoimmune diseases.

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Section: Resultsmentioning

confidence: 97%

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Wang

et al. 2016

J Cellular Molecular Medi

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“…CD4ϩCD25ϩ Treg cells can be generated peripherally from CD4ϩCD25Ϫ T cells (2,29). To determine whether the human AD-MSC-induced increase in CD4ϩCD25ϩ Treg cells during CIA was due to expansion of the existing, naturally occurring CD4ϩCD25ϩ Treg cells or to Treg cells newly generated from CD4ϩCD25Ϫ T cells, mice with CIA were depleted of CD4ϩCD25ϩ T cells before injection with human ADMSCs.…”

Section: Immune Tolerance Induction With Human Ad-mscs In Experimentamentioning

confidence: 99%

Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

González¹,

González‐Rey²,

Rico³

et al. 2009

Arthritis & Rheumatism

452

363

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Objective. Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs).Methods. DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined.Results. Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human ADMSCs also induced de novo generation of antigenspecific CD4؉CD25؉FoxP3؉ Treg cells with the capacity to suppress self-reactive T effector responses.Conclusion. Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.

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“…In mice, the deletion of these important mediators of active tolerance induces an organ-specific autoimmune syndrome that can be associated with endocrinopathies such as thyroiditis, adrenalitis, and diabetes (16). In humans, an impairment of Treg cells has recently been reported in autoimmune polyendocrine syndrome II (17), a syndrome of unknown and probably heterogeneous background, and Treg cells have also been explored in other autoimmune diseases (18). In Aire Ϫ/Ϫ mice, Treg cells develop in normal numbers, possess a normal phenotype, and have been reported to function normally (7,10,14).…”

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confidence: 99%

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

189

142

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire−/− mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire−/− mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire−/− mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

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Regulatory CD4+ T cells and the control of autoimmune disease

Cited by 108 publications

References 65 publications

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

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