Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces

Rubtsov, Yuri P.; Rasmussen, Jeffrey P.; Emil, Y.; Fontenot, Jason D.; Castelli, Luca; Ye, Xin; Treuting, Piper M.; Siewe, Lisa; Roers, Axel; Henderson, William R.; Müller, Werner; Rudensky, Alexander Y.

doi:10.1016/j.immuni.2008.02.017

Cited by 1,321 publications

(1,234 citation statements)

References 55 publications

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“…In this study, we observed that UC MSCT could markedly up-regulate the percentage of CD4ϩFoxP3ϩ Treg cells in peripheral blood mononuclear cells 3 months after transplantation, and the percentage continued to increase after 6 months. In addition, the restoration of Treg cells was associated with a concomitant increase in TGF␤ and, to a lesser degree, an increase in IL-10, 2 cytokines that play important roles in Treg cell activation and function (35,36). Augmentation of the Treg cell pathway may be one of the mechanisms underlying the therapeutic effect of UC MSCs.…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Sun

Wang

Liang

et al. 2010

Arthritis & Rheumatism

413

305

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Objective. Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE).Methods. We conducted a single-arm trial that involved 16 SLE patients whose disease was refractory to standard treatment or who had life-threatening visceral involvement. All of the patients gave consent and underwent UC MSCT. Clinical changes were evaluated before and after transplantation using the SLE Disease Activity Index (SLEDAI), measurement of serum antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, serum complement C3 and C4, and albumin levels, and assessment of and renal function. Evaluation of potential mechanisms of MSCT effects focused on the percentage of peripheral blood Treg cells and serum levels of cytokines.Results. From April 2007 to July 2009, a total of 16 patients with active SLE were enrolled and underwent UC MSCT. The median followup time after MSCT was 8.25 months (range 3-28 months). Significant improvements in the SLEDAI score, levels of serum ANA, anti-dsDNA antibody, serum albumin, and complement C3, and renal function were observed. Clinical remission was accompanied by an increase in peripheral Treg cells and a re-established balance between Th1-and Th2-related cytokines. Significant reduction in disease activity was achieved in all patients, and there has been no recurrence to date and no treatment-related deaths.Conclusion. Our findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines. These data provide a foundation for conducting a randomized controlled trial of this new therapy for severe and treatment-refractory SLE.Systemic lupus erythematosus (SLE) is an inflammatory disease with protean manifestations, ranging from relatively minor skin and joint symptoms to severe life-threatening major organ involvement, such as nephritis and neuropsychiatric complications (1). It is characterized by the presence of autoreactive T and B lymphocytes, with polyclonal activation of B cells and the consequent production of autoantibodies by plasma ClinicalTrials.gov identifier: NCT00698191.

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Section: Discussionmentioning

confidence: 99%

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Sun

Wang

Liang

et al. 2010

Arthritis & Rheumatism

413

305

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“…In mice, suppression of cellular proliferation and IL-10 secretion by Treg cells play an important role in suppressing IFN-g-positive CD4 + T cells in lymph nodes and inflamed dermis, respectively (43). Also, IL-10 produced by Treg cells is required for the control of inflammatory responses at mucosal surfaces, but is dispensable for the suppression of immune responses in other tissues (44). Thus, the HLADR + and the CD39 2 CD26 + Treg cells identified in the PBMC may be related to Treg cells from lymph nodes and mucosal surface, respectively.…”

Section: Discussionmentioning

confidence: 99%

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

Hua

Davis

Hill

et al. 2015

The Journal of Immunology

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Regulatory T (Treg) cells have a critical role in the control of immunity, and their diverse subpopulations may allow adaptation to different types of immune responses. In this study, we analyzed human Treg cell subpopulations in the peripheral blood by performing genome-wide expression profiling of 40 Treg cell subsets from healthy donors. We found that the human peripheral blood Treg cell population is comprised of five major genomic subgroups, represented by 16 tractable subsets with a particular cell surface phenotype. These subsets possess a range of suppressive function and cytokine secretion and can exert a genomic footprint on target effector T (Teff) cells. Correlation analysis of variability in gene expression in the subsets identified several cell surface molecules associated with Treg suppressive function, and pharmacological interrogation revealed a set of genes having causative effect. The five genomic subgroups of Treg cells imposed a preserved pattern of gene expression on Teff cells, with a varying degree of genes being suppressed or induced. Notably, there was a cluster of genes induced by Treg cells that bolstered an autoinhibitory effect in Teff cells, and this induction appears to be governed by a different set of genes than ones involved in counteracting Teff activation. Our work shows an example of exploiting the diversity within human Treg cell subpopulations to dissect Treg cell biology.

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“…In addition, it is likely that each mechanism plays a specific role in a given inflammatory tissue setting. It has been shown, for example, that Treg-derived IL-10 was mainly necessary for limitation of inflammation in the colon, lung, and skin (42), whereas recent data indicate that, at tumor sites, suppression is also due to the action of a subset of CD4 + CD25 + Foxp3 + T cells that release IL-10 and TGF-b1 (37,43).…”

Section: Discussionmentioning

confidence: 99%

LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

Camisaschi¹,

Casati²,

Rini³

et al. 2010

The Journal of Immunology

275

195

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Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces

Cited by 1,321 publications

References 55 publications

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

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