The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus

Wang, Dandan; Huang, Saisai; Yuan, Xinran; Liang, Jun; Xu, Renju; Yao, Genhong; Feng, Xuebing; Sun, Lingyun

doi:10.1038/cmi.2015.89

Cited by 193 publications

(159 citation statements)

References 33 publications

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“…The main T cell subsets which are pivotal for this T cell balance consist of T helper (Th) cells and regulatory T (Treg) cells, and moreover, Th cells are defined as Th1, Th2 and Th17 subtypes characterized by differential expression of certain cytokines. In SLE, increasing evidences have demonstrated that the disrupted balance between Th cells and Treg cells contributed to the disease development [5–9]. Deficiencies of Treg cells, either quantitative or functional, were found in active lupus patients, while the number of Th17 cells, as well as Th17-related cytokines, was found increased in SLE patients [10–12].…”

Section: Adenosinergic Pathway Regulates Immune Imbalance During Automentioning

confidence: 99%

The role of adenosinergic pathway in human autoimmune diseases

2016

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Autoimmune diseases are characterized by the abnormal immune response against self-tissue, which are caused by the failure of nature immune homeostasis. Nature immune homeostasis represents the normal state of appropriate immune response to nonself-antigen and unresponsiveness to self-antigens. In normal situation, immune homeostasis is regulated by immunosuppressive signal and immunostimulating signal together. Accumulating data have demonstrated that the adenosinergic pathway played key roles in immune suppression and shield body from an excessive inflammatory response. The deficiency of adenosinergic pathway results in the imbalance between the pro- and anti-inflammatory activities. Thus, researchers pay much attention to the role of adenosinergic pathway in autoimmune diseases development. To date, accumulating data have suggested an important role of adenosinergic pathway-related molecules (i.e., CD39, CD73, ADA, adenosine receptors, etc.) in many types of human autoimmune diseases. More importantly, these findings have presented potential value of adenosinergic pathway analysis to be used for autoimmune diseases diagnosis, monitoring and treatment. In this review, we will provide a comprehensive description of the role of adenosinergic pathway in human autoimmune diseases.

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Section: Adenosinergic Pathway Regulates Immune Imbalance During Automentioning

confidence: 99%

The role of adenosinergic pathway in human autoimmune diseases

2016

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“…Allogeneic MSCT in lupus mice and humans could change the immune cell imbalance in vivo, including T helper 17 cells, regulatory T cells, plasma cells [10][11][12]. Recently, Liu et al [13] showed that allogeneic MSCT could rescue autologous bone marrow MSCs function and ameliorate osteopenia in Fas-deficient-MRL/lpr mice, which could change the epigenetic cascade in vivo.…”

Section: Introductionmentioning

confidence: 96%

Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study

et al. 2016

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The aim of this study is to assess the long-term safety of allogeneic umbilical cord mesenchymal stem cells (UC MSCs) transplantation for patients with refractory systemic lupus erythematosus (SLE). Nine SLE patients, who were refractory to steroid and immunosuppressive drugs treatment and underwent MSCs transplantation in 2009, were enrolled. One million allogeneic UC MSCs per kilogram of body weight were infused intravenously at days 0 and 7. The possible adverse events, including immediately after MSCs infusions, as well as the long-term safety profiles were observed. Blood and urine routine test, liver function, electrocardiogram, chest radiography and serum levels of tumor markers, including alpha fetal protein (AFP), cancer embryo antigen (CEA), carbohydrate antigen 155 (CA155) and CA199, were assayed before and 1, 2, 4 and 6 years after MSCs transplantation. All the patients completed two times of MSCs infusions. One patient had mild dizzy and warm sensation 5 min after MSCs infusion, and the symptoms disappeared quickly. No other adverse event, including fluster, headache, nausea or vomit, was observed. There was no change in peripheral white blood cell count, red blood cell count and platelet number in these patients after followed up for 6 years. Liver functional analysis showed that serum alanine aminotransferase, glutamic-oxalacetic transaminase, total bilirubin and direct bilirubin remained in normal range after MSCs infusions. No newly onset abnormality was detected on electrocardiogram and chest radiography. Moreover, we found no rise of serum tumor markers, including AFP, CEA, CA125 and CA199, before and 6 years after MSCs infusions. Our long-term observational study demonstrated a good safety profile of allogeneic UC MSCs in SLE patients.

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“…The generation of CD4 + CD25 + Foxp3 + Tregs is reciprocally linked with IL-17 + CD4 + Th17 and IFN-γ + CD4 + Th1 cells [47,48]. Because IDO may regulate the equilibrium of CD4 + Foxp3 + Tregs and IL-17 + CD4 + Th17 cells in inflammatory diseases [49,50], we examined the generation of each CD4 + Th subset, including CD4 + Foxp3 + Tregs, IL-17 + CD4 + Th17, and IFN-γ + CD4 + Th1 cells, early during JE progression. Our results revealed that IDO-ablated mice showed no significant alterations in the frequency or number of CD4 + CD25 + Foxp3 + Tregs, compared to wild-type BL/6 mice ( Fig.…”

Section: Ido Ablation Induces a Skewed Ifn-γ + Cd4 + Th1 Response Durmentioning

confidence: 99%

Blockage of indoleamine 2,3-dioxygenase regulates Japanese encephalitis via enhancement of type I/II IFN innate and adaptive T-cell responses

Kim

Choi

Uyangaa

et al. 2016

J Neuroinflammation

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BackgroundJapanese encephalitis (JE), a leading cause of viral encephalitis, is characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV). Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function. Although the regulatory role of IDO in viral replication has been postulated, the in vivo role of IDO activity has not been fully addressed in neurotropic virus-caused encephalitis.MethodsMice in which IDO activity was inhibited by genetic ablation or using a specific inhibitor were examined for mortality and clinical signs after infection. Neuroinflammation was evaluated by central nervous system (CNS) infiltration of leukocytes and cytokine expression. IDO expression, viral burden, JEV-specific T-cell, and type I/II interferon (IFN-I/II) innate responses were also analyzed.ResultsElevated expression of IDO activity in myeloid and neuron cells of the lymphoid and CNS tissues was closely associated with clinical signs of JE. Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6Chi monocytes, NK, CD4+, and CD8+ T-cells. JE amelioration in IDO-ablated mice was also associated with enhanced NK and JEV-specific T-cell responses. More interestingly, IDO ablation induced rapid enhancement of type I IFN (IFN-I) innate responses in CD11c+ dendritic cells (DCs), including conventional and plasmacytoid DCs, following JEV infection. This enhanced IFN-I innate response in IDO-ablated CD11c+ DCs was coupled with strong induction of PRRs (RIG-I, MDA5), transcription factors (IRF7, STAT1), and antiviral ISG genes (Mx1, Mx2, ISG49, ISG54, ISG56). IDO ablation also enhanced the IFN-I innate response in neuron cells, which may delay the spread of virus in the CNS. Finally, we identified that IDO ablation in myeloid cells derived from hematopoietic stem cells (HSCs) dominantly contributed to JE amelioration and that HSC-derived leukocytes played a key role in the enhanced IFN-I innate responses in the IDO-ablated environment.ConclusionsInhibition of IDO activity ameliorated JE via enhancement of antiviral IFN-I/II innate and adaptive T-cell responses and increased CNS infiltration of peripheral leukocytes. Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

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The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus

Abstract: UC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.

Cited by 193 publications

References 33 publications

The role of adenosinergic pathway in human autoimmune diseases

The role of adenosinergic pathway in human autoimmune diseases

Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study

Blockage of indoleamine 2,3-dioxygenase regulates Japanese encephalitis via enhancement of type I/II IFN innate and adaptive T-cell responses

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