The treatment by expanded ex vivo autologous regulatory T-cells CD4+CD25+FoxP3+CD127low restores the balance of immune system in patients with remitting-relapsing multiple sclerosis

CD73, ecto-5′-nucleotidase, is the key enzyme catalyzing the conversion of extracellular AMP to adenosine that controls vascular permeability and immunosuppression. Also prostatic acid phosphatase (PAP) possesses ecto-5′-nucleotidase/AMPase activity and is present in leukocytes. However, its role related to immune system is unknown. Therefore, we analyzed enzymatic activities and leukocyte subtypes of CD73 and PAP knockouts and generated CD73/PAP double knockout mice to elucidate the contribution of CD73 and PAP to immunological parameters. Enzymatic assays confirmed the ability of recombinant human PAP to hydrolyze [3H]AMP, although at much lower rate than human CD73. Nevertheless, 5′-nucleotidase/AMPase activity in splenocytes and lymphocytes from PAP−/−mice tended to be lower than in wild-type controls, suggesting potential contribution of PAP, along with CD73, into lymphoid AMP metabolism ex vivo. Single knockouts had decreased number ofCD4+/CD25+/FoxP3+regulatory T cells in thymus and CD73/PAP double knockouts exhibited reduced percentages of CD4+cells in spleen, regulatory T cells in lymph nodes and thymus, and CD4+and CD8+cells in blood. These findings suggest that PAP has a synergistic role together with CD73 in the immune system by contributing to the balance of leukocyte subpopulations and especially to the number of regulatory T cells in lymph nodes and thymus.

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Regulatory T cells fail to suppress CD4+ T-bet+T cells in relapsing multiple sclerosis patients

Immunology ◽

10.1111/j.1365-2567.2008.02963.x ◽

2009 ◽

Vol 127 (3) ◽

pp. 418-428 ◽

Cited By ~ 49

Author(s):

Giovanni Frisullo ◽

Viviana Nociti ◽

Raffaele Iorio ◽

Agata K. Patanella ◽

Marcella Caggiula ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Regulatory T Cells ◽

Multiple Sclerosis Patients ◽

Relapsing Multiple Sclerosis

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THE ROLE OF REGULATORY T CELLS IN THE DEVELOPMENT OF AUTOIMMUNE PROCESS IN MULTIPLE SCLEROSIS

Annals of the Russian academy of medical sciences ◽

10.15690/vramn.v67i3.188 ◽

2012 ◽

Vol 67 (3) ◽

pp. 68-74 ◽

Cited By ~ 4

Author(s):

D. D. Eliseeva ◽

I. A. Zavalishin ◽

A. V. Karaulov ◽

S. N. Bykovskaya

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Regulatory T Cells ◽

Ex Vivo ◽

Immunological Tolerance ◽

Acute Stage ◽

Autoimmune Process ◽

Degree Of Disability ◽

Relationship Of

In the maintenance of immunological tolerance important role belongs to the recently discovered population of regulatory T-cells CD4 + CD25 + FoxP3 +. These cells have potential in suppressing pathologic immune responses observed at various autoimmune diseases including multiple sclerosis. We have shown a reduction in the number and functional activity of T-reg in peripheral blood of patients with multiple sclerosis in the acute stage, the increase in their number during remission, duration of the relationship of the autoimmune process and the degree of disability of patients with the contents of T-reg. The possibility of using the grown ex vivo T-reg for the correction of immunopathological process in multiple sclerosis.

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Role of Regulatory T Cells in Pathogenesis and Biological Therapy of Multiple Sclerosis

Mediators of Inflammation ◽

10.1155/2013/963748 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 35

Author(s):

Milan Buc

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Immune System ◽

Regulatory T Cells ◽

Biological Therapy ◽

Signs And Symptoms ◽

Treg Cells ◽

Autoimmune Response ◽

Brain And Spinal Cord

Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of TH1 and TH17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used.

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Chronic low-level cadmium exposure in rats affects cytokine production by activated T cells

Toxicology Research ◽

10.1039/c8tx00194d ◽

2019 ◽

Vol 8 (2) ◽

pp. 227-237 ◽

Cited By ~ 5

Author(s):

Alexandra E. Turley ◽

Joseph W. Zagorski ◽

Rebekah C. Kennedy ◽

Robert A. Freeborn ◽

Jenna K. Bursley ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Low Dose ◽

Cytokine Production ◽

Ex Vivo ◽

Cadmium Exposure ◽

Activated T Cells ◽

Low Level

The purpose of this study was to determine the effect of subchronic, oral, low-dose cadmium exposure (32 ppm over 10 weeks) on the rat immune system. We found that cadmium exposure increased the induction of IFNγ and IL-10 in T cells activated ex vivo after cadmium exposure.

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Phenotypical and Functional Characteristics of Human Regulatory T Cells during Ex Vivo Maturation from CD4+ T Lymphocytes

Applied Sciences ◽

10.3390/app11135776 ◽

2021 ◽

Vol 11 (13) ◽

pp. 5776

Author(s):

Varvara G. Blinova ◽

Natalia S. Novachly ◽

Sofya N. Gippius ◽

Abdullah Hilal ◽

Yulia A. Gladilina ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Ex Vivo ◽

Pcr Analysis ◽

Mrna Levels ◽

Rt Pcr ◽

Inflammatory Reactions ◽

Effector Cells ◽

Cycle Regulation ◽

Further Development

Regulatory T cells (Tregs) participate in the negative regulation of inflammatory reactions by suppressing effector cells. In a number of autoimmune disorders, the suppressive function and/or the number of Tregs is compromised. The lack of active functioning Tregs can be restored with adoptive transfer of expanded ex vivo autologous Tregs. In our study, we traced the differentiation and maturation of Tregs CD4+CD25+FoxP3+CD127low over 7 days of cultivation from initial CD4+ T cells under ex vivo conditions. The resulting ex vivo expanded cell population (eTregs) demonstrated the immune profile of Tregs with an increased capacity to suppress the proliferation of target effector cells. The expression of the FoxP3 gene was upregulated within the time of expansion and was associated with gradual demethylation in the promotor region of the T cell-specific demethylation region. Real-time RT-PCR analysis revealed changes in the expression profile of genes involved in cell cycle regulation. In addition to FOXP3, the cells displayed elevated mRNA levels of Ikaros zinc finger transcription factors and the main telomerase catalytic subunit hTERT. Alternative splicing of FoxP3, hTERT and IKZF family members was demonstrated to be involved in eTreg maturation. Our data indicate that expanded ex vivo eTregs develop a Treg-specific phenotype and functional suppressive activity. We suggest that eTregs are not just expanded but transformed cells with enhanced capacities of immune suppression. Our findings may influence further development of cell immunosuppressive therapy based on regulatory T cells.

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