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1.
Toxicol Appl Pharmacol ; 378: 114641, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31254568

ABSTRACT

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). This disease leads to intestinal obstruction with or without peritonitis. The imbalance between the populations of Th17 and regulatory T (Treg) cells (higher Th17 cells and lower Treg cells) is part of the pathogenesis of EPS formation. We demonstrated that dimethyl sulfoxide (DMSO) effectively inhibited autoimmune diabetes recurrence in the islet transplantation of NOD mice via the induction of the differentiation of Treg cells. In this study, we investigated the therapeutic potential of DMSO in the inhibition of EPS formation by a mouse model. Under DMSO treatment, the thickening of the parietal and visceral peritoneum was significantly reduced. The populations of CD4, CD8, and IFN-γ-producing CD4 and CD8 T cells were decreased. The populations of IL-4-producing CD4 T lymphocytes, IL-10-producing CD4 T lymphocytes, CD4 CD69 T lymphocytes and Treg lymphocytes were increased. The expression levels of the cytokines IFN-γ, IL-17a, TNF-α and IL-23, in ascites, were significantly decreased following the DMSO treatment. Furthermore, the differentiation of Treg cells was induced by DMSO from naïve CD4 T cells in vitro, and these cells were adoptively transferred into the EPS mice and significantly prevented EPS formation, exhibiting a comparable effect to the in vivo DMSO treatment. We also demonstrated that the differentiation of Treg cells by DMSO occurred via the activation of STAT5 by its epigenetic effect, without altering the PI3K-AKT-mTOR or Raf-ERK pathways. Our results demonstrated, for the first time, that in vivo DMSO treatment suppresses EPS formation in a mouse model. Furthermore, the adoptive transfer of Treg cells that were differentiated from naïve CD4 T cells by an in vitro DMSO treatment exhibited a similar effect to the in vivo DMSO treatment for the prevention of EPS formation.


Subject(s)
Dimethyl Sulfoxide/immunology , Peritoneal Fibrosis/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer/methods , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Cytokines/immunology , Diabetes Mellitus, Type 1/immunology , Female , Interleukin-17/immunology , Islets of Langerhans Transplantation/methods , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Phosphatidylinositol 3-Kinases/immunology , Th17 Cells/immunology
2.
Toxicol Appl Pharmacol ; 282(2): 207-14, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25481496

ABSTRACT

Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing ß cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells.


Subject(s)
Autoimmune Diseases/prevention & control , Diabetes Mellitus/prevention & control , Dimethyl Sulfoxide/pharmacology , T-Lymphocytes, Regulatory/drug effects , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Cell Differentiation/drug effects , Insulin/metabolism , Islets of Langerhans Transplantation , Mice , Mice, Inbred NOD , Mice, SCID
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