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      Potential Role of Regulatory T Cells in Reversing Obesity-Linked Insulin Resistance and Diabetic Nephropathy

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          Abstract

          OBJECTIVE

          To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.

          RESEARCH DESIGN AND METHODS

          To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.

          RESULTS

          Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4 +FoxP3 + Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8 +CD69 + T cells in visceral adipose tissue and kidneys of Treg-treated animals.

          CONCLUSIONS

          Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

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          Most cited references21

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          Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

          Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
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            Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.

            OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.
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              Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells.

              CD4(+)CD25(+) regulatory T cells have been shown to prevent T cell-mediated immune pathology; however, their ability to ameliorate established inflammation has not been tested. Using the CD4(+)CD45RB(high) T cell transfer model of inflammatory bowel disease, we show that CD4(+)CD25(+) but not CD4(+)CD25(-)CD45RB(low) T cells are able to cure intestinal inflammation. Transfer of CD4(+)CD25(+) T cells into mice with colitis led to resolution of the lamina propria infiltrate in the intestine and reappearance of normal intestinal architecture. CD4(+)CD25(+) T cells were found to proliferate in the mesenteric lymph nodes and inflamed colon. They were located between clusters of CD11c(+) cells and pathogenic T cells and found to be in contact with both cell types. These studies suggest that manipulation of CD4(+)CD25(+) T cells may be beneficial in the treatment of chronic inflammatory diseases.
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                Author and article information

                Journal
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                November 2011
                17 October 2011
                : 60
                : 11
                : 2954-2962
                Affiliations
                [1] 1Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria
                [2] 2Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
                [3] 3Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria
                [4] 4Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria
                [5] 5Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria
                [6] 6Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Salzburg, Austria
                [7] 7Clinical Division of Angiology, Department of Internal Medicine, Medical University Graz, Graz, Austria
                Author notes
                Corresponding author: Kathrin Eller, kathrin.eller@ 123456medunigraz.at .
                Article
                0358
                10.2337/db11-0358
                3198056
                21911743
                d9d48bcd-715c-424d-aa87-7e99bb00fa83
                © 2011 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 15 March 2011
                : 12 August 2011
                Categories
                Pathophysiology

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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