Insulin Treatment in Patients with Type 1 Diabetes Induces Upregulation of Regulatory T-cell Markers in Peripheral Blood Mononuclear Cells Stimulated with Insulin in Vitro.
From: National Public Health Institute, Department of Viral Diseases and Immunology, Laboratory for Immunology, Mannerheimintie 166, 00300 Helsinki, Finland. minna.tiittanen@ktl.fi
Diabetes
- Publish Date: Dec 2006
- ISSN: 0012-1797
- Volume: 55
- Issue: 12
- Pages: 3446-54
- Medium: Print
- Language: English
- Citation (JAMA): Tiittanen Minna, Huupponen Johanna T, Knip Mikael, et al. Insulin Treatment in Patients with Type 1 Diabetes Induces Upregulation of Regulatory T-cell Markers in Peripheral Blood Mononuclear Cells Stimulated with Insulin in Vitro.. Diabetes Dec 2006;55:3446-54
Abstract
Patients with type 1 diabetes are treated with daily injections of human insulin, an autoantigen expressed in thymus. Natural CD4(+)CD25(high) regulatory T-cells are derived from thymus, and accordingly human insulin-specific regulatory T-cells should exist. We had a chance to study peripheral blood mononuclear cells (PBMCs) from children with type 1 diabetes both before and after starting insulin treatment, and thus we could analyze the effects of insulin treatment on regulatory T-cells in children with type 1 diabetes. PBMCs were stimulated for 72 h with bovine/human insulin. The mRNA expression of regulatory T-cell markers (transforming growth factor-beta, Foxp3, cytotoxic T-lymphocyte antigen-4 [CTLA-4], and inducible co-stimulator [ICOS]) or cytokines (gamma-interferon [IFN-gamma], interleukin [IL]-5, IL-4) was measured by quantitative RT-PCR. The secretion of IFN-gamma, IL-2, IL-4, IL-5, and IL-10 was also studied. The expression of Foxp3, CTLA-4, and ICOS mRNAs in PBMCs stimulated with bovine or human insulin was higher in patients on insulin treatment than in patients studied before starting insulin treatment. The insulin-induced Foxp3 protein expression in CD4(+)CD25(high) cells was detectable in flow cytometry. No differences were seen in cytokine activation between the patient groups. Insulin stimulation in vitro induced increased expression of regulatory T-cell markers, Foxp3, CTLA-4, and ICOS only in patients treated with insulin, suggesting that treatment with human insulin activates insulin-specific regulatory T-cells in children with newly diagnosed type 1 diabetes. This effect of the exogenous autoantigen could explain the difficulties to detect in vitro T-cell proliferation responses to insulin in newly diagnosed patients. Furthermore, autoantigen treatment-induced activation of regulatory T-cells may contribute to the clinical remission of the disease.
Mesh Headings (Keywords): Adolescent, Antigens, CD, Antigens, Differentiation, Antigens, Differentiation, T-Lymphocyte, Biological Markers, Blood Glucose, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Forkhead Transcription Factors, Hemoglobin A, Glycosylated, Humans, Hypoglycemic Agents, Infant, Insulin, Leukocytes, Mononuclear, Male, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes
Check for Full Text / PubMed Unique Identifier (PMID): 17130491
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