| HLA-A2-Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but not Nondiabetic Donors, Transfer Insulitis to NOD-scid/{gamma}cnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells. | |
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MedLine Citation:
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PMID: 21521873 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVE Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin- producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc(null)/HLA-A*0201 (NOD-scid/γc(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node (PLN), and islets of NOD-scid/γc(null)/A2 mice after transfer. RESULTS Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining PLN, and most importantly, islets of NOD-scid/γc(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS We show that insulitis is transferred to NOD-scid/γc(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γc(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes. |
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Authors:
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Fatima Whitfield-Larry; Ellen F Young; Garrick Talmage; Elizabeth Fudge; Anita Azam; Shipra Patel; Joseph Largay; Warren Byrd; John Buse; Ali S Calikoglu; Leonard D Shultz; Jeffrey A Frelinger |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-26 |
Journal Detail:
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Title: Diabetes Volume: - ISSN: 1939-327X ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill North Carolina. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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