Abstract
Transgenic models and administration of mAbs directed against the LFA-1/intercellular adhesion molecule 1 (ICAM-1) pathway have shown that these costimulatory molecules play a key role in generating effector cells mediating inflammatory responses. In this report, durable remission of recent diabetes in nonobese diabetic (NOD) mice was induced by transient expression of an immunoadhesin gene encoding the soluble form of ICAM-1 (sICAM-1/Ig). A single i.v. injection of an adenovirus vector encoding the immunoadhesin gene led to 70% diabetes remission as opposed to 0% in mice injected with a control adenovirus vector. Despite the rapid decline of sICAM-1/Ig serum levels, diabetes remission remained stable in 50% of NOD mice for >6 mo. sICAM-1/Ig expression also led to long-term protection against diabetes in prediabetic NOD mice. sICAM-1/Ig in vitro induced an agonistic effect of T cell activation in a TCR-transgenic model, increasing T cell proliferation and IL-2 secretion. Importantly, protected mice were not immunosuppressed because they rejected skin allografts normally and developed immunity against the adenovirus vector. Rather, sICAM-1/Ig induced active tolerance, as assessed by the persistence of diabetogenic T cells in protected mice and the reversal of protection by immunosuppression with cyclophosphamide.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Animals
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology
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Autoimmune Diseases / prevention & control
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Cell Movement / genetics
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Cell Movement / immunology
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 1 / prevention & control*
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Female
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Gene Transfer Techniques
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Genetic Vectors / administration & dosage
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Genetic Vectors / agonists
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Genetic Vectors / biosynthesis
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Genetic Vectors / immunology
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HeLa Cells
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Humans
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / biosynthesis
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin G / administration & dosage
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / genetics
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Immunosuppressive Agents / administration & dosage*
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Immunosuppressive Agents / chemical synthesis
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Injections, Intravenous
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / immunology
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Intercellular Adhesion Molecule-1 / physiology*
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Lymphocyte Activation
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Lymphocyte Depletion
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Lymphocyte Function-Associated Antigen-1 / immunology
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Lymphocyte Function-Associated Antigen-1 / physiology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Time Factors
Substances
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Immunosuppressive Agents
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Lymphocyte Function-Associated Antigen-1
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Intercellular Adhesion Molecule-1