Abstract
The induction of tolerance in a primed immune system is a major aim for therapy in autoimmunity and transplant rejection. In this paper, we investigate the action of the nondepleting anti-CD4 Ab, YTS 177. Although this Ab is nondepleting, we have demonstrated a direct action in vivo on activated effector cells. We show that the Ab inhibits transfer of insulin-dependent diabetes mellitus by the CD4+ Th1 clone BDC2.5 to nonobese diabetic mice. Furthermore, we show that this Ab acts directly on diabetogenic effector cells because it prevented BDC2.5-induced insulin-dependent diabetes mellitus in nonobese diabetic-scid recipients in the absence of other T cells. The Ab halts the diabetic process even when it is administered after the BDC2.5 cells have infiltrated the pancreas and destruction of islets is already underway. This is accompanied by an immediate decrease in proinflammatory cytokine production with cessation of beta cell destruction and disappearance of infiltrating cells from the pancreas, leaving any remaining beta cells intact. These data suggest that Abs such as this may be effective not only because they induce regulatory T cells but also because they are able to directly prevent effector cell function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Animals, Newborn / immunology
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology*
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CD4 Antigens / immunology*
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Cell Movement / immunology
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Clone Cells / immunology
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Clone Cells / transplantation
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Cytotoxicity, Immunologic / immunology*
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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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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology
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Epithelium / immunology
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Epithelium / metabolism
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Female
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / pharmacology
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Histocompatibility Antigens Class II / biosynthesis
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / pharmacology
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Injections, Intraperitoneal
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Interleukin-2 / genetics
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Islets of Langerhans / enzymology
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Islets of Langerhans / immunology*
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Islets of Langerhans / pathology
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Lymphocyte Activation / immunology
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Lymphocyte Depletion*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Pancreatic Ducts / immunology
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Pancreatic Ducts / metabolism
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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T-Lymphocytes / immunology*
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T-Lymphocytes / transplantation
Substances
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Antibodies, Monoclonal
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CD4 Antigens
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Enzyme Inhibitors
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Growth Inhibitors
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Histocompatibility Antigens Class II
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Immunosuppressive Agents
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Interleukin-2
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RNA, Messenger
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Interferon-gamma
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse