Abstract
Anti-CD3 therapy of type 1 diabetes results in a temporary halt of its pathogenesis but does not constitute a permanent cure. One problem is the reinfiltration of islets of Langerhans with regenerated, autoaggressive lymphocytes. We aimed at blocking such a reentry by neutralizing the key chemokine CXCL10. Combination therapy of diabetic RIP-LCMV and NOD mice with anti-CD3 and anti-CXCL10 antibodies caused a substantial remission of diabetes and was superior to monotherapy with anti-CD3 or anti-CXCL10 alone. The combination therapy prevented islet-specific T cells from reentering the islets of Langerhans and thereby blocked the autodestructive process. In addition, the local immune balance in the pancreas was shifted toward a regulatory phenotype. A sequential temporal inactivation of T cells and blockade of T-cell migration might constitute a novel therapy for patients with type 1 diabetes.
© 2015 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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / therapeutic use*
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Autoimmunity / drug effects*
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CD3 Complex / chemistry*
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CD3 Complex / metabolism
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Cell Survival / drug effects
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Cells, Cultured
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Chemokine CXCL10 / antagonists & inhibitors*
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Chemokine CXCL10 / metabolism
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Crosses, Genetic
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Diabetes Mellitus, Type 1 / drug therapy*
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / metabolism
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Diabetes Mellitus, Type 1 / pathology
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Disease Models, Animal*
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Drug Therapy, Combination
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Female
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Hypoglycemic Agents / adverse effects
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Hypoglycemic Agents / therapeutic use
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Islets of Langerhans / drug effects*
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Islets of Langerhans / immunology
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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Lymphocyte Activation / drug effects
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Transgenic
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Molecular Targeted Therapy
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Remission Induction
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Spleen / drug effects
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Spleen / pathology
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Survival Analysis
Substances
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Antibodies, Monoclonal
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CD3 Complex
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Chemokine CXCL10
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Cxcl10 protein, mouse
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Hypoglycemic Agents