Abstract
Calcineurin inhibitors such as cyclosporine A and FK506 have been used for transplant therapy and treatment of autoimmune diseases. However, the inhibition of calcineurin outside the immune system has a number of side effects, including hyperglycemia. In the search for safer drugs, we developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide provided immunosuppression for fully mismatched islet allografts in mice. In addition, it did not affect insulin secretion, whereas FK506 caused a dose-dependent decrease in insulin secretion. Cell-permeable peptides can thus provide a new strategy for drug development and may eventually be useful clinically.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Graft Survival
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Humans
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology*
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Insulin / metabolism
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Insulin Secretion
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Interleukin-2 / metabolism
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Islets of Langerhans Transplantation*
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Jurkat Cells
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Lymphocyte Activation
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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NFATC Transcription Factors
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Nuclear Proteins*
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Oligopeptides / chemistry
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Oligopeptides / genetics
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Oligopeptides / metabolism
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Peptides
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Permeability
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Recombinant Fusion Proteins / pharmacology*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Tacrolimus / metabolism
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Tacrolimus / pharmacology
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
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Transplantation, Homologous
Substances
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DNA-Binding Proteins
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Immunosuppressive Agents
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Insulin
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Interleukin-2
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NFATC Transcription Factors
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Nuclear Proteins
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Oligopeptides
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Peptides
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Recombinant Fusion Proteins
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Transcription Factors
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VIVIT peptide
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polyarginine
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Tacrolimus