Abstract
The ectoenzymes dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) have been implicated in the regulation of T cell activation and function. Both DP IV and APN serve as targets of efficient enzymatic inhibitors which induce autocrine production of TGF-beta1 and subsequent suppression of T cell proliferation and cytokine release. Here, we tested the hypothesis that the simultaneous inhibition of DP IV and APN enzymatic activity on leukocytes potentiates the anti-inflammatory effect of single DP IV or APN inhibitors. Our data show that the combined application of DP IV and APN inhibitors increased suppression of DNA synthesis in human peripheral blood mononuclear cells and isolated T cells in vitro when compared to the use of a single ectopeptidase inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF-beta1 production associated with the observed immunosuppressive effects. In vivo, targeting DP IV and APN provided a potent therapeutic approach for the treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Taken together, our study suggests that combined DP IV and APN inhibition on pathogenic T cells represents a novel and efficient therapy for autoimmune disease of the central nervous system by a mechanism that involves an active TGF-beta1-mediated anti-inflammatory effect at the site of pathology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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CD13 Antigens / antagonists & inhibitors*
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Cell Proliferation / drug effects
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Dipeptidyl-Peptidase IV Inhibitors*
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Drug Synergism
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Drug Therapy, Combination
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Humans
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Hydroxamic Acids / pharmacology
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Lymphocyte Activation / drug effects
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Lysine / analogs & derivatives
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Lysine / pharmacology
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Mice
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Mice, Inbred Strains
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Myelin Proteolipid Protein / immunology
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Peptide Fragments / immunology
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Phytohemagglutinins / pharmacology
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Pokeweed Mitogens / pharmacology
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Protease Inhibitors / pharmacology
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Protease Inhibitors / therapeutic use*
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Pyrrolidines / pharmacology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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Thiazoles / pharmacology
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Transforming Growth Factor beta1 / immunology
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Transforming Growth Factor beta1 / metabolism
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Vaccination
Substances
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Antibodies
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Dipeptidyl-Peptidase IV Inhibitors
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Hydroxamic Acids
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Immunosuppressive Agents
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Myelin Proteolipid Protein
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Peptide Fragments
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Phytohemagglutinins
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Pokeweed Mitogens
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Protease Inhibitors
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Pyrrolidines
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Thiazoles
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Transforming Growth Factor beta1
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lysyl-(Z(nitro))pyrrolidide
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lysyl-(Z(nitro))thiazolidide
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myelin proteolipid protein (139-151)
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CD13 Antigens
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Lysine
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actinonin