title: DP IV/CD26, APN/CD13 and related enzymes as regulators of T cell immunity: implications for experimental encephalomyelitis and multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Peptidases like dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) play a regulatory role in T cell activation and represent potential targets for the treatment of inflammatory disorders. Synthetic inhibitors of DP IV and/or APN enzymatic activity induce production of the immunosuppressive cytokine TGF-beta1 and subsequently suppress DNA synthesis and Th1 cytokine production of activated human T cells. Compelling evidence has demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to the pathogenesis of autoimmune inflammation. Here, we report that inhibitors of DP IV-like activity as well as of APN activity inhibit IL-17 production in activated human and mouse T cells. Combining inhibitors of DP IV and APN increases the suppressive effect on T cell specific IL-17 production in vitro compared to a single peptidase inhibitor. In the following, we summarize the evidence for the role of both ectoenzymes in T cell activation in vitro and in vivo and provide a rationale for the use of combined or dual ectopeptidase inhibitors to treat autoimmune diseases like MS.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Ute
authors.initials: U
authors.lastname: Bank
authors.forename: Michael
authors.initials: M
authors.lastname: Täger
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ansorge
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.forename: Anja
authors.initials: A
authors.lastname: Thielitz
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Faust
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
authors.forename: Stefan
authors.initials: S
authors.lastname: Brocke
mesh_terms: D000818:Animals; D017209:Apoptosis; D018826:CD13 Antigens / Q000096:biosynthesis* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis*; D004679:Encephalomyelitis / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation; D013058:Mass Spectrometry / Q000379:methods; D009103:Multiple Sclerosis / Q000201:enzymology / Q000276:immunology*; D010447:Peptide Hydrolases / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020381:Interleukin-17; D010447:Peptide Hydrolases; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4