title: Targeting kallikrein 6 proteolysis attenuates CNS inflammatory disease.
abstract: Kallikrein 6 (K6, MSP) is a newly identified member of the Kallikrein family of serine proteases that is preferentially expressed in the adult central nervous system (CNS). We have previously demonstrated that K6 is abundantly expressed by inflammatory cells at sites of CNS inflammation and demyelination in animal models of multiple sclerosis (MS) and in human MS lesions. To test the hypothesis that this novel enzyme is a mediator of pathogenesis in CNS inflammatory disease, we have evaluated whether autonomously generated K6 antibodies alter the clinicopathological course of disease in murine proteolipid protein139-151-induced experimental autoimmune encephalomyelitis (PLP139-151 EAE). We demonstrate that immunization of mice with recombinant K6 generates antibodies that block K6 enzymatic activity in vitro, including the breakdown of myelin basic protein (MBP), and that K6-immunized mice exhibit significantly delayed onset and severity of clinical deficits. Reduced clinical deficits were reflected in significantly less spinal cord pathology and meningeal inflammation and in reduced Th1 cellular responses in vivo and in vitro. These data demonstrate for the first time that K6 participates in enzymatic cascades mediating CNS inflammatory disease and that this unique enzyme may represent a novel therapeutic target for the treatment of progressive inflammatory disorders, including MS.
authors.affiliation: Institute of Molecular Biophysics, Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
authors.forename: Sachiko I
authors.initials: SI
authors.lastname: Blaber
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.forename: George P
authors.initials: GP
authors.lastname: Christophi
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bernett
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Isobel A
authors.initials: IA
authors.lastname: Scarisbrick
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006023:Glycoproteins / Q000633:toxicity; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007167:Immunotherapy; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D008578:Meninges / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009103:Multiple Sclerosis; D018991:Myelin Proteolipid Protein / Q000276:immunology / Q000633:toxicity; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction; D013116:Spinal Cord / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D001323:Autoantibodies; D006023:Glycoproteins; D007074:Immunoglobulin G; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011994:Recombinant Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151); D007610:Kallikreins; C491223:Prss18 protein, mouse