title: Autoimmune diabetes is suppressed by treatment with recombinant human tissue Kallikrein-1.
abstract: The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Lilia
authors.initials: L
authors.lastname: Maneva-Radicheva
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Amatya
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Camille
authors.initials: C
authors.lastname: Parker
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellefson
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Ilian
authors.initials: I
authors.lastname: Radichev
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Raghavan
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Charles
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Robbins
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Savinov
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D015415:Biomarkers; D001786:Blood Glucose / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D020840:Tissue Kallikreins / Q000008:administration & dosage / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D020840:Tissue Kallikreins