Open AccessAutoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1
Author(s) -
Lilia Maneva-Radicheva,
Christina Amatya,
Camille Parker,
Jacob Ellefson,
Ilian Radichev,
Arvind Raghavan,
Matthew L. Charles,
Mark S. Williams,
Mark S. Robbins,
Alexei Y. Savinov
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0107213
Subject(s) - insulitis , kallikrein , endocrinology , medicine , type 1 diabetes , diabetes mellitus , beta cell , vasoactive intestinal peptide , pancreas , biology , immunology , chemistry , islet , neuropeptide , enzyme , biochemistry , receptor
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.