title: Cathepsin L inhibition prevents murine autoimmune diabetes via suppression of CD8(+) T cell activity.
abstract: BACKGROUND
  Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet β cells. To determine whether specific lysosomal proteases might influence the outcome of a T cell-mediated autoimmune response, we examined the functional significance of cathepsin inhibition on autoimmune T1D-prone non-obese diabetic (NOD) mice.
  
  
  RESULTS
  Here it was found that specific inhibition of cathepsin L affords strong protection from cyclophosphamide (CY)-induced insulitis and diabetes of NOD mice at the advanced stage of CD8(+) T cell infiltration via inhibiting granzyme activity. It was discovered that cathepsin L inhibition prevents cytotoxic activity of CD8(+) T cells in the pancreatic islets through controlling dipeptidyl peptidase I activity. Moreover, the gene targeting for cathepsin L with application of in vivo siRNA administration successfully prevented CY-induced diabetes of NOD mice. Finally, cathepsin L mRNA expression of peripheral CD8(+) T cells from NOD mice developing spontaneous T1D was significantly increased compared with that from control mice.
  
  
  CONCLUSIONS
  Our results identified a novel function of cathepsin L as an enzyme whose activity is essential for the progression of CD8(+) T cell-mediated autoimmune diabetes, and inhibition of cathepsin L as a powerful therapeutic strategy for autoimmune diabetes.
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamada
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Rieko
authors.initials: R
authors.lastname: Arakaki
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D056668:Cathepsin L / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D056668:Cathepsin L