| Abstract: |
We developed a panel of non-obese diabetic (NOD) mice deficient in major lysosomal cysteine proteases (cathepsins S, L and B) to identify protease enzymes essential for autoimmune diabetes. Null alleles for cathepsins (Cts) S, L or B were introgressed onto the NOD genetic background with 19 Idd markers at homozygosity. Diabetes onset was determined among females aged up to 6 months. We evaluated insulitis and sialadenitis in tissues using histology and computer assisted morphology. NOD mice deficient in Ctss or Ctsb were partially protected from diabetes with incidence at 33% and 28%, respectively, versus wild-type NOD (69%; p < 0.00001). NODs lacking cathepsin L (Ctsl-/-) are completely protected from IDDM, as originally shown by others. Ctsl, Ctss, or Ctsb heterozygous mice were able to develop IDDM, although incidence levels were significantly lower for Ctsb+/- (50%) and Ctsl+/- (55%) as compared to NODs (69%; p < 0.03). Ctsl-/- mice contain functional, diabetogenic T cells and an enriched Foxp3+ regulatory T cell population, and diabetes resistance was due to the presence of an expanded population of regulatory T cells. These data provide additional information about the potency of the diabetogenic T cell population in Ctsl-/- mice which were comparable in potency to wild-type NOD mice. These data illustrate the critical contribution of each of these proteases in determining IDDM in the NOD mouse and provide a useful set of models for further studies. |
| Keywords: |
controlled study; histopathology; nonhuman; transcription factor foxp3; forkhead transcription factors; animal cell; mouse; animals; mice; mice, knockout; allele; animal tissue; animal experiment; animal model; heterozygote; wild type; mice, inbred c57bl; homozygosity; regulatory t lymphocyte; t-lymphocytes, regulatory; pancreatitis; cell movement; cathepsin; cathepsin b; cathepsins; t-lymphocyte subsets; autoimmune disease; insulin dependent diabetes mellitus; diabetes mellitus, type 1; mice, inbred nod; antigens, cd4; nonobese diabetic mouse; onset age; age of onset; lymphopenia; t lymphocyte subpopulation; mice, congenic; cathepsin l; cathepsin s; nod; type 1 diabetes; insulitis; sialoadenitis; sialadenitis
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