Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 4, Pages 577-585Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.165
Keywords
type 1 diabetes; pancreatic beta-cell; apoptosis; perforin
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Funding
- National Health and Medical Research Council of Australia (NHMRC)
- Juvenile Diabetes Research Foundation/NHMRC
- Australian Government through the Department of Health and Ageing
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Type 1 diabetes results from autoimmune destruction of pancreatic beta-cells by CD8(+) T cells. The requirement for CD8(+) T cells implicates perforin and granzymes as effectors of tissue destruction. Diabetogenic cytotoxic T cells kill beta-cells by the perforin/granzyme pathway in vitro. In the non-obese diabetic mouse model of type I diabetes, perforin deficiency results in a highly significant reduction in disease, indicating a direct role for perforin in beta-cell death in vivo, although other cell death pathways must account for the residual diabetes in perforin-deficient mice. Perforin and granzyme B are also important in allogeneic destruction of islets. The dominant role of the perforin/granzyme pathway in beta-cell destruction in type I diabetes and allogeneic islet graft rejection make this pathway an important target for blockade in future therapies for type I diabetes. In addition, granzymes have a newly recognized role in inflammation, a feature of both type I and II diabetes, suggesting their role should be further explored in both the common forms of diabetes. Cell Death and Differentiation (2010) 17, 577-585; doi:10.1038/cdd.2009.165; published online 20 November 2009
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