The role of perforin and granzymes in diabetes.
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.
Thomas
H E
HE
Department of Immunology and Diabetes, St Vincent's Institute, 41 Victoria Parade, Fitzroy, Melbourne 3065, Australia. hthomas@svi.edu.au
Trapani
J A
JA
Kay
T W H
TW
D000818:Animals; D016923:Cell Death / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000276:immunology* / Q000503:physiopathology; D006084:Graft Rejection / Q000276:immunology; D053804:Granzymes / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000276:immunology; D054353:Perforin / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*
D054353:Perforin; D053804:Granzymes