Prospective prediction of spontaneous but not recurrent autoimmune diabetes in the non-obese diabetic mouse.
OBJECTIVE
Type 1 diabetes is a T cell-mediated autoimmune disease with a clinically silent prodrome, during which prediction and treatment of disease are theoretically possible. Using retrospective analysis, spontaneous disease in the non-obese diabetic (NOD) mouse has been correlated with islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells in the peripheral blood. In this study, we determined prospectively whether IGRP-reactive T cells in peripheral blood could predict disease occurrence. Since recurrent autoimmunity is an important contributor to transplant failure, we also determined whether failure of islet grafts (syngeneic and allogeneic) could be predicted by the presence of circulating autoreactive T cells.


METHODS
Peripheral blood samples were taken weekly from female NOD mice between the ages of 8 and 30 weeks and from NOD mice transplanted with NODscid islets. Peripheral blood cells and islet grafts were analysed for the presence of IGRP-reactive CD8+ T cells by flow cytometry.


RESULTS
Prospective analysis of peripheral blood IGRP-reactive T cells in the prediabetic period predicted disease development with a sensitivity of 100% and a specificity of 60%, resulting in positive and negative predictive values of 85 and 100%, respectively. Significant proportions of IGRP-reactive T cells were found in the grafts, but not in peripheral blood of NOD mice undergoing syngeneic and allogeneic rejection.


CONCLUSIONS
The occurrence of spontaneous diabetes can be predicted prospectively by measuring peripheral blood autoreactive T cells. Rejection of syngeneic or allogeneic islets is associated with large populations of autoreactive CD8+ T cells within islets, suggesting that immunodominant autoreactive T cells during the prediabetic period are also responsible for autoimmune graft rejection.
Trudeau
J D
JD
Child and Family Research Institute, BC Children's Hospital, Vancouver, BC, Canada.
Chandler
T
T
Soukhatcheva
G
G
Verchere
C B
CB
Tan
R
R
D000818:Animals; D001327:Autoimmune Diseases / Q000503:physiopathology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011506:Proteins / Q000378:metabolism; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology
D011506:Proteins; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse