Liver Natural Killer Cells Play a Role in the Destruction of Islets After Intraportal Transplantation

Background. A significant loss of islet function observed in type 1 diabetic recipients after intraportal islet transplantation raises a question about the suitability of the liver as a transplant site. We hypothesize that natural killer (NK) cells in the liver play a role in the islet graft destruction. Methods. Phenotypical and functional differences between liver and splenic NK cells isolated from mice were examined by flow cytometry and in vitro cytotoxicity assays. In vivo, the role of liver NK cells was determined by examining the function of intraportally administered islet iso- and allografts by treating recipients with anti-asialo GM1 to deplete NK cells. Results. NK cell-depleted diabetic C57BL/6 mice receiving 400 syngeneic islets into the liver rapidly ameliorated hyperglycemia, whereas control recipients did not. The same number of BALB/c islets grafted in the liver of diabetic nonimmunosuppressed C57BL/6 mice failed to function, whereas NK cell-depleted recipients reversed hyperglycemia for up to 10 days. NK cells from the liver of naive C57BL/6 mice showed significantly higher cytotoxicity than splenic NK cells as tested with a &bgr;-cell line and allogeneic islets. The cell proportion and the expression level of activation markers on liver NK cells significantly increased after intraportal islet transplantation as compared with the control. Liver NK cells also increased anti-islet cytotoxicity, but not splenic NK cells, after islet transplantation. Conclusions. Our results clearly show the destructive activity of liver NK cells toward islets, suggesting that NK cells play a role in early islet graft loss after intraportal islet transplantation.

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