Recent evidence suggests that liver transplants may be immunologically protective for other simultaneously transplanted organs. One possible explanation is that the liver secretes MHC class I molecules. Here we show that these donor-specific secreted molecules can inhibit the priming effect of donor derived membrane-bound MHC antigen. Lewis rats were injected with syngeneic hepatocytes transfected with plasmids encoding either a membrane-bound or a secreted form of the RT1. A allo-MHC class I antigen of ACI rats. To test the immunologic effects of the different forms of alloantigen, ACI to Lewis liver transplants were performed 7 days after injection. As demonstrated previously, injection of hepatocytes expressing membrane-bound alloantigen sensitizes host immunity, leading to accelerated allograft rejection. However, after simultaneous injection of hepatocytes expressing the two different forms of the alloantigen, the accelerated liver allograft rejection caused by hepatocytes expressing membrane-bound molecules was no longer evident. Our results show that soluble allo-MHC class I antigen can inhibit the sensitizing effect of the same molecule in a membrane-bound form.