Role of natural killer and killer cells in concordant xenograft rejection.

This study was designed to test the alternative hypothesis to the T-cell cytotoxicity as a primary element in concordant xenograft rejection. Two sets of studies were done with one involving the known NK- and K-cell deficient Be mouse and another in which a normal mouse was induced with high levels (3 to 5 times normal) of LAK cell killing by a constant Osmolar Mini-Pump infusion of rIL-2. In the Be animals the CXR of skin and cardiac CXR grafts was slightly prolonged and the graft survived for a longer time than normal grafts, indicating the NK- and K-cell mechanisms are operative in CXR. These studies suggest that the NK and K cells act as ancillary mechanisms in cytotoxicity in CXR. In the second portion of these studies, the increasing of LAK cell activity by infusions of rIL-2 failed to delay rejection beyond that in the Be mouse but did delay rejection beyond controls. These results suggest that the NK- and K-cell killing acts as an ancillary mechanism in CXR. Because these animals had only a slight rise in ADCC shortly after transplantation with maximum titers of 1:256 in this model, it would be presumptive to assume that cell killing was not important in CXR because many xenograft models show extraordinarily high levels of ADCC after transplantation, especially in a late transplant period. As in human allografting, the vasculitis seen with ADCC antibody could be expected to represent a significant pathology long after transplantation and this mechanism of cytotoxicity involving NK and K cells may be important in a later phase after xenografting when chronic vasculitis develops in the long surviving xenografts. Techniques for immunomodulation of the NK and K activity are now being actively pursued in our laboratory.