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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.

These studies provide insight into the immunobiology of xenograft rejection. They suggest that xenograft rejection involves T-cell phenomena, although the ability of the nude rat (functionally known to be T-cell deficient) to reject the vascularized xenograft normally is striking and clearly indicates a need for future studies of this phenomenon. These studies strongly suggest a role for NK and K cell-type activity in xenograft rejection, although they also indicate this immune function is only an ancillary one and that xenograft rejection will eventually occur despite deficiencies in these systems. These studies are most provocative in showing a failure of efficiency of skin graft rejection in the purest model of B-cell deficiency, the XID model. Since these results are obtained with the so-called secondarily vascularized xenograft (skin grafts) it is not possible to exclude the role of B-cell and B-cell-associated phenomena in vascularized organ grafts without further studies.