THE CONTRASTING EFFECTS OF CYCLOPHOSPHAMIDE AND RADIATION ON THE IMMUNE RESPONSES OF THE MOUSE

The immunosuppressant cyclophosphamide easily induces specific immunological tolerance in CBA mice, but is unable to produce an immunological defect in adult thymectomized animals. In contrast, lethal (and sublethal) irradiation does not induce tolerance but readily brings out the deficit of thymectomy. Furthermore, bone marrow cells which protect lethally irradiated animals do not prevent drug deaths. This sharp dichotomy indicates that the drug and radiation influence the lymphoid system by different mechanisms. It seems likely from the work of others that cyclophosphamide action is markedly dependent on rapid cell proliferation, while radiation is not. From this it follows that the cell which must be depleted to expose the immune defect of the thymectomized animal is a nonproliferating lymphoid element with the slow mitotic rate of the marrow stem cell.

THE THYMUS AND RECOVERY OF THE SHEEP ERYTHROCYTE RESPONSE IN IRRADIATED MICE

The role of the thymus in the recovery of the sheep erythrocyte response after lethal irradiation has been studied in adult CBA mice with the hemolytic plaque technique of Jerne. This immunological parameter is markedly thymus-dependent. 10 wk after irradiation and after antigenic challenge the thymectomized animal has only one-twentieth to one-fortieth the number of plaque-forming cells as does the irradiated animal with intact thymus. The thymus continues to function into the 7th and 8th month of life in this strain. Unlike the drug-tolerant animal, the incompetent irradiated thymectomized mouse retains base line plaques (plaques without antigenic stimulation). Thymectomy 18 days after irradiation is as effective as prior thymectomy in preventing recovery of the sheep cell response. Thymectomized animals receiving grafts of isogenic neonatal thymus (placed beneath the kidney capsule) 1 day, 1 wk, or 2 wk after irradiation are somewhat more responsive at 10 wk than intact animals. Grafts in place for 1 or 2 wk after irradiation and then removed result in one-fifth the recovery of grafts in place the entire time, while only slight restoration is obtained from grafts in place for the final 3 wk of the experiment. The results indicate that the thymus is not required for the 18 days after irradiation, that a period of at least 3 wk residence is required for complete restoration, and that the thymus itself is somewhat radiation-sensitive. Allogeneic thymus grafts failed to restore the hemolysin response of irradiated thymectomized animals.