About forty years ago, Henry Kaplan and collaborators reported that four sweekly X-ray doses of 160 rads each were highly leukemogenic in C57BL mice. A single dose of 350 Rads had a weak leukemogenic effect. These authors also demonstrated that lead shielding of the thigh during irradiation prevented the development of leukemia. They reported that intravenous injection of syngeneic bone marrow cells into irradiated mice facilitated the regeneration of the thymus and prevented the development of X-ray-induced tumors. We characterized the thymic Ia+ dendritic cells (DC) with the aid of a fluorescence-activated cell-sorter (FACS). It was found that exposure of mice to a leukemogenic regimen of fractionated X-irradiation treatment led to a gradual decrease in the number of thymic DC. The disappearance of thymic DC and the development of leukemia were prevented by intravenous injection of syngeneic bone marrow or by lead shielding of the femur during irradiation. These results indicated that the fractionated irradiation caused a decline in the number of DC and, as a result, diminution of the natural defense against the developing tumor. Homing of the injected bone marrow DC into the thymus can be connected to the prevention of tumor development. Since leukemogenic T cells produce interleukin-4(IL-4), we tested the effect of the conditioned medium in which YAB-3 cells (tumorigenic T(h) cells: CD4+, CD8-, Thy-1+) were cultivated. Following injection of the conditioned medium into the mouse footpads, the number of skin Langerhans cells (LC) decreased. Injection of 106 YAB-3 cells into the footpads of mice resulted in a decrease in the number of LC in the mouse footpad at the site of injection, followed by mouse death after one week, presumably due to the invasiveness of the tumor cells. Recombinant IL-4 (rIL-4) was injected into the mouse footpad and a decline in the number of LC was noted. It was suggested that the anticancer activity of the bone marrow-derived thymic DC in the protection against X-irradiation- induced leukemia in mice may be due to the ability of DC to inhibit IL-4 gene activation in transformed T(h) cells. However, if the DC return to the thymus at a later stage when IL-4 producing CD4+ T(h) cells are present in the thymus, the DC are inactivated by the cytokine IL-4 produced by the transformed T cells. The abrogation of the protective effect of DC by a cytokine released by the tumor cells leads to the progression of the thymoma.
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|Published - 1993