Cytotoxic effects of irradiation and deoxyguanosine on fetal thymus

Effects of irradiation and deoxyguanosine on the fetal thymus were examined both in vitro and in vivo. Fetal thymi (gestation day 15) of C57BL/6 mice that had been irradiated (0-25 Gy) or treated with various doses of deoxyguanosine (dGuo) were engrafted under the renal capsules of BALB/c nu/nu mice, and the differentiation of T cells was investigated in the engrafted thymi or spleens of these mice. After in vitro treatment of fetal thymi with 1.35 mM dGuo (which was previously reported to be an optimal dose), T cell precursors still remained in some cultures, whereas 1.80 mM dGuo was highly cytotoxic not only to T cell precursors but also to thymic epithelial cells. In contrast, 25 Gy irradiation totally eliminated the T cell precursors from the fetal thymi, though the capacity of epithelial cells to induce T cell differentiation was retained. Although irradiated thymi had the capacity to induce T cell differentiation when assayed in an in vitro organ culture system, long-term observation of thymi engrafted into BALB/c nu/nu mice revealed that, if they had been irradiated (9.5 Gy or 25 Gy), the thymi became scarred by 12 wks after their transplantation. Furthermore, the expression of cell interaction molecules such as ICAM-1 and MHC class II on the thymus stromal cells decreased after irradiation. The interaction molecules decreased 3 wks after 25 Gy irradiation and 7 wks after 9.5 Gy irradiation. The alteration in T cell subsets in the thymus (decreases in both double- and single- positive cells and an increase in double-negative cells) correlated with the decreases in the interaction molecules. This indicates that irradiation (even 9.5 Gy) impairs the T cell-induction capacity of the thymus stromal cells, resulting in an alteration of the T cell subsets followed by a change in the T cell counts in the thymus. Therefore, the long-term effects of irradiation of the thymus should be considered in cases of fetal thymus grafts or total body irradiation before bone marrow transplantation, particularly in the newborn.