INHIBITION OF HYBRID RESISTANCE BY 5-FLUOROURACIL

Abstract

Hybrid resistance designates the poor proliferation of parent-strain bone marrow cells injected into lethally irradiated hybrids. While testing a variety of oncostatic drugs for their capacity to inhibit hybrid resistance, we found that 5-fluorouracil (5-FU) injected into B6D2F1 hybrids three days before grafting enhances the growth of parent-strain B6 bone marrow cells. Hybrid resistance can be restored in these 5-FU-treated B6D2F1 recipients by the injection of spleen cells from untreated (normal) B6D2F1 mice. Treatment of these normal B6D2F1 spleen cells with anti-Thy-1 or anti-Lyt-1 antibodies plus complement abolishes their capacity to restore resistance, whereas treatment with anti Lyt-2 antibody plus complement has no effect. It is known that the rejection of parent-strain bone marrow cells by the F1 hybrid is a multistep process in which more than one cell type is involved, and that the final effector cell is asialo-GMI+, cyclophosphamide-sensitive, and responsive to IFN (possibly the natural killer cell). The Thy-1+Lyt-1+2- spleen cell we describe here, which is eliminated by the 5-FU, doesn't seem to be the final effector cell for hybrid resistance since transfer of spleen cells from cyclophosphamide-treated (final-effector-cell-depleted) B6D2F1 hybrids into 5-FU treated B6D2F1 mice restores hybrid resistance just as well as do normal B6D2F1 spleen cells; and, when injected into 5-FU-treated B6D2F1 hybrids, the IFN inducer pI:pC also restores resistance. The cell we now describe would be a third cell type, probably responsible for the initial recognition of grafted parent-strain bone marrow cells, which triggers the mechanism of hybrid resistance. This hypothesis could explain the observed specificity of parent-strain bone marrow graft rejection by F1 hybrids.