Natural resistance against nonsyngeneic normal or malignant hemopoietic cells is most strongly expressed when the host and the graft are not identical at the H-2 complex. Following the survival and organ distribution of injected leukemia cells that have been prelabeled with radioactive IdUrd provides a convenient and sensitive assay for H-2 associated natural resistance (H-2NR) and has been used to demonstrate that classical immune responses are not involved. Our recent genetic analyses have shown that natural killer cell activity is not sufficient to account for H-2NR. Thus, a primary objective of our research is to determine the effector mechanisms involved. lf cytolytic effector cells are directly responsible, the cells surviving the selective pressure of H-2NR would be phenotypic or genotypic variants expressing either (or both) reduced cell surface H-2 or resistance to cytolysis by the effector. To date, we have not recovered stable variant clones indicative of selection in resistant animals. We are developing flow cytofluorimetric techniques to enable us to detect transient phenotypic alterations in H-2 expression in the selective environment. Comparison of H-2 expression in H-2 heterozygous versus homezygous cell lines will receive particular attention, given that heterozygous cells are refractory to rejection by parental strain mice. The possibility that H-2NR is a manifestation of H-2 restricted recognition of monomorphic determinants responsible for cell positioning will be tested in vivo by comparing the trafficking and positioning of H-2 identical and mismatched fluorochrome-labeled cells and in vitro by searching for functional self-H-2 preference in cell-cell interactions in long-term bone marrow cultures. These studies should yield information on the physiological functions of the major histocompatibility complex in controlling nonimmune cell interactions and on resistance mechanisms against neoplasia. (SR)
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