Cell surface glycoproteins that are coded for by genes within the MHC are known to be critically important to a variety of immune and nonimmune cell-cell interactions. We recently found that some tumor cells express histocompatibility antigens different from those on syngeneic normal cells. We intend to exploit this system to investigate three aspects of the biology of H-2 antigens: (1) the frequency of occurrence and origin of modified H-2 antigens on tumor cells; (2) the relationship between altered H-2 antigens and the malignant phenotype; and (3) the bases of mechanisms which operate at the genetic level to maintain homology among H-2 antigens. To investigate the frequency of occurrence and origin of tumors expressing altered H-2 antigens, our research will induce additional tumors. These tumor cells will be characterized in both early and late passages and compared with cells derived from the primary host. These studies will allow us to assess the frequency of tumors with modified H-2 antigens, the effects of these antigens on the growth properties of the tumor, and the influence of continuous passage and host chimerism on the appearance of tumors with altered histocompatibility antigens. In addition, DNA-mediated gene transfer will be used to investigate the relationship between malignant transformation and the appearance of altered H-2 antigens. Finally, we will perform in-depth analyses of the chemical structure of both the H-2 antigens themselves and the genes which encode these cell surface glycoproteins. The results obtained in these studies will allow us to determine precisely which regions of the H-2 molecule have been affected and to identify the nature and probable origin of the underlying genetic changes. The information generated by these coordinated studies will provide greater insight into the function of H-2 antigens in host-tumor interactions and the influence of altered H-2 antigens on the malignant phenotype. Furthermore, these studies will provide a better understanding of the relationship between mechanisms that generate H-2 antigen diversity and mechanisms which maintain homology within this gene family. More generally, these studies should significantly facilitate understanding and manipulation of eukaryotic genetics and the mammalian immune response. (AG)
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