The long-term objective is to define the role of MHC class I transplantation antigens in tumor progression, in order to identify immunological and molecular interactions which might be relevant to the origins and treatment of human cancer. These studies are intended to address the molecular origin and functional significance of novel class I products on murine tumors. The experiments are intended to probe the generality and significance of the phenomena defined by the UV-induced C3H fibrosarcoma, 1591. This tumor expresses at least three novel class I products, encoded by genes which appear to have been derived by recombination. Two complementary sets of studies are proposed. First, DNA from a large variety of tumors will be examined by genomic Southern blot analysis for evidence of class I alterations comparable to those observed in 1591. A variety of chemotherapeutic and mutagenic treatments will be tested for their potential to elicit class I alterations in vitro. These studies will address the etiologic component of class I alterations. The second set of experiments involve the characterization of the novel class I product expressed on the C3Hf adenocarcinoma, LT85. Peptide mapping studies suggest that, as in the case of 1591, the gene encoding the LT85 molecule was generated by recombination from an endogenous H-2 gene. Furthermore, 40% of the C3Hf tumors tested express immunologically cross-reactive molecules suggesting that the LT85 mutational event occurs reproducibly. The gene encoding this novel antigen will be cloned, and its origin identified. Specific molecular probes will be generated, and the generality of the LT85 event will be analyzed in other C3Hf tumors. The potential reproducibility of the class I alterations in the C3Hf system might afford histological identification of the activation of altered class I molecules in nascent C3Hf tumors and to help elucidate the subtle consequences of their expression on the process of tumorigenesis. Given the complexity of the human HLA system as well as the absence of appropriate transplant hosts to determine the immunogenicity of human tumors, immunobiological studies of genetically defined models, such as those described here, are essential in providing fundamental biological information applicable to the molecular characterization of comparable phenomena in human disorders.
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