Little is known about the immunological mechanisms that lead to generation of phenotypic variants of tumor cells during their natural progression in a tumor-bearing host. Using a homogeneous population of an antigen-specific murine B-cell tumor, 2C3E1, we have observed that stable idiotype-negative variants of 2C3E1, which express a private idiotype on its surface, are found in the spleens of BALB/c mice bearing this tumor. We have developed a method to monitor generation of these somatic variants in vitro and to study the mechanisms that lead to suppression of the tumor-specific surface marker (idiotype) of this homogeneous B-cell hybrid tumor model. Preliminary experiments suggest that idiotype-specific mature T cells cause a marked and irreversible suppression of the idiotypic expression of 2C3E1. It is anticipated that this model will permit us to study the mechanisms leading to tumor cell heterogeneity and will help in the design of effective therapeutic modalities. The goal of the proposed research is to study immunoregulatory events associated with the generation of phenotypic heterogeneity of the B-cell line, 2C3E1. Experiments described in this proposal will determine the requirements for the induction of idiotype-binding T cells (such as MHC-linked associative recognition and the role of surface idiotype) and T-cell effector mechanisms. Selective elimination of the idiotype-binding T cells will be done to determine if such elimination prevents generation of the variants. It is expected that the information derived from our proposed studies with the neoplastic B-cell tumor model will provide a better understanding of the physiologically relevant mechanism by which T cells recognize and thereby cause the generation of somatic variants during the growth of a tumor. (SR)
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