ANTIGEN RECEPTOR GENES IN T CELL MALIGNANCIES

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Approximately 80% of lymphoblastic lymphomas and 20% of acute lymphoblastic leukemias express phenotypes consistent with prethymic and intrathymic stages of T cell differentiation. Immunophenotyping and, more recently, T cell receptor (TCR) gene rearrangement patterns have been of enormous help in diagnosing and classifying such malignancies. Their exact clonotypic origin, important in diagnosis and therapy, however, has not yet been defined. Utilization of T cell receptor (TCR) variable (V) region-specific nucleotide probes, and corresponding anti- variotypic (V-region-specific) antibodies will be extremely useful in this regard. In addition, anti-variotypic antibodies may be useful as specific therapeutic agents for malignancies of the mature T cell type. The major objective of this proposal is to molecularly characterize the expressed TCR V beta genes of human leukemias/lymphomas and to subsequently attempt to treat such malignancies transplanted into severe combined immunodeficiency disease (scid) mice with anti-V beta-specific antibodies. To accomplish this, a survey on the clonal origin of several human T cell leukemias and lymphomas will first be made by assessing TCR gene rearrangement profiles and, importantly, by identifying their TCR V beta gene usage protection assay. Subsequently, monoclonal antibodies against the most prevalent V beta gene products will be made in mice immunized with a syngeneic lymphoma cell line transfected with corresponding full-length human, or molecularly engineered mouse/human hybrid, V beta genes. Human leukemic cells will be transplanted into scid mice, their growth characteristics established, and the effects of corresponding anti-variotypic antibodies, alone or conjugated with a toxin, will be assessed. These studies will allow the accurate clonal classification of T cell tumors, provide TCR V beta-specific reagents for identification of human TCR V beta usage in malignant and other disorders, and permit the investigation of anti-idiotypic antibodies as specific means of T cell tumor eradication.