ANTIGEN RECEPTOR GENES IN T CELL MALIGNANCIES

大约80%的淋巴母细胞性淋巴瘤和20%的急性 淋巴母细胞白血病表达与胸腺前和胸腺后白血病一致的表型， 胸腺内T细胞分化阶段。 免疫分型， 最近，T细胞受体（TCR）基因重排模式已经 在诊断和分类这些恶性肿瘤方面有巨大的帮助。 它们的确切克隆型起源，在诊断和治疗中很重要， 但尚未确定。 T细胞受体（TCR）的利用 可变（V）区特异性核苷酸探针，和相应的抗- 变异型（V区特异性）抗体将在以下方面极其有用： 这方面。 此外，抗变异型抗体可用作 用于成熟T细胞类型的恶性肿瘤的特异性治疗剂。 该提案的主要目标是从分子上表征 表达的人白血病/淋巴瘤的TCR V β基因， 随后尝试治疗移植到严重 联合免疫缺陷病（scid）小鼠与抗V β特异性 抗体的 为了实现这一点，调查了几个克隆起源 人类T细胞白血病和淋巴瘤将首先通过评估TCR 基因重排谱，重要的是，通过鉴定他们的TCR V β基因使用保护测定。 随后，单克隆抗体 针对最普遍的V β基因产物的疫苗将在小鼠中制备 用转染有 相应的全长人或分子工程小鼠/人 杂种V β基因 人类白血病细胞将被移植到 scid小鼠，它们的生长特性建立，以及 相应的抗变异型抗体，单独或与相应的抗变异型抗体缀合， 毒素，将被评估。 这些研究将使准确的克隆 T细胞肿瘤的分类，提供TCR V β特异性试剂， 鉴定人TCR V β在恶性肿瘤和其它肿瘤中使用 疾病，并允许研究抗独特型抗体， T细胞肿瘤根除的特定手段。

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.