ANTIGEN RECEPTOR GENES IN T CELL MALIGNANCIES

约80%的淋巴母细胞性淋巴瘤和20%的急性 淋巴母细胞性白血病表达的表型与胸腺前和 胸腺内T细胞分化的阶段。免疫表型和， 最近，T细胞受体(TCR)基因重排模式 在诊断和分类这类恶性肿瘤方面有很大帮助。 它们确切的克隆起源，在诊断和治疗中很重要， 然而，还没有被定义。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反式 各种类型(V区特异性)抗体将在以下方面非常有用 这方面。此外，抗变异型抗体可能有助于 针对成熟T细胞型恶性肿瘤的特定治疗剂。 这项提议的主要目标是从分子上表征 人白血病/淋巴瘤TCR Vβ基因的表达 随后试图治疗这种移植到重症 具有抗Vβ特异性的联合免疫缺陷病(SCID)小鼠 抗体。为了实现这一点，一项关于几个克隆起源的调查 人类T细胞白血病和淋巴瘤将首先通过评估TCR 基因重排图谱，重要的是通过鉴定它们的TCR V β基因使用保护试验。随后，单抗 针对最流行的Vβ基因产物将在小鼠身上制造 转基因同基因淋巴瘤细胞株的免疫 相应的全身人，或分子工程小鼠/人 混合的，Vβ基因。人类白血病细胞将被移植到 建立了SCID小鼠的生长特性，并观察了 相应的抗变型抗体，单独或与 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 Vβ特异性试剂 人类TCRVβ在恶性肿瘤和其他疾病中的应用鉴定 疾病，并允许研究抗独特型抗体，如 T细胞肿瘤根除的具体手段。

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.