NCI CLINICAL INVESTIGATOR AWARD

急性转化的Abelson癌基因(Abl) 近年来，人们对小鼠白血病病毒(AMLV)进行了深入研究 它的原始发现。AMLV基因组编码一种重组 具有酪氨酸激酶活性的GAG-ABL蛋白，属于 癌基因SRC家族。在人类慢性粒细胞白血病中 (CML)表达一种类似的重组bcr-abl蛋白 由9：22的染色体易位导致的 费城的染色体。虽然可以检测到Gag-ABL蛋白 在有特异性抗体的细胞表面，它不会受到 表面标记，并且是非糖基化的。因此，从一个 从免疫学的角度来看，它和大多数其他癌基因产品一样， 主要是一种细胞内的蛋白质。最近的一些 研究表明，细胞内的蛋白质确实是 T细胞可能在蛋白分解后才能识别， 展开，或其他加工和贩运到细胞表面。 对ABL或其他基因编码的蛋白质可能产生的T细胞免疫 致癌基因以前从未被研究过。 本项目的目标是：1)确定 小鼠T细胞对Abelson癌基因产物的反应，2) 在小的水平上确定反应的特异性 多肽，3)确定这种抗原肽的能力 对小鼠进行免疫，以对天然蛋白质做出反应，最后是4) 为了评估这种抗肽反应在治疗中的有效性 保护小鼠免受AMLV的攻击。要采取的方法是 受雇人员是最近确定帮手T的工作的副产品 利用人工合成的艾滋病病毒包膜蛋白中的细胞位置 多肽及其在结构特征研究中的应用 T细胞识别的免疫优势部位。两个帮手都是 并将研究细胞溶解T细胞的反应。ABL的选择 作为详细描述的原型，提供了 有机会在老鼠身上做仔细的研究，包括疾病 挑战和保护研究，重点是一种蛋白质，其 癌基因编码序列与相关序列几乎相同 带着人类的恶毒。因此这些研究可能会产生 有效使用基本知识和试剂 研究人类T细胞对ABL和ABL编码蛋白的反应 其他癌基因。人们希望这样的研究最终可能会 阐明抗原特异性T细胞的诱导策略 对人类恶性肿瘤具有免疫力。

The Abelson oncogene (abl) of the acutely transforming Abelson Murine Leukemia Virus (AMLV) has been intensively studied since its original discovery. The AMLV genome encodes a recombinant gag-abl protein with tyrosine kinase activity and belonging to the src family of oncogenes. In human chronic myelogenous leukemia (CML) an analagous recombinant bcr-abl protein is expressed resulting from the 9:22 chromosomal translocation forming the Philadelphia chromosome. While the gag-abl protein is detectable on the cell surface with specific antibody, it is not subject to surface labeling and is non-glycosylated. Thus from an immunologic perspective it, like most other oncogene products, is predominantly an intracellular protein. A number of recent studies have indicated that intracellular proteins are indeed accessible to T cell recognition probably after proteolysis, unfolding, or other processing and trafficking to the cell surface. Possible T cell immunity against proteins encoded by abl or other oncogenes has not been previously explored. The objectives of this project are: 1) to determine the extent of the murine T cell response to the Abelson oncogene product, 2) to determine the specificity of the response at the level of small peptides, 3) to determine the ability of such antigenic peptides to immunize mice for a response to the native protein, and finally 4) to evaluate the effectiveness of such an anti-peptide response in protecting mice from challenge with AMLV. The methods to be employed are an outgrowth of recent work identifying helper T cell sites in the AIDS virus envelope protein using synthetic peptides and applying recent insights into the structural features of immunodominant sites recognized by T cells. Both the helper and the cytolytic T cell responses will be studied. Selection of abl as a prototype for detailed characterization offers the opportunity to do careful studies in the mouse, including disease challenge and protection studies, focusing on a protein whose oncogene-encoded sequence is nearly identical to that associated with human malignancy. These studies may therefore generate the basic knowledge and reagents necessary for effectively studying the human T cell response to proteins encoded by abl and other oncogenes. It is hoped that such studies may eventually elucidate strategies for induction of antigen-specific T cell immunity to human malignancies.