IMMUNOBIOLOGY OF CUTANEOUS T CELL LYMPHOMA

皮肤 T 细胞淋巴瘤的免疫生物学

• 批准号: 3184932
• 负责人: RICHARD Leslie EDELSON
• 金额: $ 23.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3184932
• 关键词: CD3 molecule; DNA repair; T cell receptor; T lymphocyte; antibody formation; antibody receptor; antiidiotype antibody; antireceptor antibody; cell sorting; cytokine receptors; diagnosis design /evaluation; human subject; human tissue; hybridomas; immunoglobulin idiotypes; interleukin 1; interleukin 2; laboratory mouse; monoclonal antibody; mycosis fungoides lymphoma; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic cell; nonvisual photosensitivity; nucleic acid probes; psoralens; southern blotting; tissue /cell culture; tumor antigens; ultraviolet radiation

Cutaneous T cell lymphoma (CTCL)is a malignancy of epidermotropic helper/inducer T lymphocytes which subsequently become systemically metastatic. In each individual patient, CTCL cells express a distinctive T cell receptor (TCR) for antigen which is simultaneously a marker of clonality, a tumor specific antigen and an historical link with the normal T cells from which they evolved. In this project, the features of CTCL TCRs will be exploited to achieve four interrelated goals. First, to increase sensitivity of diagnostic techniques and to obtain CTCL cells for in-depth studies, a two step approach will be taken. Peripheral blood and lymph node preparations will be substantially enriched for CTCL cells by fluorescence-activated cell sorting with monoclonal antibody (mAb) BE2 which recognizes a CTCL tumor-associated antigen. The presence of clonal populations of malignant cells in the resulting cell suspensions will be established by Southern blot analysis of their rearranged TCR genes. Second, these BE2-positive CTCL cells will be used to produce clonotypic (anti-TCR) mAbs (mAb- l), Important for the even more sensitive identification and analysis of CTCL cells in the relevant patients. Third, another set of mAbs (mAb-2) will be produced against idiotypic determinants of mAb-l. Some mAb-2 will structurally mimic the CTCL TCR antigen- binding sites and will be used in direct examination of frozen sections of skin to recognize putative targets for CTCL cells and to identify normal "defensive" an:l-CTCL lymphocytes reactive with the CTCL TCR. That such natural or induced anti-CTCL immunity is directed at unique determinants of the CTCL TCRs will be examined by modulation of the TCRs on target CTCL cells by antibody against CD3, a membrane molecule which comodulates with the TCR. Fourth, human and murine cells will be studied to determine whether extracorporeal exposure of CTCL cells to ultraviolet A (UVA)-- irradiated 8-methoxypsoralen (8-MOP) increases the immunogenicity of these cells in CTCL patients by altering membrane antigenicity. Since CTCL cells are preferentially injured by 8-MOP/UVA, their capacity to repair damage in total extractable nuclear DNA and in specific genes (TCR, IL2 receptor and IL2) will be assessed, as will the membrane expression of the products of these genes. The effects of 8-MOP/UVA on the capacity of an established anti- cytochrome C murine tumorigenic T cell hybridoma to vaccinate against its own in vivo growth will be assessed through use of an available mAb which binds selectively to the TCR of those hybridoma cells. Together, these studies should markedly enhance understanding of the immunobiology of CTCL.

皮肤T细胞淋巴瘤（CTCL）是一种亲表皮性恶性肿瘤 随后变得全身性的辅助/诱导T淋巴细胞 转移性的。 在每个患者个体中，CTCL 细胞表达 抗原的独特 T 细胞受体 (TCR) 同时是克隆性标记、肿瘤特异性抗原和 与它们进化而来的正常T细胞有历史联系。 在这个项目中，CTCL TCR 的特性将被利用 实现四个相互关联的目标。 一、提高敏感度 诊断技术并获得 CTCL 细胞进行深入研究 研究中，将采取两步走的方法。 外周血和 CTCL的淋巴结准备工作将大大丰富 通过单克隆荧光激活细胞分选细胞 抗体（mAb）BE2，可识别 CTCL 肿瘤相关 抗原。 恶性细胞克隆群的存在 所得细胞悬液将通过 Southern blot 建立 分析其重排的 TCR 基因。 其次，这些BE2阳性 CTCL 细胞将用于生产克隆型（抗 TCR）单克隆抗体（mAb- l), 对于更灵敏的识别和 对相关患者的CTCL细胞进行分析。 三、另一个 将针对独特型决定簇生产一组单克隆抗体 (mAb-2) mAb-1。 一些 mAb-2 在结构上会模仿 CTCL TCR 抗原 - 结合位点并将用于直接检查冷冻 皮肤切片识别 CTCL 细胞的假定目标 识别正常的“防御性”an:l-CTCL淋巴细胞 CTCL TCR。 这种天然或诱导的抗 CTCL 免疫是 将检查针对 CTCL TCR 的独特决定因素 通过抗体调节靶 CTCL 细胞上的 TCR CD3，一种与 TCR 共调节的膜分子。 第四， 将研究人类和小鼠细胞以确定是否 CTCL细胞体外暴露于紫外线A (UVA)-- 辐照的 8-甲氧基补骨脂素 (8-MOP) 增加免疫原性 通过改变膜抗原性来控制 CTCL 患者中的这些细胞。 由于 CTCL 细胞优先受 8-MOP/UVA 损伤，因此 修复总可提取核 DNA 损伤的能力 将评估特定基因（TCR、IL2 受体和 IL2），如 这些基因的产物将在膜上表达。 这 8-MOP/UVA 对已建立的抗-能力的影响 细胞色素C鼠致瘤性T细胞杂交瘤疫苗接种 对其自身体内生长的影响将通过使用 可用的 mAb 选择性结合那些杂交瘤的 TCR 细胞。 总之，这些研究应该显着增强 了解 CTCL 的免疫生物学。