IMMUNOBIOLOGY OF CUTANEOUS T CELL LYMPHOMA

皮肤 T 细胞淋巴瘤的免疫生物学

• 批准号: 3184931
• 负责人: RICHARD Leslie EDELSON
• 金额: $ 24.72万
• 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/3184931
• 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 hybridization; nucleic acid probes; psoralens; 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）是一种嗜表皮性的恶性肿瘤， 辅助/诱导T淋巴细胞，随后成为系统性的 转移性的 在每一个个体患者中，CTCL细胞表达 特异性T细胞受体（TCR）抗原， 同时，克隆性标志物、肿瘤特异性抗原和 与它们进化而来的正常T细胞之间的历史联系。 在本项目中，将利用CTCL TCR的特性， 实现四个相互关联的目标。 第一，提高灵敏度 诊断技术，并获得CTCL细胞进行深入研究， 研究，将采取两个步骤的方法。 外周血和 淋巴结制备物将显著富集CTCL 用单克隆荧光激活细胞分选法 抗体（mAb）BE 2，其识别CTCL肿瘤相关的 抗原的 恶性细胞克隆群的存在， 通过Southern印迹建立所得细胞悬浮液 分析其重排的TCR基因。 其次，这些BE 2阳性 CTCL细胞将用于产生克隆型（抗TCR）mAb（mAb-1）。 l），对于更敏感的识别非常重要， 相关患者CTCL细胞分析。 第三，另 将针对独特型决定簇产生一组mAb（mAb-2） 的mAb-1。 一些mAb-2将在结构上模拟CTCL TCR抗原- 结合位点，并将用于直接检查冷冻 皮肤切片以识别CTCL细胞的假定靶点， 为了鉴定正常的“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 针对CTCL TCR的独特决定因素， 通过用抗TCRs的抗体调节靶CTCL细胞上的TCR， CD 3，一种与TCR共调节的膜分子。 第四、 将研究人类和鼠细胞以确定是否 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 这些细胞在CTCL患者通过改变膜抗原性。 由于CTCL细胞优先受到8-MOP/UVA的损伤，因此其 修复总可提取的核DNA和 将评估特定基因（TCR、IL 2受体和IL 2）， 将这些基因产物的膜表达。 的 8-MOP/UVA对已建立的抗- 细胞色素C小鼠致瘤性T细胞杂交瘤以接种 针对其自身的体内生长将通过使用 选择性结合那些杂交瘤TCR的可用mAb 细胞 总之，这些研究应该显著提高 了解CTCL的免疫生物学。