IMMUNOBIOLOGY OF CUTANEOUS T CELL LYMPHOMA

皮肤 T 细胞淋巴瘤的免疫生物学

• 批准号: 2642005
• 负责人: RICHARD Leslie EDELSON
• 金额: $ 8.11万
• 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 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2642005
• 关键词: B lymphocyte; MHC class I antigen; T cell receptor; T lymphocyte; autoimmunity; human tissue; hybridomas; leukocyte activation /transformation; molecular chaperones; mycosis fungoides lymphoma; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic cell; protein structure function; tissue /cell culture; tumor antigens

Cutaneous T cell lymphoma (CTCL) is a clonal malignancy of T cells with a marked propensity to infiltrate epidermis and a phenotype characteristic of the normal cells from which they are thought to be derived: CD4+ (helper/inducer), CD45RO+ (memory) and CLA+ (cutaneous lymphoid antigen). Observations made during the current funding period suggest that two other CTCL cell membrane molecules, capable of housing small peptides distinctive to malignant clones, are also of substantial importance. Class I bound peptides on the malignant T cells are strong candidates for tumor specific antigens, and the abundantly displayed glycoprotein BE2 is homologous with members of the heat shock protein 70(hsp70) family, thought to expedite transfer of peptide antigens to class I major histocompatibility complex (MHC) molecules. As in vivo anti-CTCL immune response directed against class I MHC-associated peptides is suggested by the large number of nonmalignant CD8+ T cells in early plaque stage CTCL lesions, by the capacity of CD8+ T cells to selectively lyse autologous CTCL cells and by CTCL cell display of distinctive peptides in the groove of class I MHC. Since CD8+ T cells recognize peptides in the context of class I MHC, it is noteworthy that photopheresis produces longstanding remissions in only those erythrodermic CTCL patients who retain normal levels of CD8+ T cells, supporting the possibility that a natural CD8+ T cell mediated anti-CTCL response can be therapeutically enhanced. In this project, class I- associated peptides which distinguish CTCL cells will be eluted and sequenced; the cytoplasmic proteins of origin of these peptides will be identified; and the capacity of the peptides to serve as targets for anti-tumor CD8+ T cell responses will be determined. First, purified populations of leukemic cell will be isolated on the basis of their already established binding of individual anti-Vbeta (T cell receptor or TCR) family specific monoclonal antibodies. These freshly obtained CTCL cells will serve as the principal source of peptides to be characterized. In addition, hybridoma cell lines will be derived in which CTCL cells contribute the expressed class I MHC and TCR membrane proteins, and lines of autologous CD8+ anti-CTCL cells, extracted form blood and lesions of patients, will be propagated. Second, from solubilized CTCL cells, distinctive class I MHC-associated peptides will be eluted, affinity column purified, analyzed by HPLC and compared to sequences of known proteins to determine their cytoplasmic molecules of origin. The capacity of these peptides to sensitize autologous B lymphoblasts to lysis by autologous anti-CTCL CD8+ T cells will also be examined. Third, the significance of the abundant expression of BE2 antigen on the surface of CTCL cells will be explored in the context of the homology between this molecule and hsp70, a family of proteins known to have important immunologic functions and to be capable of chaperoning tumor specific peptide antigens in experimental systems. The structure of CTCL-derived BE2, as well as of BE2-bound small peptides, will be more firmly delineated, and the capacity of these BE2-bound peptides to sensitize autologous target cells for specific anti-tumor lysis will also be determined. Together, these studies should facilitate an improved understanding of CTCL cell peptide processing and immunogenicity.

皮肤T细胞淋巴瘤(CTCL)是一种克隆性恶性T细胞。 有明显的表皮浸润性和表型 正常细胞的具有正常细胞特征的，它们被认为来自正常细胞 衍生：CD4+(辅助/诱导者)，CD45RO+(记忆)和CLA+(皮肤 淋巴抗原)。在本供资期间提出的意见 提示另外两种CTCL细胞膜分子，能够容纳 对恶性克隆具有特异性的小肽，也是重要的 重要性。恶性T细胞表面的I类结合肽很强 肿瘤特异性抗原的候选，并丰富地展示了 糖蛋白BE2与热休克蛋白的成员同源 70(HSP70)家族，被认为加速多肽抗原转移到 I类主要组织相容性复合体(MHC)分子。就像在体内一样 针对I类MHC相关的抗CTCL免疫应答 多肽是由大量非恶性CD8+T细胞提示的 在斑块早期的CTCL病变中，通过CD8+T细胞的能力 选择性裂解自体CTCL细胞及CTCL细胞显示 在I类MHC的沟槽中有独特的多肽。由于CD8+T细胞 在I类MHC的上下文中识别肽，值得注意的是 光分离术只在这些患者中产生长期缓解 保持CD8+T细胞正常水平的红皮性CTCL患者， 支持天然CD8+T细胞介导的抗CTCL的可能性 反应可以在治疗上得到增强。在这个项目中，I类- 区分CTCL细胞的相关多肽将被洗脱并 测序；这些多肽来源的细胞质蛋白将是 鉴定；以及作为靶标的多肽的能力 将测定抗肿瘤CD8+T细胞反应。第一，提纯 白血病细胞群体的分离将基于它们的 已建立的单个抗Vbeta(T细胞受体或 TCR)家族特异性单抗。这些新获得的CTCL 细胞将作为要表征的多肽的主要来源。 此外，还将获得杂交瘤细胞系，其中CTCL细胞 贡献表达的I类MHC和TCR膜蛋白，并克隆 自体CD8+抗CTCL细胞，从血液和皮损中提取 患者，将被宣传。第二，从溶解的CTCL细胞， 独特的I类MHC相关多肽将被洗脱，亲和力强 柱纯化，高效液相色谱分析，并与已知序列进行比较 蛋白质以确定其细胞质分子的来源。这个 这些多肽对自体B淋巴母细胞的增敏能力 也将检测自身抗CTCL CD8+T细胞的裂解情况。 第三，BE2抗原在卵巢癌组织中大量表达的意义 CTCL细胞的表面将在同源背景下进行探索 在这个分子和HSP70之间，一个已知的蛋白质家族 重要的免疫功能，并能够陪伴肿瘤 实验系统中的特定多肽抗原。的结构 CTCL衍生的BE2以及BE2结合的小肽将会更多 以及这些BE2结合多肽的能力 使自体靶细胞敏化特异性抗肿瘤裂解也将 要下定决心。总而言之，这些研究应该有助于改善 了解CTCL细胞多肽的加工和免疫原性。

项目成果

Photopheresis: present and future aspects.

光采：现在和未来的方面。

• DOI: 10.1016/1011-1344(91)80221-3
• 发表时间: 1991
• 期刊: Journal of photochemistry and photobiology. B, Biology
• 作者: Edelson,RL

Characterization of immature T cell subpopulations in neonatal blood.

新生儿血液中未成熟 T 细胞亚群的特征。

• 发表时间: 1984
• 期刊: Blood
• 影响因子: 20.3
• 作者: Griffiths-Chu,S;Patterson,JA;Berger,CL;Edelson,RL;Chu,AC
• 通讯作者: Chu,AC

Thymopoietin-like substance in human skin.

人体皮肤中的胸腺生成素样物质。

• DOI: 10.1111/1523-1747.ep12517686
• 发表时间: 1983
• 期刊: The Journal of investigative dermatology
• 作者: Chu,AC;Patterson,JA;Goldstein,G;Berger,CL;Takezaki,S;Edelson,RL
• 通讯作者: Edelson,RL

Clinical evolution of cutaneous T cell lymphoma in a patient with antibodies to human T-lymphotropic virus type I.

具有人类 T 淋巴细胞病毒 I 型抗体的患者皮肤 T 细胞淋巴瘤的临床演变。

• DOI: 10.1016/s0190-9622(87)70278-3
• 发表时间: 1987
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Knobler,RM;Rehle,T;Grossman,M;Saxinger,CW;Berger,CL;Oster,M;McKiernan,GE;Edelson,RL
• 通讯作者: Edelson,RL

Tumor-associated antigen is expressed on lymphocytes from patients with acquired immunodeficiency syndrome.

肿瘤相关抗原在获得性免疫缺陷综合征患者的淋巴细胞上表达。

• DOI: 10.1111/1523-1747.ep12696687
• 发表时间: 1986
• 期刊: The Journal of investigative dermatology
• 作者: Berger,CL;Friedman-Kien,AE;DiFranco,M;Rehle,T;Ostreicher,R;Knobler,R;Donofrio,S;Laubenstein,LJ;Edelson,RL
• 通讯作者: Edelson,RL