DNA LEVEL STUDY OF ALLOREACTIVE T-CELL CLONE TARGETS

同种反应性 T 细胞克隆靶标的 DNA 水平研究

• 批准号: 3136586
• 负责人: MASSIMO M. TRUCCO
• 金额: $ 15.87万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3136586
• 关键词: MHC class II antigen; alleles; antileukocyte isoantibody; clone cells; genetic manipulation; histocompatibility; histocompatibility antigens; human tissue; immunosuppressive antileukocyte serum; isoantibody; laboratory mouse; major histocompatibility complex; molecular cloning; monoclonal antibody; synthetic antigens; transfection

Using restriction fragment length polymorphism analysis (RFLP), three allelic DQ-alpha and three allelic DQ-beta patterns associated DQw1 have been recognized. One of these alpha/beta pairs was found to associate with DR1, two with DR2, and a fourth with DRw6. "Complementary" alloreactive T-cell clones were generated that were able to specifically recognize one or the other of the two DR2 associated, DQw1-positive molecules of the stimulator cells. These molecules carry the same alpha chain but a different (allelic) form of beta chain. In the last few months, evidence has also been obtained by nucleotide sequencing that there are as many allelic forms of DQ-alpha and DQ-beta genes as there are different molecular DQ-alpha and DQ-beta (RFLP) patterns, and each alpha/beta gene combination is associated with the same DR allele as its corresponding molecular alpha/beta pattern pair. It would now be certainly interesting to definitively prove that: a) antibodies may recognize determinants present only on the alpha or on the beta chain of the DQ molecule, while T-cells recognize simultaneously alpha and beta determinants. An allelic modification on only one chain is sufficient to completely abrogate the T-cell alloreaction, but may not interfere with the ability of the antibodies to recognize other epitopes or epitopes of the other chain; b) specificities, against which reagents in general cannot be found because of the strong association of certain alpha with certain beta genes, can be artificially generated by co-transfecting alpha and beta genes in anusual associations; c) specific reagents (monoclonal antibodies as well as T-cell clones) can be generated against these "new" specificities. The spontaneous generation of these "new" specificities may rarely take place by transcomplementation in the presence of particular haplotype combinations. This may be the cause of the immunological failure or the immunological auto-aggression which has generally been found present in the majority of HLA associated diseases. The reagents generated against the artificially obtained "new" specificities would be useful for the early recognition of their presence at the surface of the patient cells.

使用限制性片段长度多态性分析（RFLP）， 三个等位基因DQ-α和三个等位基因DQ-β模式 已识别出相关的DQw 1。 其中一个alpha/beta 发现有2对与DR 1相关，2对与DR 2相关， 第四个是DRW 6。 “互补”同种异体反应性T细胞克隆 能够特异性地识别一个或多个 两个DR 2相关的DQw 1阳性分子中的另一个 刺激细胞 这些分子携带着相同的α链 而是β链的不同（等位）形式。 过去几 几个月后，通过核苷酸测序， DQ-α和DQ-β的等位基因 因为有不同的分子DQ-α和DQ-β （RFLP）模式，每个α/β基因组合是 与其相应分子的相同DR等位基因相关 Alpha/Beta模式对。 现在， 明确证明：a）抗体可以识别决定簇 仅存在于DQ的α链或β链上 分子，而T细胞同时识别α和β 决定因素 仅在一条链上的等位基因修饰是 足以完全消除T细胞同种异体反应，但可能 不干扰抗体识别其他抗体的能力， 表位或其它链的表位; B）特异性，针对 这些试剂通常不能被发现，因为 某些α基因与某些β基因的关联， 人工合成的α和β基因 异常关联; c）特异性试剂（单克隆抗体 以及T细胞克隆）可以针对这些“新的” 特殊性 这些“新”特异性的自发产生可能 很少发生反式互补， 特定的单倍型组合。 这可能是导致 免疫失败或免疫性自我攻击， 在大多数HLA中普遍存在 相关疾病。 生成的试剂针对 人工获得的“新”特异性将有助于 早期识别它们在患者体表的存在 细胞