T CELL IMMUNITY IN COLLAGEN BIOSYNTHESIS OF SCLERODERMA

硬皮病胶原蛋白生物合成中的 T 细胞免疫

• 批准号: 7378270
• 负责人: STEPHEN J OLIVER
• 金额: $ 2.71万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378270
• 关键词: CELL; IMMUNITY; COLLAGEN; BIOSYNTHESIS; SCLERODERMA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Scleroderma, a disease of abnormal collagen biosynthesis, has been characterized as a Th2-type immune-driven disease. The investigators hypothesize that if this is the case, an immune modulatory intervention that shifts the disease to a Th1-type immune response should alter the disease course beneficially by altering collagen biosynthesis. To test whether such an effect in scleroderma can be accomplished, the investigators will expose patients to thalidomide, an immune modulatory drug that has been shown both in vitro and in vivo to stimulate the production of Th1-type cytokines. In this two-part study, including both in vivo and in vitro investigations, they will carry out a patient-based protocol to demonstrate that collagen biosynthesis in scleroderma skin is decreased during thalidomide treatment and that this is associated with a shift towards a Th1-type immune response. To confirm the effects of Th1 immune stimulation by thalidomide on scleroderma collagen biosynthesis, the investigators will also measure collagen and procollagen production in cultured dermal fibroblasts in the presence of exogenous cytokines (IFNg, IL-4, IL-10, IL-12) or activated T cells from normal volunteers and scleroderma patients treated or untreated with thalidomide. Thus far, patients have tolerated the study protocol without undue difficulty. Collection and processing of specimens and data have proceeded smoothly to date. Although the study is double-blinded, subjects have reported the appearance of dry skin and ulcer healing, noted in the investigators' prior, open-label study. Evaluation of the skin biopsy specimens or ELISAs on plasma samples have not yet begun. Cultured dermal fibroblast collagen production has been markedly decreased after exposure to culture supernatants from thalidomide-treated T cells, compared to supernatants from non-thalidomide-treated controls. This collagen-suppressive effect is seen even in the presence of TGFb activation of the fibroblasts. Additional study is required to identify how thalidomide mediates this effe

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。硬皮病是一种胶原蛋白生物合成异常的疾病，被认为是一种th2型免疫驱动疾病。研究人员假设，如果是这种情况，将疾病转变为th1型免疫反应的免疫调节干预应该通过改变胶原蛋白的生物合成来有益地改变疾病的进程。为了测试硬皮病是否可以实现这种效果，研究人员将患者暴露于沙利度胺，一种免疫调节药物，在体外和体内都显示可以刺激th1型细胞因子的产生。在这项由两部分组成的研究中，包括体内和体外研究，他们将开展一项基于患者的方案，以证明在沙利度胺治疗期间硬皮病皮肤中的胶原生物合成减少，这与向th1型免疫反应的转变有关。为了证实沙利度胺Th1免疫刺激对硬皮病胶原生物合成的影响，研究人员还将在外源性细胞因子（IFNg、IL-4、IL-10、IL-12）或来自正常志愿者和接受沙利度胺治疗或未接受沙利度胺治疗的硬皮病患者的活化T细胞存在的情况下，测量培养的真皮成纤维细胞中胶原和前胶原的生成。到目前为止，患者对该研究方案的耐受性没有出现过大的困难。迄今为止，标本和数据的收集和处理工作进展顺利。虽然这项研究是双盲的，但研究人员在之前的开放标签研究中指出，受试者报告了皮肤干燥和溃疡愈合的外观。尚未开始对皮肤活检标本或血浆样品的elisa进行评估。经沙利度胺处理的T细胞培养上清液与未经沙利度胺处理的对照组上清液相比，培养的真皮成纤维细胞胶原蛋白的产生明显减少。即使在TGFb激活成纤维细胞的情况下，也可以看到这种胶原抑制作用。需要进一步的研究来确定沙利度胺如何介导这种效应