T CELL IMMUNITY IN COLLAGEN BIOSYNTHESIS OF SCLERODERMA

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。硬皮病是一种胶原蛋白生物合成异常的疾病，其特征是Th 2型免疫驱动的疾病。研究人员假设，如果是这种情况，将疾病转变为Th 1型免疫应答的免疫调节干预应该通过改变胶原蛋白生物合成来有益地改变疾病进程。为了测试这种作用是否可以在硬皮病中实现，研究人员将患者暴露于沙利度胺，沙利度胺是一种免疫调节药物，在体外和体内都显示出刺激Th 1型细胞因子的产生。在这项包括体内和体外研究的两部分研究中，他们将进行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蛋白生物合成减少，并且这与向Th 1型免疫应答的转变有关。为了证实沙利度胺对硬皮病胶原蛋白生物合成的Th 1免疫刺激作用，研究人员还将在外源性细胞因子（IFNg，IL-4，IL-10，IL-12）或正常志愿者和用沙利度胺治疗或未治疗的硬皮病患者的活化T细胞存在下，测量培养的真皮成纤维细胞中胶原蛋白和前胶原蛋白的产生。到目前为止，患者已经耐受了研究方案，没有过度的困难。迄今为止，标本和数据的收集和处理进展顺利。尽管该研究是双盲的，但受试者报告了研究者先前的开放标签研究中观察到的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本的ELISA进行评价。培养的真皮成纤维细胞胶原蛋白的产生已显着减少后，暴露于培养上清液从沙利度胺处理的T细胞，与上清液从非沙利度胺处理的控制。即使在成纤维细胞的TGF β活化的存在下也观察到这种胶原抑制作用。需要进一步的研究来确定沙利度胺是如何介导这种效应的。

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