T CELL IMMUNITY IN COLLAGEN BIOSYNTHESIS OF SCLERODERMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 硬皮病是一种胶原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，如果是这样的话，通过改变胶原蛋白的生物合成，将疾病转变为Th1型免疫反应的免疫调节干预应该会有益地改变疾病的进程。为了测试是否可以在硬皮病中实现这种效果，研究人员将让患者接触沙利度胺，这是一种免疫调节药物，在体外和体内都已被证明可以刺激Th1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，他们将实施一项基于患者的方案，以证明沙利度胺治疗期间硬皮病皮肤中胶原蛋白的生物合成减少，这与向Th1型免疫反应的转变有关。为了证实沙利度胺对Th1免疫刺激对硬皮病胶原生物合成的影响，研究人员还将测量在外源细胞因子(IFNG、IL-4、IL-10、IL-12)或正常志愿者和硬皮病患者经沙利度胺治疗或未治疗的T细胞激活的情况下，培养的真皮成纤维细胞中胶原和前胶原的产生。到目前为止，患者对该研究方案的耐受性没有不适当的困难。迄今为止，标本和数据的收集和处理进展顺利。尽管这项研究是双盲的，但研究人员先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现象。对皮肤活检标本或血浆样本的ELISA的评估尚未开始。与非沙利度胺对照组的培养上清液相比，经沙利度胺处理的T细胞培养上清液中培养的真皮成纤维细胞胶原蛋白的产量显著减少。即使在成纤维细胞存在TGFb激活的情况下，也能看到这种胶原抑制作用。还需要进一步的研究来确定沙利度胺是如何调节这种效应的。

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 effect.