Novel Chemistry to Monitor and Manipulate the Immune System

该项目将开发一种基于化学的方法来监测和操纵免疫系统。如果成功，它将提供一个非常实用的诊断平台，以及药物的先导化合物，以抑制特定的免疫反应，而不产生一般的免疫抑制。我们将采用由数千种被称为类肽的肽样化合物组成的微阵列，并将血清样本与这些阵列杂交，从而将数千种蛋白质和几种细胞类型结合到固定的类肽上。将使用适当的荧光标记抗体来可视化感兴趣的杂交模式，例如标记的抗IgG抗体将“点亮”所有IgG抗体的结合模式。每个抗体将显示出不同的结合模式，基于该分子对阵列上数千个类肽的亲和谱。这些结合特征的加权和预计将提供一个“超模式”，应该提供一个循环抗体群体的敏感读数。通过比较合适的患者和匹配的对照样本，我们应该能够识别出目标疾病共有的超模式特征，反映自身免疫疾病、癌症、特定感染等中扩增的自身抗体的捕获。同样的实验也可以用来鉴定与疾病状态相关的T细胞。信息量最大的类肽可作为诊断的伪生物标志物。最后，确定为疾病状态良好的伪生物标志物的类肽将作为各种自身免疫性疾病的可能治疗药物进行检查，其想法是这些类肽可能捕获抗体或T细胞，这些抗体或T细胞不仅指示疾病，而且可能是致病的。这种方法提供了发现能够阻断特定免疫反应的试剂而不抑制免疫系统的可能性。

This project will develop a chemistry-based approach to monitoring and manipulating the immune system. If successful, it will provide a diagnostic platform of extraordinary utility as well as lead compounds for drugs to inhibit specific immune responses without general immunosuppression. We will employ microarrays comprised of thousands of peptide-like compounds called peptoids and hybridize serum samples to these arrays, resulting in the binding of thousands of proteins and several cell types to the immobilized peptoids. The hybridization pattern of interest will be visualized using an appropriate fluorescently labeled antibody, for example a labeled anti-IgG antibody will "light up" the pattern of binding of all IgG antibodies. Each antibody will evince a different pattern of binding to the array based on the spectrum of affinities of that molecule for the thousands of peptoids on the array. The weighted sum of these binding signatures is expected to provide a "superpattern" that should provide a sensitive readout of the population of circulating antibodies. By comparison of appropriate patients and matched control samples, we should be able to identify features in the superpatterns that are common to the disease of interest, reflecting capture of autoantibodies that are amplified in an autoimmune disease, cancer, a particular infection, etc. The same type of experiment could be done to identify disease state-associated T cells. The most informative peptoids could be used as pseudo biomarkers for diagnosis. Finally, the peptoids identified as good pseudo biomarkers for the disease state will be examined as possible therapeutic agents in various autoimmune conditions, the idea being that these peptoids may capture antibodies or T cells that are not only indicative of the disease, but may be causative as well. This approach holds out the possibility of discovering reagents capable of blocking specific immune responses without global suppression of the immune system.