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。如果成功的话，它将提供一个非常有用的诊断平台，以及用于药物抑制特异性免疫反应而无需一般免疫抑制的先导化合物。我们将采用由数千种称为类肽的肽样化合物组成的微阵列，并将血清样品与这些阵列杂交，从而使数千种蛋白质和几种细胞类型与固定的类肽结合。将使用适当的荧光标记的抗体使感兴趣的杂交模式可视化，例如标记的抗IgG抗体将“照亮”所有IgG抗体的结合模式。基于该分子对阵列上数千种类肽的亲和力谱，每种抗体将显示与阵列结合的不同模式。 这些结合特征的加权和预期提供“超模式”，其应提供循环抗体群体的灵敏读数。通过比较适当的患者和匹配的对照样本，我们应该能够识别出感兴趣的疾病常见的超模式中的特征，反映了在自身免疫性疾病，癌症，特定感染等中扩增的自身抗体的捕获。信息量最大的类肽可作为假生物标志物用于诊断。最后，被鉴定为疾病状态的良好假生物标志物的类肽将被检查为各种自身免疫性病症中的可能治疗剂，其想法是这些类肽可以捕获不仅指示疾病，而且也可能是病因的抗体或T细胞。这种方法提供了发现能够阻断特异性免疫反应而不全面抑制免疫系统的试剂的可能性。

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.