Autoantibody Arrays Guide Tolergenic Therapy for Multiple Sclerosis

描述(申请人提供)：这些研究汇集了发表了大规模微阵列创新论文的实验室，以检测蛋白质、肽、脂类和碳水化合物的抗体。“表位扩散”是多发性硬化症(MS)和实验性自身免疫性脑脊髓炎(EAE)的免疫学标志，EAE是多发性硬化症的动物模型。它被定义为抗原特异性免疫反应的扩展，超出了最初免疫的目标。这一过程的复杂性不仅包括扩散到同一蛋白质分子的其他多肽表位(定义为分子内扩散)，还包括扩散到其他分子(定义为分子间扩散)。免疫反应的传播不仅限于多肽表位，还包括对脂类和碳水化合物的免疫反应。如果自身免疫性疾病的治疗需要对抗原特异性自身免疫反应的耐受，那么必须设计出实用的措施来耐受广泛的免疫系统，包括多种蛋白质/肽、碳水化合物和脂类。我们将耐受正在进行的EAE的动物，使用在用于研究MS和EAE的阵列上检测到的自身抗体所针对的关键蛋白质/肽、脂类和碳水化合物。我们已经展示了对髓鞘这些成分的耐受性的有希望的临床和临床前结果。对蛋白质和脂类的耐受性均可改善EAE的瘫痪。我们假设，为了减少表位扩散，有必要对潜在致病的自体抗原肽/蛋白质、脂类和碳水化合物耐受，而不仅仅是对这些类型的化学成分中的一种耐受。我们现在将看看是否单独耐受髓鞘的这些不同的化学成分是最佳的，还是同时耐受蛋白质/肽、脂类和碳水化合物，获得更有益的结果。在新的目标1中，我们将对作为MS和EAE免疫反应靶点的有希望的脂类进行a)结构功能研究。B)我们将分析这些耐受原如何影响表位扩散。C)我们将深入研究在三种不同的EAE模型中抑制正在进行的EAE的每个有希望的候选对象诱导耐受的作用机制。在新的目标2中，我们将进行MS和EAE免疫反应靶点的各种甘露糖簇的耐受性研究，例如比较(Man9)n和[(Man9)4]n在三种复发和进展性EAE模型中减少疾病的作用。在新的目标3中，我们将耐受患有持续EAE的动物，同时给予关键蛋白质/肽、脂类和碳水化合物，这些关键蛋白/肽、脂类和碳水化合物被用于研究MS和EAE的阵列检测到的自身抗体所靶向。我们现在将看到，在减少复发、改善临床功能、减少三种EAE模型中的表位扩散方面，联合耐受蛋白质/肽、脂类和碳水化合物是否比耐受这三种化学物质中的每一种更有益。抗原特异性耐受是自身免疫性疾病治疗长期以来追求的目标。我们将制定策略来耐受髓鞘中的蛋白质、脂肪和碳水化合物。这种方法可能会带来更好的治疗多发性硬化症的方法。

DESCRIPTION (provided by applicant): These studies bring together laboratories who have published innovative papers on large scale microarrays to detect antibodies to proteins, peptides, lipids and carbohydrates. "Epitope spreading" is an immunological hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. It is defined as the expansion of antigen-specific immune responses beyond those targeted in the initial immunization. The complexity of the process includes spread not only to other peptide epitopes of the same protein molecule, defined as intramolecular spreading, but to other molecules, defined as intermolecular spreading. Spreading of the immune response is not confined to peptide epitopes, but also includes immune responses to lipids and carbohydrates. If tolerization to antigen specific autoimmune responses is desirable for treatment of autoimmune disease, then one must devise practical measures to tolerize the immune system across a wide front including multiple proteins/peptides, carbohydrates and lipids. We shall tolerize animals with ongoing EAE, using key proteins/peptides, lipids and carbohydrates that are targeted by autoantibodies detected on the arrays used to study both MS and EAE. We have already shown promising clinical and pre- clinical results with tolerization to these components of the myelin sheath. Both tolerization to proteins and to lipids ameliorates paralysis in EAE. We hypothesize that in order to reduce epitope spreading it will be necessary to tolerize to potentially pathogenic autoantigenic peptides/proteins, lipids AND carbohydrates, and not simply to one of these types of chemical constituents. We will now see if tolerizing individually to each of these distinct chemical components of myelin is optimal, or if tolerization in concert to proteins/peptides AND lipids AND carbohydrates, achieves even more beneficial results. In New Aim 1 we will undertake a) structure function studies on promising lipids that are the target of the immune response in MS and EAE. b) We will analyze how these tolerogens influence epitope spreading. c) We will investigate the mechanisms of action for induction of tolerance in depth on each promising candidate that suppresses ongoing EAE in three different models of EAE. In New Aim 2 we will undertake studies on tolerization to various mannose clusters that are the target of the immune response in MS and EAE, comparing for example, (Man9)n and [(Man9)4]n in reducing disease in three models of relapsing and progressive EAE. In New Aim 3, we shall tolerize animals with ongoing EAE, using SIMULTANEOUS administration of key proteins/peptides, lipids and carbohydrates shown to be targeted by autoantibodies detectable with the arrays used to study MS and EAE. We will now see if tolerizing in concert to proteins/peptides AND lipids AND carbohydrates achieves even more beneficial results in terms of reducing relapses, improving clinical function, reducing epitope spreading in three models of EAE, than tolerizing INIDIVIDUALLY to each of these three chemical types.Antigen specific tolerance is a long sought after goal for treatment of autoimmune disease. We shall develop strategies for tolerizing to proteins, lipids and carbohydrates of the myelin sheath. This approach may lead to better therapies to treat multiple sclerosis.