Autoantibody Arrays Guide Tolergenic Therapy for Multiple Sclerosis

描述（由申请人提供）：这些研究汇集了在大规模微阵列检测蛋白质、多肽、脂质和碳水化合物抗体方面发表过创新论文的实验室。“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） （MS的一种动物模型）的免疫学标志。它被定义为抗原特异性免疫反应超出初始免疫目标的扩展。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）。免疫反应的扩散不仅限于肽表位，还包括对脂质和碳水化合物的免疫反应。如果对抗原特异性自身免疫反应的耐受性是治疗自身免疫性疾病所需要的，那么必须设计出实际的措施来耐受性免疫系统，包括多种蛋白质/肽、碳水化合物和脂类。我们将使用在用于研究MS和EAE的阵列上检测到的自身抗体靶向的关键蛋白/肽、脂质和碳水化合物来耐受持续EAE的动物。我们已经显示出对髓鞘这些成分的耐受性有希望的临床和临床前结果。对蛋白质和脂类的耐受均可改善EAE患者的瘫痪。我们假设，为了减少表位扩散，有必要耐受潜在致病性自身抗原肽/蛋白质、脂质和碳水化合物，而不仅仅是这些类型的化学成分中的一种。我们现在将看到，单独耐受髓磷脂的这些不同化学成分是最佳的，还是协同耐受蛋白质/多肽、脂质和碳水化合物，获得更有益的结果。在New Aim 1中，我们将进行a)有前途的脂质结构功能研究，这些脂质是MS和EAE中免疫反应的目标。b)我们将分析这些耐受性原如何影响表位扩散。c)我们将在三种不同的EAE模型中深入研究每个有希望抑制正在进行的EAE的候选药物诱导耐受的作用机制。在New Aim 2中，我们将对MS和EAE中作为免疫反应目标的各种甘露糖簇的耐受性进行研究，例如比较（Man9）n和[(Man9)4]n在三种复发性和进行性EAE模型中的疾病减轻作用。在New Aim 3中，我们将对持续EAE的动物进行耐受性治疗，同时给药关键蛋白/肽、脂质和碳水化合物，这些蛋白/肽被用于研究MS和EAE的阵列检测到的自身抗体所靶向。我们现在将看到，在三种EAE模型中，与单独耐受这三种化学类型相比，蛋白质/肽、脂质和碳水化合物协同耐受是否在减少复发、改善临床功能、减少表位扩散方面取得了更有益的结果。抗原特异性耐受性是长期以来寻求治疗自身免疫性疾病的目标。我们将发展对髓鞘蛋白质、脂质和碳水化合物的耐受策略。这种方法可能会导致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.