Autoantibody Arrays Guide Tolergenic Therapy for Multiple Sclerosis

描述（由申请人提供）：这些研究汇集了已发表大规模微阵列创新论文的实验室，以检测蛋白质，肽，脂质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）（MS的动物模型）的免疫学标志。它被定义为抗原特异性免疫应答的扩展超出初始免疫中靶向的那些。该过程的复杂性不仅包括扩散到相同蛋白质分子的其他肽表位，定义为分子内扩散，而且还包括扩散到其他分子，定义为分子间扩散。免疫应答的传播不限于肽表位，还包括对脂质和碳水化合物的免疫应答。如果对抗原特异性自身免疫应答的耐受化对于治疗自身免疫性疾病是期望的，则必须设计实际措施以在包括多种蛋白质/肽、碳水化合物和脂质的广泛战线上耐受免疫系统。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质/肽、脂质和碳水化合物，耐受患有持续EAE的动物。我们已经显示了对髓鞘的这些组分的耐受性的有希望的临床和临床前结果。对蛋白质和脂质的耐受性都改善了EAE的瘫痪。我们假设，为了减少表位扩散，有必要耐受潜在的致病性自身抗原肽/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之一。我们现在将看到单独耐受髓鞘的这些不同化学成分中的每一种是否是最佳的，或者是否与蛋白质/肽和脂质和碳水化合物协同耐受，实现甚至更有益的结果。在新目标1中，我们将进行a）对MS和EAE中免疫应答靶点的有前景的脂质的结构功能研究。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的每种有希望的候选物诱导耐受的作用机制。在新目标2中，我们将进行对MS和EAE中免疫应答靶点的各种甘露糖簇的耐受性研究，例如，比较（Man 9）n和[（Man 9）4]n在三种复发性和进行性EAE模型中减少疾病的作用。在新目标3中，我们将通过同时给予关键蛋白质/肽、脂质和碳水化合物来耐受正在进行EAE的动物，这些蛋白质/肽、脂质和碳水化合物被用于研究MS和EAE的阵列可检测的自身抗体靶向。我们现在将看到，在减少复发、改善临床功能、减少EAE的三种模型中的表位扩散方面，与对这三种化学类型中的每一种单独耐受相比，对蛋白质/肽和脂质和碳水化合物一致耐受是否实现甚至更有益的结果。抗原特异性耐受是治疗自身免疫性疾病的长期追求的目标。我们将开发策略，以耐受髓鞘的蛋白质，脂质和碳水化合物。这种方法可能会导致更好的疗法来治疗多发性硬化症。

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.