Autoantibody Arrays Guide Tolergenic Therapy for Multiple Sclerosis

自身抗体阵列指导多发性硬化症的耐受性治疗

• 批准号: 7777368
• 负责人: LAWRENCE STEINMAN
• 金额: $ 31.46万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777368
• 关键词: Animal Model; Animals; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Carbohydrates; Central Nervous System Diseases; Chemicals; Clinical; Development; Disease; Disease Progression; Encephalomyelitis; Epitopes; Experimental Autoimmune Encephalomyelitis; Goals; Immune response; Immune system; Immunization; Individual; Interleukin-4; Laboratories; Lead; Lipids; Mannose; Measures; Microbe; Modeling; Multiple Sclerosis; Myelin; Myelin Sheath; Paper; Paralysed; Pathway interactions; Peptides; Phosphorylcholine; Process; Proteins; Publishing; Relapse; Sphingomyelins; Structure; T cell response; T-Lymphocyte; Tolerogen; anergy; cytokine; improved; innovation; osteopontin; pre-clinical

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.

描述（由申请人提供）：这些研究汇集了已经发表有关大规模微阵列的创新论文的实验室，以检测对蛋白质，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）的免疫学标志，这是MS的动物模型。它被定义为抗原特异性免疫反应的扩展，而不是针对初始免疫的抗原免疫反应。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，而且还与其他分子（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。如果需要对抗原特异性自身免疫反应的耐受性来治疗自身免疫性疾病，则必须制定实用措施，以在包括多种蛋白质/肽，碳水化合物和脂质的宽阔前沿容忍免疫系统。我们将使用持续的EAE耐受动物，使用关键蛋白/肽，脂质和碳水化合物，这些脂质和碳水化合物是由用于研究MS和EAE的阵列中检测到的自身抗体靶向的。我们已经显示出有希望的临床和临床前结果，并耐受髓鞘的这些成分。对蛋白质的耐受性和脂质都可以改善EAE的瘫痪。我们假设，为了减少表位扩散，必须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。现在，我们将看看髓磷脂的这些不同化学成分中的每一个都是最佳的，还是对蛋白质/肽，脂质和碳水化合物的耐受性的耐受性会取得更大的效果。在新目标1中，我们将进行a）关于有希望的脂质的结构功能研究，这是MS和EAE中免疫反应的靶标。 b）我们将分析这些耐受元如何影响表位扩散。 c）我们将研究对每个有前途的候选人诱导耐受性的作用机制，这些候选者在三种不同的EAE模型中抑制了持续的EAE。在新目标2中，我们将对MS和EAE中免疫反应的各种甘露糖簇进行耐受性研究，例如（MAN9）N和[（MAN9）4] N在减少三种复发和进行性EAE模型中的疾病中。在新目标3中，我们将使用持续的EAE耐受动物，同时使用关键蛋白/肽，脂质和碳水化合物，该动物被证明是由可用于研究MS和EAE的阵列可检测到的自身抗体靶向的。现在，我们将看到对蛋白质/肽，脂质和碳水化合物的耐受性是否在减少复发，改善临床功能，减少EAE中的三种模型中的临床功能，减少三种化学类型的每种化学类型的每种远离eAE的eAE中，更有益地取得了更有益的效果。对这些化学类型的每种疾病，对抗原特异性耐受性的疗效是一种自动耐受性的治疗方法。我们将制定耐受蛋白质，脂质和髓鞘碳水化合物的策略。这种方法可能会导致更好的治疗多发性硬化症的疗法。