IMMUNOLOGIC MECHANISMS IN EXPERIMENTAL AUTOIMMUNE DISEASES OF THE NERVOUS SYSTEM

神经系统实验性自身免疫性疾病的免疫机制

• 批准号: 6432881
• 负责人: Henry F McFarland
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432881
• 关键词: T lymphocyte; apoptosis; disease /disorder model; experimental allergic encephalomyelitis; laboratory mouse; leukocyte activation /transformation; magnetic resonance imaging; model design /development; myelin basic proteins; myelin proteolipid; myelinopathy; neuroimmunomodulation; retinoate

The overall objective is to identify immunological mechanisms that lead to myelin damage using animal models of autoimmune demyelinating disease. Studies currently focus on the use of the mouse model, experimental allergic encephalomyelitis (EAE). EAE is an experimental disease that is characterized by inflammatory lesions of the central nervous system followed by demyelination. The disease model used in these studies involves the adoptive immunization of naive animals using T cells derived from animals immunized with myelin, myelin proteins or portions of these proteins that are know to be encephalitogenic. The course of the disease studied in this project is relapsing-remitting. In addition to examining mechanisms of damage, studies also examine treatments that can modify the disease process. Recent studies have examined mechanisms that can lead to the generation of autoreactive T cells. It is thought that diseases such as multiple sclerosis are due to the occurrence of autoreactive t cells but it has been unclear how these cells are generated. One mechanism that has been considered is that the autoreactive T cells are generated in response to environmental antigens such as viruses. Considerable progress has been made in defining the molecular requirements for cross reactivity or molecular mimicry. It is now clear that even limited sequence homology can allow cross-reactivity if the amino acids(aa) necessary for binding to the MHC and those important for T cell receptor recognition are identical or similar between the native peptide and another antigen. Using these criteria antigens that cross-react with encephalitogenic portions of MBP such as the 88-99 region have been identified. However, it has been uncertain if cross reactivity can actually lead to T cells that have biological properties similar to those derived with the encephalitogenic peptides and, specifically, if they can induce disease. To test the concepts of molecular mimicry, the ability of T cells selected with peptides predicted to cross-react with an encephalitogenic portion of MPB, aa 87-99, were studied. Previous studies have demonstrated that a peptide derived from human papillomavirus 12 can be recognized by MBP-specific T cells clones from humans. In addition, a peptide derived from EBV that has also predicted to cross-react with MBP 87-99 was studied. Lymph node cells derived from animals were immunized with the papillomavirus peptide and then stimulated in vitro with MBP were encephalitogenic when transferred to naive mice. Further, when different doses of the papillomavirus peptide was used, it was found that lower doses were more effective at generating cross-reactive clones. Similar experiments with the EBV peptide failed to generate T cells able to transfer disease. However, when T cells were generated with MBP, EBV peptide could be used to expand these cells in vitro prior to transferring disease.These results support the hypothesis that environmental antigens can contribute to the generation or activation of autoreactive T cells. The results also indicate that the selection of autoreactive T cells can depend on the dose of the foreign antigen. While preliminary, these results indicate that the potential for molecular mimicry as a mechanism for driving autoimmunity exists.

总体目的是确定使用自身免疫性脱髓鞘疾病的动物模型导致髓磷脂损伤的免疫机制。目前的研究重点是使用小鼠模型，实验性过敏性脑脊髓炎（EAE）。 EAE是一种实验性疾病，其特征是中枢神经系统的炎症性病变，随后是脱髓鞘。这些研究中使用的疾病模型涉及使用用髓磷脂，髓磷脂蛋白或这些蛋白质的部分免疫的T细胞对幼稚动物进行的继承免疫免疫，这些动物或这些蛋白质的一部分被称为脑源性。该项目中研究的疾病过程正在复发。除了检查损害机制外，研究还检查可以改变疾病过程的治疗方法。最近的研究检查了可能导致自动反应性T细胞产生的机制。人们认为诸如多发性硬化症之类的疾病是由于自动反应性T细胞的发生，但尚不清楚这些细胞是如何产生的。一种被认为的机制是自动反应性T细胞是根据病毒等环境抗原而产生的。在定义交叉反应性或分子模仿的分子要求方面取得了长足的进步。现在很明显，如果有限的序列同源性可以允许与MHC结合所需的氨基酸（AA），而对T细胞受体识别重要的氨基酸（AA）在天然肽和另一种抗原之间相同或相似。使用这些标准抗原与MBP的脑作用部分（例如88-99区域）交叉反应。但是，尚不确定交叉反应性是否实际上会导致具有类似于具有脑源性肽的生物学特性的T细胞，特别是它们是否可以诱导疾病。为了测试分子模仿的概念，研究了用MPB的脑生成部分进行交叉反应的T细胞的能力，AA 87-99。先前的研究表明，源自人乳头瘤病毒12的肽可以被人类的MBP特异性T细胞克隆识别。此外，还研究了从EBV衍生的肽，该肽也预测与MBP 87-99进行了反应。将源自动物衍生的淋巴结细胞用乳头瘤病毒肽免疫，然后在转移到幼稚小鼠的情况下用MBP刺激MBP刺激。此外，当使用不同剂量的乳头瘤病毒肽时，发现较低剂量在产生交叉反应克隆方面更有效。与EBV肽的类似实验未能产生能够转移疾病的T细胞。但是，当用MBP产生T细胞时，EBV肽在转移疾病之前可以在体外扩展这些细胞。这些结果支持了以下假设：环境抗原可以有助于自动反应性T细胞的产生或激活。结果还表明，自动反应性T细胞的选择可以取决于外抗原的剂量。虽然初步，但这些结果表明，分子模仿作为驱动自身免疫性的机制的潜力。