Regulation of Autoimmune Encephalomyelitis

自身免疫性脑脊髓炎的调节

• 批准号: 7610918
• 负责人: HABIB ZAGHOUANI
• 金额: $ 31.46万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610918
• 关键词: Affinity; Amino Acids; Animal Model; Antigen-Presenting Cells; Autoimmune Process; Autoimmunity; Automobile Driving; Avidity; Basic Science; Binding; Cells; Characteristics; Chimera organism; Complementarity Determining Region III; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Exposure to; Fetus; Frequencies; Genetic; Human; Immune system; Immunoglobulins; Inflammatory; Investigation; Labor Presentation; Life; Ligands; Maintenance; Major Histocompatibility Complex; Mediating; Molecular; Mothers; Mouse Strains; Multiple Sclerosis; Mus; Mutate; Myelin; Neonatal; Neuraxis; Peptides; Perinatal Exposure; Peripheral; Placenta; Play; Proteins; Proteolipids; Regulation; Relative (related person); Role; SJL/J Mouse; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Uncertainty; Work; clinical practice; complementarity-determining region 3; design; fetal; migration; mutant; offspring; prevent; prototype; restoration; trait

DESCRIPTION (provided by applicant): Experimental allergic encephalomyelitis (EAE), an inflammatory disease within the central nervous system (CNS) is used as an animal model for human multiple sclerosis (MS). The involvement of the immune system in these diseases is beyond doubt and both EAE and MS manifest as a consequence of activation of myelin- reactive pathogenic T lymphocytes. Usually, T regulatory cells (Tregs), a subset of suppressive T lymphocytes, keep the myelin-specific pathogenic T cells in check and maintain peripheral tolerance. However, circumstances exist under which this control fails and autoimmunity transpires. To date much work has been done to demonstrate the suppressive function of Tregs. However, little is known regarding the development of Tregs and the circumstances under which they expand to counter autoimmunity. The long term objective of this proposal is to determine whether Tregs undergo selection and if they do, whether such selection is driven by the strength of T cell receptor (TCR)-ligand interactions. The hypothesis in this application postulates that Tregs undergo thymic selection and require rather high avidity for maturation. To test this hypothesis we propose to deliver altered peptides with degenerate TCR affinity for fetal presentation and test for fetal thymic Tregs selection and maturation and evaluate the consequences of such development on the peripheral expansion of Tregs in the offspring as well as their ability to modulate EAE. The SJL/J mouse expresses only the DM20 form of proteolipid protein (PLP) during fetal and neonatal life. DM20 is a mutant form of PLP missing the immunodominant PLP1 sequence corresponding to amino acid residues 139-151 of PLP. It has been shown that thymic negative selection against PLP1 is defective during the fetal/neonatal period. Immunoglobulins (Igs) can cross the maternal placenta and transfer from mother to fetus. Igs are also permissive for molecular grafting and expression of peptides within the heavy complementarily determining region-3 (CDR3). Herein, we propose to express PLP1 as well as PLP1-derived altered peptides on Igs and utilize the resulting Ig chimeras to deliver the peptides through the SJL/J maternal placenta and restore presentation during fetal life. Subsequently, we will evaluate the effect of such fetal presentation on Tregs selection, maturation, migration to the periphery and modulation of EAE.T regulatory cells (Tregs) represent a subset of suppressive cells that control peripheral tolerance and prevent the development of autoimmunity. Understanding how Tregs develop, mature, and carry out suppressive functions should impact the design of approaches to modulate autoimmunity. This proposal takes advantage of a unique peptide delivery system and a suitable mouse strain to investigate the development of Tregs. The study is highly significant and could impact the field of autoimmunity both at the level of basic science and clinical practice.

描述（由申请人提供）：实验性过敏性脑脊髓炎（EAE），一种中枢神经系统（CNS）内的炎症性疾病用作人类多发性硬化症（MS）的动物模型。免疫系统参与这些疾病是毫无疑问的，而EAE和MS由于髓磷脂反应性致病T淋巴细胞的激活而表现出来。通常，T调节细胞（Tregs）（Tregs）是抑制性T淋巴细胞的子集，使髓磷脂特异性的病原T细胞保持检查并保持周围耐受性。但是，存在这种控制失败和自身免疫性的情况。 迄今为止，已经做了很多工作来证明Treg的抑制作用。但是，关于Tregs的发展以及它们扩展以应对自身免疫性的情况知之甚少。该提案的长期目标是确定Treg是否接受选择以及是否这样做，是否由T细胞受体（TCR） - 配体相互作用的强度驱动。该应用中的假设假设Treg经历了胸腺的选择，并且需要相当高的持续成熟。为了检验这一假设，我们建议提供改变肽的变化肽，以进行胎儿表现和测试胎儿胸腺treg选择和成熟，并评估这种发展对tregs外围膨胀的后果以及它们调节EAE的能力。 SJL/J小鼠在胎儿和新生儿生活中仅表示蛋白质蛋白（PLP）的DM20形式。 DM20是PLP的一种突变形式，缺少与PLP的氨基酸残基139-151相对应的免疫主导PLP1序列。已经表明，在胎儿/新生儿期间，针对PLP1的胸腺阴性选择是有缺陷的。免疫球蛋白（IGS）可以穿越母体胎盘并从母亲转移到胎儿。 Ig在重互补的区域-3（CDR3）内也允许肽的分子移植和表达。在此，我们建议在IGS上表达PLP1以及PLP1衍生的改变肽，并利用所得的IG嵌合体通过SJL/J母体胎盘和胎儿寿命中的恢复表现来传递肽。随后，我们将评估这种胎儿表现对TREG选择，成熟，迁移到周围和调节的影响。了解Tregs如何发展，成熟和执行抑制功能应影响调节自身免疫性的方法的设计。该建议利用了独特的肽递送系统和合适的小鼠菌株来研究Tregs的发展。这项研究非常重要，在基础科学和临床实践水平上都可能影响自身免疫领域。