CD4 PEPTIDE ANALOG EFFECT ON EAE

多发性硬化症涉及慢性复发性炎症反应， 导致中枢神经系统脱髓鞘。CD+4+ 辅助性/诱导性T细胞参与炎症的发展 中枢神经系统中与多发性硬化症发作相关的反应。 实验性变态反应性脑脊髓炎(EAE)是一种 多发性硬化症的研究，因为它有许多相同的临床和 作为人类疾病的组织病理学特征，包括主要作用 为CD4+T细胞在诱导疾病中的作用。的一个主要目标 免疫学研究一直在寻找一种方法，可以特异性地 抑制与中枢神经系统发生反应的CD4+T细胞 抗原，而不会损害整个免疫系统。在这方面， 我们最近开发了一种设计合理的多肽，它是 被设计成显示与CDR3的一部分相同的分子表面 小鼠CD4分子的区域。早期的体外实验已经 表明该多肽能抑制混合性T细胞的增殖 淋巴细胞反应性检测和阻断正常T细胞的激活 T细胞受体激活后的细胞和T细胞系。从理论上讲， 这种多肽的作用是将cd4分子从侧向相互作用中分离出来。 从而中断T细胞表面的激活信号 T细胞，导致细胞凋亡。EAE中的初步数据 模型表明，当我们可以抑制临床疾病的发展时 这种多肽在诱导或诱导过程中给小鼠服用 效应器阶段。最重要的是，老鼠在两周后接受了检查 治疗后CD4+和CD8+T细胞均处于正常水平，并保持 混合淋巴细胞反应中对同种异体抗原的免疫反应。这个 目前的提案旨在研究阿司匹林的疗效和机制 CD4-CDR3多肽在获得性和过继转移中的作用 小鼠EAE模型系统。对免疫学有一个清晰的认识 这些小鼠模型中的参数将有助于支持 CD4-CDR3多肽类似物在临床治疗中的应用 治疗多发性硬化症。

Multiple sclerosis involves a chronic relapsing inflammatory response that results in demyelination in the central nervous system. CD4+ helper/inducer T cells are involved in the development of the inflammatory responses in the CNS that correlate with multiple sclerosis attacks. Experimental allergic encephalomyelitis (EAE) is an animal model for the study of multiple sclerosis since it shares many of the same clinical and histopathological features as the human disorder, including a primary role for CD4+ T cells in the induction of disease. A major goal of immunological research has been to find an approach that can specifically inhibit those CD4+ T cells that are reacting to central nervous system antigens, without compromising the entire immune system. In this regard, we have recently developed a rationally-designed peptide that was engineered to exhibit the same molecular surface as a portion of the CDR3 region of the murine CD4 molecule. Earlier in vitro experiments have shown that this peptide can inhibit T cell proliferation in mixed lymphocyte reactivity assays and can block activation of both normal T cells and T cell lines after T cell receptor triggering. Theoretically, this peptide acts to uncouple the CD4 molecule from lateral interactions on the T cell surface and thereby interrupts the activation signal to the T cell, with apoptosis as a consequence. Preliminary data in the EAE model indicated that we can inhibit development of clinical disease when this peptide is administered to the mice in either the induction or effector phases. Of most importance, mice examined two weeks after treatment had normal levels of both CD4+ and CD8+ T cells and remained immunoresponsive to alloantigen in a mixed lymphocyte reaction. The current proposal is designed to investigate the efficacy and mechanism of action of the CD4-CDR3 peptide in both acquired and adoptive transfer murine EAE model systems. A clear understanding of the immunological parameters within these murine models would help support the potential application of the CD4-CDR3 peptide analog as a clinical therapeutic agent for multiple sclerosis.