IMMUNE REGULATION

描述(改编自研究人员摘要)：胸腺内 成年大鼠注射豚鼠MBP或免疫显性， MBP的致脑片段p68-86，水相--不含 损害外周淋巴细胞库--显著抑制 CFA接种MBP疫苗引起的EAE发病。这一发现 证明了水基抗原与一个或多个 完整胸腺的组成部分可以通过T细胞调节全身反应 已经存在于外周淋巴细胞池中。的目标是 本申请中提出的研究是为了更好地理解 抑制自身免疫性疾病的机制(S) 诱导胸腺耐受，考虑到这可能 为临床治疗自身免疫性疾病提供了一条有效的途径。两者都使用 大鼠和小鼠EAE模型，涉及胸腺的细胞亚群 将探索耐受性：胸腺耐受性是否可以转移 过继应用胸腺细胞悬液，无论细胞因子谱 改变，是否涉及到更成熟的胸腺细胞群， 胸腺抗原提呈细胞(APC)是否抑制T细胞反应； 抑制性胸腺细胞是否进入中枢神经系统。特异性 研究将探索胸腺耐受性的两个方面：是否正在进行 对多种抗原系统的免疫反应可以通过诱导 胸腺对其中一种受体的耐受性，以及TCR和/或MHC是否结合 耐受肽的残基与胸腺耐受性有关。 这些研究涉及胸腺耐受性是否相似的问题 多肽诱导免疫低反应性的其他机制。细胞因子 胸腺耐受动物外周血淋巴样细胞的变化 并在用抗原进行培养后进行探索。自适应传输 实验将探索TCR+CD8+群体的意义 以及TCR+CD4-8-T细胞的出现，伴随着急剧增加 在抗原选择的培养中IL-4mRNA的水平。

DESCRIPTION (Adapted from investigator's abstract): Intrathymic injection in adult rats with guinea pig MBP or the immunodominant, encepalitogenic fragment p68-86 of MBP, in aqueous form -- without compromising the peripheral lymphocyte pool -- dramatically inhibits onset of EAE caused by vaccination with MBP in CFA. This finding demonstrates that interaction between aqueous antigen and one or more components of an intact thymus can regulate systemic responses by T-cells already existing in the peripheral lymphocyte pool. The goal of the studies proposed in this application is to develop a better understanding of the mechanism(s) involved in suppression of autoimmune disease by induced thymic tolerance, with a view of the possibility that this might be a useful approach for clinical treatment of autoimmunity. Using both the rat and mouse models for EAE, the cell subsets involved in thymic tolerance will be explored: Whether thymic tolerance can be transferred adoptively with thymus cell suspensions, whether cytokine profiles are altered, whether the more mature thymocyte population is involved, whether thymic antigen presenting cells (APCs) inhibit T-cell responses; and whether inhibitory thymic cells traffic to the CNS. Specificity studies will explore two aspects of thymic tolerance: Whether ongoing immune responses to multiple antigen systems can be regulated by induced thymic tolerance to one of them, and whether TCR and/or MHC binding residues of the tolerizing peptide are involved in thymic tolerance. These studies relate to the question of whether thymic tolerance is akin to other mechanisms of peptide induced immune hyporeactivity. Cytokine profiles of peripheral lymphoid cells from thymic tolerant animals before and after culture with antigen will be explored. Adaptive transfer experiments will explore the significance of a population of TCR+ CD8+ and TCR+ CD4-8- T cells that appear, along with dramatically increased levels of IL-4 mRNA, in antigen selected cultures.