ALLOTYPE-LINKED RESISTANCE TO HERPES STROMAL KERATITIS

描述：(改编自调查人员摘要)：有很好的证据 从小鼠模型，如EAE，表达TCR特异性的T细胞 自体多肽可引发组织特异性自身免疫性疾病，通常在 故意进行免疫接种。然而，导致自发的事件 人们对这些细胞的激活知之甚少。是什么触发了自身免疫 T细胞？它们是如何引起致病组织破坏的？是环保的吗 在这一过程中涉及的微生物病原体等因素以及这些因素是如何 T细胞逃避胸腺内或外周耐受机制？一旦激活， 哪些T细胞细胞因子是疾病进展所必需的？以及罐头细胞和 可能下调自身反应的扩张和分化的分子 T细胞克隆被描绘出来，从而减少自身免疫性疾病？这个 研究人员建议继续进行研究，以定义细胞和分子 导致自身免疫性疾病发生和发展的事件 近交系小鼠感染单纯疱疹病毒1型(HSV-1，Kos)的过程。这个 研究人员发现，这种疾病是由占主导地位的CD4+T细胞引起的 表达特定TCR的克隆(Valpha11.b Jalpha33；Vbeta8.1/Dbeta1。 1/Jbeta1.4/Cbeta1)。这种名为CI-6的致病T细胞克隆的活性， 受两种类型的TCR调节：多肽相互作用：1)与 从IgG2a b衍生的交叉反应自肽抑制这些反应 细胞；2)与HSV-1衍生的(UL6)肽相互作用激活这些 细胞。研究人员已经构建了表达V病毒的小鼠 转Alpha11/Vbeta8.1C1TCR和产生复制能力强的UL6 突变的单纯疱疹病毒I型(Kos)株进一步定义这一过程。调查员已经 在定义控制疾病的机制方面也取得了进展 进步。自身抗原的识别是必要的，但不是充分的 自身免疫性疾病；特定细胞因子基因的表达是必要的 渐进性组织破坏。研究人员发现了一种新的T细胞 称为Eta-1(代表早期T淋巴细胞活化-1)的细胞因子似乎 在这一过程中以及在挑衅类型1中发挥重要作用 豁免权。最后，研究人员对免疫调节的研究 控制疾病进展的相互作用揭示了一个重要的 Ib类MHC分子QA1的抑制作用 旨在描绘这种免疫调节效应的细胞基础的努力 并确定其治疗潜力。

DESCRIPTION: (Adapted from the Investigator's abstract): There is good evidence from murine models such as EAE that T-cells that express a TCR specific for a self-peptide can incite tissue-specific autoimmune disease, usually after deliberate immunization. However, the events that lead to spontaneous activation of these cells are poorly understood. What triggers autoimmune T-cells? How do they induce pathogenic tissue destruction? Are environmental factors such as microbial pathogens involved in this process and how do these T-cells escape intrathymic or peripheral tolerance mechanisms? Once activated, which T-cell cytokines are necessary for disease progression? And can cells and molecules that may down-regulate expansion and differentiation of autoreactive T-cell clones be delineated and thereby diminish autoimmune disease? The investigator proposes studies to continue to define the cellular and molecular events responsible for initiation and progression of the autoimmune disease process that is initiated by HSV-1 (KOS) infection of inbred mice. The investigator has found that this disorder is provoked by a dominant CD4+ T-cell clone that expresses a particular TCR (Valpha11.b Jalpha33; Vbeta8. 1/Dbeta1. 1/Jbeta1.4/Cbeta1). The activity of this pathogenic T-cell clone, termed CI-6, is regulated by two types of TCR:peptide interactions: 1) an interaction with a cross-reactive self-peptide derived from IgG2a b inhibits the response of these cells; 2) an interaction with an HSV-1-derived (UL6) peptide activates these cells. The investigator has constructed mice that express the V alpha11/Vbeta8.1 C1-6 TCR transgene and generated replication-competent UL6 mutant HSV-I (KOS) strains to further define this process. The investigator has also made progress in defining the mechanisms that regulate disease progression. Recognition of autoantigen is necessary but not sufficient for autoimmune disease; expression of particular cytokine genes is necessary for progressive tissue destruction. The investigator has identified a novel T-cell cytokine termed Eta-1 (for Early T-lymphocyte activation-1) that appears to play an essential role in this process and in the provocation of Type 1 immunity. Finally, the investigator's studies of the immunoregulatory interactions that control disease progression have uncovered an important inhibitory role for the class Ib MHC molecule Qa1 and form the basis of an effort intended to delineate the cellular basis of this immunoregulatory effect and establish its therapeutic potential.