ALLOTYPE-LINKED RESISTANCE TO HERPES STROMAL KERATITIS

描述：（改编自研究者摘要）：有良好的证据 从鼠模型如EAE中，表达特异性TCR的T细胞被证明是特异性的。 自身肽可以引发组织特异性自身免疫性疾病，通常在 故意免疫。然而，导致自发性 对这些细胞的激活知之甚少。是什么引发了自身免疫 T细胞它们是如何引起致病组织破坏的？是环境 微生物病原体等因素参与这一过程，以及这些因素如何影响 T细胞逃避胸腺内或外周耐受机制？一旦被激活， 哪些T细胞因子是疾病进展所必需的？细胞和 可能下调自身反应性免疫球蛋白的扩增和分化的分子 T细胞克隆被划定，从而减少自身免疫性疾病？的 研究人员建议继续研究确定细胞和分子 导致自身免疫性疾病发生和进展的事件 由HSV-1（科斯）感染近交系小鼠引发的过程。的 研究人员发现，这种疾病是由占主导地位的CD 4 + T细胞引起的， 表达特定TCR的克隆（V β 11.b J α 33; V β 8. 1/D β 1。 1/Jbeta1.4/Cbeta1）。这种称为CI-6的致病性T细胞克隆的活性， 由两种类型的TCR调节：肽相互作用：1）与TCR的相互作用。 衍生自IgG 2a B的交叉反应性自身肽抑制这些抗体的反应， 2）与HSV-1衍生的（UL 6）肽的相互作用激活这些细胞; 细胞研究者构建了表达V α 11/V β 8.1 C1-6 TCR转基因并产生有复制能力的UL 6 突变的HSV-1（科斯）菌株以进一步确定该过程。研究者已 在确定疾病调节机制方面也取得了进展 进展识别自身抗原是必要的，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， 进行性组织破坏研究人员发现了一种新的T细胞 称为Eta-1（早期T淋巴细胞活化-1）的细胞因子似乎 在这一过程中发挥着至关重要的作用，并在1型的挑衅 免疫力最后，研究者对免疫调节的研究 控制疾病进展的相互作用揭示了一个重要的 抑制作用的Ib类MHC分子Qa 1和形成的基础上， 试图描述这种免疫调节作用的细胞基础 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.