TH1, TH2 AND INTERLEUKIN 12 IN IDDM

这项研究探讨了Th1/Th2发育的遗传基础。 自身免疫性疾病。在上一个资助期，我们开发了 D011.10建立Th1/Th2转基因动物模型。我们是第一个 确定病原体和巨噬细胞在Th1发育中的作用 确定IL-12为Th1发展的发起者，并确定 IL-12受体的信号机制。 我们和其他人认为Th1/Th2的发展可以改变易感性 自身免疫力。大卫·罗博士(斯克里普斯诊所)和休·麦克德维特博士(斯坦福大学) 大学)最近报道，B10.D2小鼠在遗传上更容易 一种实验性的自身免疫性疾病，而不是Balb/c小鼠。这 易感性与Th1发展的更大趋势相关。更多 最近，我们的同事乔纳森·卡茨博士展示了Th1，但不是Th2， 胰岛反应性T细胞可在NOD中转移糖尿病。因此，我们的工作 假设多基因IDDM易感性与某些基因座有关 控制Th1的发育。 这一建议扩展了我们发表的B10.D2小鼠发育的研究结果 Balb/c小鼠更强的默认Th1反应。我们现在有强大的 IL-12信号在遗传上不同的初步数据 B10.D2和Balb/c.B10/D2中IL-12信令的延长维持 与Balb/c相比，会促进观察到的Th1发育增加。 因此： 目标1分析了在IL-12信令、构建 基于我们先前在IL-12信号通路方面的研究进展。强劲的预赛 数据支持这一目标的可行性。 我们还开始对所涉及的基因座进行基因测绘。身份识别 老鼠体内的这些基因座可以直接用于筛查、分析 以及对糖尿病患者的研究。我们展示了至少两种基因的证据 并将其中一个与Idd-4基因座相关联。我们建议 确定易感人群中有利于Th1发育的基因座 菌株。因此： 目标2将确定影响B10.D2中Th1发育的遗传位点， 建立表达这些B10.D2等位基因的Balb/c同源菌株，并建立 为它们的鉴定和位置克隆提供了舞台。我们出版的 初步验证了遗传座位分析的可行性。 这有利于使用D011.10 TCR-转基因促进Th1的发展 体外表型分析。

This study examines the genetic basis of Th1/Th2 development as it relates to autoimmune disease. In the previous funding period, we developed the D011.10 transgenic model for Th1/Th2 development. We were first to identify the role of pathogens and macrophages in Th1 development, to identify Il-12 as the initiator of Th1 development, and to identify signaling mechanisms of Il-12 receptors. We and others suggest that Th1/Th2 development can modify susceptibility to autoimmunity. Drs. David Lo (Scripps Clinic) and hugh McDevitt (Stanford University) recently reported that B10.D2 mice are genetically more prone to an experimental autoimmune disease than Balb/c mice. This susceptibility correlated with greater tendency for Th1 development. More recently our colleague Dr. Jonathan Katz showed that Th1, but not Th2, islet reactive T cells could transfer diabetes in NOD. Thus, our working hypothesis is that multigenic IDDM susceptibility involves some loci controlling Th1 development. This proposal extends our published finding that B10.D2 mice develop stronger default Th1 responses that Balb/c mice. We now have strong preliminary data that Il-12 signaling is genetically different between B10.D2 and Balb/c. Prolonged maintenance of Il-12 signaling in B10/D2 compared to Balb/c would promote the observed increased Th1 development. Thus: Aim 1 analyzes the basis for this difference in Il-12 signaling, building upon our previous progress in Il-12 signaling pathway. Strong preliminary data support the feasibility of this aim. We have also begun genetic mapping of the loci involved. Identification of these loci in the mouse could directly contribute to screening, analysis and studies in diabetic humans. We show genetic evidence for at least two loci, and linking one of these to near the Idd-4 locus. We propose to identify these genetic loci that favor Th1 development in susceptible strains. Thus: Aim 2 will identify genetic loci that factor Th1 development in B10.D2, develop Balb/c congenic strains expressing these B10.D2 alleles, and set the stage for their identification and positional cloning. Our published and preliminary dat demonstrate the feasibility of analyzing genetic loci that favor Th1 development using the D011.10 TCR-transgene to facilitate in vitro phenotype analysis.