av Integrina in Cognate Immunity and Airway Hyperresponsiveness

我们已经证明，缺乏上皮整合素avpe的小鼠可以激活潜在的TGFp，从而保护小鼠免受 慢性变应原激发后的持续性呼吸道高反应性(AHR)。令人惊讶的是，这 保护与亚上皮下气道纤维化的任何减少无关，这是一种中枢的TGFp依赖 此型号的功能。小鼠白细胞特异性敲除了相关的整合素avp8，它也 激活TGFp表明有增强的适应性免疫的证据。在这份提案中，我们将确定是否 P6亚单位敲除小鼠的这些改变反应是avp6整合素丢失的直接结果 和/或使用表达TGFp的“救援”小鼠从传导的呼吸道上皮细胞激活TGFp 呼吸道上皮细胞中的野生型整合素或活性的TGFp。我们将评估avpe抗体和 在这些相同的终点上的TGFpRII-LG嵌合体，以进一步证实这一途径的重要性 评估以此通路为靶点进行治疗干预的可行性。要确定机制， 通过失去avp6来预防AHR的诱导，我们将评估气道与AHR之间的关系 少数与该表型相关的候选基因的反应性和表达 在利用表达微阵列的初步实验中。我们还将确定细胞的分布 通过免疫染色和/或原位杂交进行表达，并将使用 商业上可获得的表达特定候选基因零突变的小鼠品系。因为细胞因子 已知IL-13在多种模型的AHR诱导中发挥核心作用，而且因为最多的两个 通过微阵列确定的有希望的候选基因亮三烯C4合成酶和白细胞介素18已经被 建议在呼吸道诱导IL-13的上游，我们还将检查IL-13的细胞来源 13在长期挑战野生型和P6基因敲除小鼠中。最后，我们将确定白细胞的损失如何 Avp8导致获得性免疫增强，并研究这一途径与过敏的相关性 呼吸道炎症及其后果。 本项目将研究单一的生长因子，转化生长因子p，如何 有助于慢性哮喘的发展或抑制过敏性过敏及其后果，具体取决于 关于这种生长因子在哪里以及如何被激活。

Mice lacking the epithelial integrin, avpe, that we have shown activates latent TGFp, are protected from the persistent airway hyperresponsiveness (AHR) that follows chronic allergen challenge. Surprisingly, this protection is not associated with any decrease in sub-epithelial airway fibrosis, a central TGFp-dependent feature of this model. Mice Iwith leukocyte specific knockout of the related integrin, avp8, which also activates TGFp show evidence of enhanced adaptive immunity. In this proposal, we will determine whether these altered responses in P6 subunit knockout mice are a direct consequence of loss of the avp6 integrin and/or of TGFp activation from conducting airway epithelial cells using "rescue" mice expressing either the wild type integrin or active TGFp in airway epithelial cells. We will evaluate the effects of avpe antibodies and a TGFpRII-lg chimera on these same endpoints to further confirm the importance of this pathway and evaluate the feasibility of targeting this pathway for therapeutic intervention. To determine the mechanisms by which loss of avp6 protects from induction of AHR, we will eavluate the relationship between airway responsiveness and expression of a small number of candidate genes identified as linked to this phenotype in preliminary experiments utilizing expression microarrays. We will also determine the cellular distribution of expression by immunostaining and/or in situ hybridization, and will evaluate functional significance using commercially available lines of mice expressing null mutations of specific candidates. Because the cytokine IL-13 is known to play a central role in induction of AHR in multiple models, and because two of the most promising candidates identified by microarrays, leuotriene C4 synthase and interleukin-18 have been suggested to be upstream of IL-13 induction in the airways, we willl also examine the cellular sources of IL- 13 in chronically challenged wild type and P6 knockout mice. Finally, we will determine how loss of leukocyte avp8 leads to enhancement of adaptive immunity and examine the relevance of this pathway to allergic airway inflammation and its consequences. Lay summary- This project will examine how a single growth factor, transforming growth factor p, can either contribute to development of chronic asthma or inhibit allergic sensitization and its consequences, depending on where and how this growth factor is activated.