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TGF β， 慢性过敏原激发后持续气道高反应性（AHR）。令人惊讶的是，这 保护作用与上皮下气道纤维化的任何减少无关， 这一模式的特点。白细胞特异性敲除相关整合素avp 8的小鼠， 活化TGF β显示增强的适应性免疫的证据。在这份提案中，我们将确定 P6亚基敲除小鼠中这些改变的反应是α ν β 6整联蛋白缺失的直接结果 和/或TGF β激活的“拯救”小鼠的气道上皮细胞的表达。 气道上皮细胞中的野生型整联蛋白或活性TGF β。我们将评估avpe抗体的作用， 在这些相同的终点上使用TGF β RII-Ig嵌合体，以进一步证实该途径的重要性， 评估针对这一途径进行治疗干预的可行性。为了确定 通过avp 6的缺失对AHR诱导的保护作用，我们将评估气道与AHR的关系。 反应性和表达的少数候选基因被确定为与这种表型相关 在利用表达微阵列的初步实验中。我们还将确定细胞分布 通过免疫染色和/或原位杂交来表达，并将使用 表达特定候选物的无效突变的市售小鼠系。因为细胞因子 已知IL-13在多种模型中诱导AHR中起核心作用，并且因为其中两种最重要的作用是诱导AHR。 通过微阵列鉴定的有希望的候选物，白三烯C4合酶和白细胞介素-18， 提示在气道中IL-13诱导的上游，我们还将检查IL-13的细胞来源。 13在慢性攻击的野生型和P6敲除小鼠中。最后，我们将确定白细胞的损失 AVP 8导致获得性免疫的增强，并检查该途径与过敏性疾病的相关性。 呼吸道炎症及其后果。 奠定总结-本项目将研究如何一个单一的生长因子，转化生长因子p，可以 有助于慢性哮喘的发展或抑制过敏性致敏及其后果，这取决于 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.