Hausding Michael, Sauer Kerstin, Maxeiner Joachim H, Finotto Susetta
Laboratory of Cellular and Molecular Lung Immunology, I Medical Clinic, Mainz, Germany.
Curr Drug Targets. 2008 Jun;9(6):503-10. doi: 10.2174/138945008784533570.
The immunoresponses are mediated by cells presenting the antigen to T cells. The transcription factors involved in the differentiation of T helper cells enclose T-bet (Th1), c-maf (Th2), GATA-3 (Th2), Foxp3 (T reg) and RORgammaT (Th17). They are regulated in allergic asthma. The use of murine models either as germline or as tissue specific transgenic mice has given decisive immunological tools to understand the importance of selected transcription factors or cytokines. Tissue specific transgenic lines have been generated into the Clara Cell or CD2 promoter directing tissue- and immune cells specific expression of the gene of interest. We identified T cell transcription factors important for asthma - such as T-bet, c-maf, GATA-3. Transgenic and knockout murine models of these transcription factors provided very important information for the human disease. Regarding to the pathogenesis of chronic asthma, we generated transgenic lines overexpressing IL-18 and analyzed a dominant negative mutant of the TGF-betareceptor II. These models will offer to us a great input for the understanding of the T cell memory and the processes like airway remodelling. Beside DNA microinjection and stem cell transfer the On/Off systems like Cre-lox models have helped to understand the role of selected genes in different steps of experimental disease. Moreover, the transgenic model provide reliable models for the pre-clinical approval of therapy for allergic asthma to develop more efficient compounds and functional antibodies.
免疫反应由将抗原呈递给T细胞的细胞介导。参与辅助性T细胞分化的转录因子包括T-bet(Th1)、c-maf(Th2)、GATA-3(Th2)、Foxp3(调节性T细胞)和RORγT(Th17)。它们在过敏性哮喘中受到调控。使用种系或组织特异性转基因小鼠的鼠模型提供了决定性的免疫学工具,以了解选定转录因子或细胞因子的重要性。已经构建了组织特异性转基因系,使其在克拉拉细胞或CD2启动子的控制下,指导感兴趣基因在组织和免疫细胞中的特异性表达。我们确定了对哮喘重要的T细胞转录因子,如T-bet、c-maf、GATA-3。这些转录因子的转基因和基因敲除鼠模型为人类疾病提供了非常重要的信息。关于慢性哮喘的发病机制,我们构建了过表达IL-18的转基因系,并分析了TGF-β受体II的显性负突变体。这些模型将为我们理解T细胞记忆和气道重塑等过程提供很大的帮助。除了DNA显微注射和干细胞移植外,像Cre-lox模型这样的开关系统有助于了解选定基因在实验性疾病不同阶段的作用。此外,转基因模型为过敏性哮喘治疗的临床前批准提供了可靠的模型,以开发更有效的化合物和功能性抗体。