Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.
Am J Respir Cell Mol Biol. 2010 Mar;42(3):331-40. doi: 10.1165/rcmb.2008-0397OC. Epub 2009 May 15.
We previously reported in an ovalbumin-induced model of allergic asthma that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c(high)CD8 alpha(high)CD11b(low) dendritic cells in the lung. In this study, we investigated the effect of Flt3-L in a clinically relevant aeroallergen-induced asthma on the phenotypic expression of lung T cells. Balb/c mice were sensitized and challenged with cockroach antigen (CRA), and AHR to methacholine was established. These mice received three intraperitoneal injections of anti-CD25 antibody (PC61; 250 microg) and Flt3-L (3 microg) daily for 10 days. Cytokines and Ig levels in the serum were measured and differential bronchoalveolar lavage fluid (BALF) cell counts were examined. Flt3-L reversed AHR to methacholine to the control level. Flt3-L significantly decreased levels of BALF IL-5, IFN-gamma, eosinophilia and substantially increased IL-10 and the number of CD4(+)CD25(+) Forkhead winged helix transcription factor box P3 (Foxp3(+)) IL-10(+) T cells in the lung. Administration of PC61 antibody blocked the effect of Flt3-L and substantially increased AHR, eosinophilia, and BALF IL-5 and IFN-gamma levels, and decreased BALF IL-10 levels and the number of CD4(+)CD25(+)Foxp3(+)IL-10(+) T cells. Flt3-L significantly decreased CD62-L, but increased inducible costimulatory molecule and Foxp3 mRNA expression in the CD4(+)CD25(+) T cells isolated from lungs of Flt3-L-treated, CRA-sensitized mice compared to CRA-sensitized mice without Flt3-L treatment and PBS control group. Flt3-L significantly inhibited the effect of CRA sensitization and challenge to increase GATA3 expression in lung CD4(+)CD25(+) T cells. Collectively, these data suggest that the therapeutic effect of Flt3-L is mediated by increased density of naturally occurring CD4(+)CD25(+)Foxp3(+)IL-10(+)ICOS(+) T-regulatory cells in the lung. Flt3-L could be a therapeutic strategy for the management and prevention of allergic asthma.
我们之前曾在卵清蛋白诱导的变应性哮喘模型中报告称，Fms 样酪氨酸激酶 3 配体（Flt3-L）可逆转气道高反应性（AHR）和气道炎症，并增加肺部调节性 CD11c（高）CD8α（高）CD11b（低）树突状细胞的数量。在这项研究中，我们研究了 Flt3-L 在临床上相关的变应原诱导的哮喘中对肺 T 细胞表型表达的影响。Balb/c 小鼠用蟑螂抗原（CRA）致敏和激发，建立对乙酰甲胆碱的 AHR。这些小鼠每天接受三次腹膜内注射抗 CD25 抗体（PC61；250μg）和 Flt3-L（3μg），共 10 天。测量血清中的细胞因子和 Ig 水平，并检查差异支气管肺泡灌洗液（BALF）细胞计数。Flt3-L 将对乙酰甲胆碱的 AHR 逆转至对照水平。Flt3-L 显著降低了 BALF 中的 IL-5、IFN-γ、嗜酸性粒细胞计数，并显著增加了 IL-10 和肺中 CD4+CD25+叉头翼状螺旋转录因子盒 P3（Foxp3+）IL-10+T 细胞的数量。给予 PC61 抗体可阻断 Flt3-L 的作用，并显著增加 AHR、嗜酸性粒细胞计数以及 BALF 中的 IL-5 和 IFN-γ 水平，同时降低 BALF 中的 IL-10 水平和 CD4+CD25+Foxp3+IL-10+T 细胞的数量。Flt3-L 显著降低了 CD62-L，但增加了从接受 Flt3-L 治疗的 CRA 致敏小鼠肺部分离的 CD4+CD25+T 细胞中诱导性共刺激分子和 Foxp3 mRNA 的表达，与未接受 Flt3-L 治疗的 CRA 致敏小鼠和 PBS 对照组相比。Flt3-L 显著抑制了 CRA 致敏和激发对肺 CD4+CD25+T 细胞中 GATA3 表达的影响。总的来说，这些数据表明，Flt3-L 的治疗效果是通过增加肺中天然存在的 CD4+CD25+Foxp3+IL-10+ICOS+T 调节细胞的密度来介导的。Flt3-L 可能是治疗和预防变应性哮喘的一种治疗策略。
