Hellings Peter W, Kasran Ahmad, Bullens Dominique, Overbergh Lutgart, Mathieu Chantal, Heremans Hubertine, Matthys Patrick, Boon Louis, Jorissen Mark, Ceuppens Jan L
Laboratory of Experimental Immunology, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
J Immunol. 2006 Oct 15;177(8):5138-44. doi: 10.4049/jimmunol.177.8.5138.
Interaction between CD154 (CD40 ligand) on activated T lymphocytes and its receptor CD40 has been shown to be critically involved in the generation of cell-mediated as well as humoral immunity. CD40 triggering activates dendritic cells (DC), enhances their cytokine production, up-regulates the expression of costimulatory molecules, and induces their maturation. It is unknown how stimulation of CD40 during sensitization to an airborne allergen may affect the outcome of allergic airway inflammation. We took advantage of a mouse model of allergic asthma and a stimulatory mAb to CD40 (FGK45) to study the effects of CD40-mediated DC activation on sensitization to OVA and subsequent development of OVA-induced airway inflammation. Agonistic anti-CD40 mAb (FGK45) injected during sensitization with OVA abrogated the development of allergic airway inflammation upon repeated airway challenges with OVA. Inhibition of bronchial eosinophilia corresponded with reduced Th2 cytokine production and was independent of IL-12, as evidenced by a similar down-regulatory effect of anti-CD40 mAb in IL-12 p40-deficient mice. In addition, FGK45 equally down-regulated allergic airway inflammation in IL-10-deficient mice, indicating an IL-10-independent mechanism of action of FGK45. In conclusion, our results show that CD40 signaling during sensitization shifts the immune response away from Th2 cytokine production and suppresses allergic airway inflammation in an IL-12- and IL-10-independent way, presumably resulting from enhanced DC activation during sensitization.
活化T淋巴细胞上的CD154（CD40配体）与其受体CD40之间的相互作用已被证明在细胞介导免疫和体液免疫的产生中起关键作用。CD40激活可活化树突状细胞（DC），增强其细胞因子产生，上调共刺激分子的表达，并诱导其成熟。尚不清楚在对空气传播变应原致敏期间刺激CD40如何影响过敏性气道炎症的结果。我们利用过敏性哮喘小鼠模型和针对CD40的刺激性单克隆抗体（FGK45）来研究CD40介导的DC活化对OVA致敏及随后OVA诱导的气道炎症发展的影响。在OVA致敏期间注射激动性抗CD40单克隆抗体（FGK45）可消除OVA反复气道激发后过敏性气道炎症的发展。支气管嗜酸性粒细胞增多的抑制与Th2细胞因子产生减少相对应，且与IL-12无关，这在IL-12 p40缺陷小鼠中抗CD40单克隆抗体的类似下调作用中得到证实。此外，FGK45在IL-10缺陷小鼠中同样下调过敏性气道炎症，表明FGK45的作用机制不依赖IL-10。总之，我们的结果表明，致敏期间的CD40信号传导使免疫反应从Th2细胞因子产生转向，并以不依赖IL-12和IL-10的方式抑制过敏性气道炎症，这可能是由于致敏期间DC活化增强所致。
