Blocking airway inflammation with B7-DC cross-linking Ab

树突状细胞（DC）是炎症的调节因子，可用于预防过敏性哮喘， 慢性肺损伤我们已经鉴定了一种人单克隆抗体，其交联B7-DC共- 由小鼠和人DC表达的刺激分子，诱导细胞内信号，导致重要的 调节抗原呈递的信号分子和决定簇表达的变化， 在两个物种中的免疫激活功能。交联B7-DC不会导致DC的成熟， 与其它DC激活治疗如CpG-ODN、CD 40-配体、TNF-α或LPS相反，事实上， 改变用传统DC调节剂活化的细胞的表型。我们的抗体在 抗原再攻击致敏动物的时间完全阻断气道肺的发育 炎症和伴随的哮喘症状，没有明显的毒性。我们的假设是 树突状细胞功能的调节导致免疫功能的发展， 促炎细胞因子的产生和致病细胞进入肺的募集， 在致敏个体暴露于过敏原后发生。这种抗体改变了 树突状细胞，调节产生的细胞因子、趋化因子和趋化因子受体的分布， 这些免疫中枢调节因子的共刺激特性。免疫机制 使用B7-DC交联抗体的调节将通过评估DC的功能变化来探索， 从经处理和遗传修饰的动物中分离的T细胞以及通过过继转移操作的细胞 致敏或天然宿主了解病理肺的调节机制 用这种人抗体治疗炎症将为人类患者的未来研究提供基础。

Dendritic cells (DC) are regulators of inflammation that can be manipulated to prevent allergic asthma and chronic lung damage. We have identified a human monoclonal antibody that cross-links the B7-DC co- stimulatory molecule expressed by mouse and human DC, inducing intracellular signals leading to important changes in the expression of signaling molecules and determinants regulating antigen-presenting and immune-activating functions in both species. Cross-linking B7-DC does not lead to maturation of DC, in contrast to other DC-activating treatments such as CpG-ODN, CD40-ligand, TNF-a, or LPS, and in fact, can alter the phenotype of cells activated with traditional DC modulators. Administration of our antibody at the time of antigen rechallenge to presensitized animals completely blocks the development of airway lung inflammation and accompanying symptoms of asthma, without apparent toxicity. Our hypothesis is that modulation of dendritic cell function leads to the development of immune functions that de-emphasize production of pro-inflammatory cytokines and the recruitment of pathogenic cells into the lungs that normally occurs following allergen exposure in sensitized individuals. This antibody alters the activation state of dendritic cells, modulating the profile of cytokines, chemokines, and chemokine receptors produced and the co-stimulatory properties of these central regulators of immunity. The mechanisms underlying immune modulation using B7-DC cross-linking antibodies will be explored by assessing functional changes in DC and T cells isolated from treated and genetically modified animals and by adoptive transfer of manipulated cells into sensitized or naTve hosts. Understanding the mechanisms governing modulation of pathologic lung inflammation with this human antibody will provide the basis for future studies in human patients.