Blocking airway inflammation with B7-DC cross-linking Ab

树突状细胞(DC)是炎症的调节者，可以被操纵来预防过敏性哮喘和 慢性肺损伤。我们已经鉴定出一种人源性单抗，它能将B7-DC共... 小鼠和人DC表达的刺激分子，诱导细胞内信号导致重要的 调节抗原提呈的信号分子和决定因素的表达变化 这两个物种都有免疫激活功能。B7-DC的交联化不会导致DC的成熟 与其他DC激活治疗相比，如CpG-ODN、CD40-配体、肿瘤坏死因子-α或内毒素，实际上可以 改变用传统DC调节剂激活的细胞的表型。在医院注射我们的抗体 抗原再攻击预敏动物的时间完全阻断了呼吸道肺的发育 炎症及哮喘伴随症状，无明显毒性。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在正常情况下重新进入肺部 发生在致敏个体的过敏原暴露后。这种抗体改变了细胞的激活状态。 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，以及 这些免疫中枢调节器的协同刺激特性。免疫的潜在机制 将通过评估DC和DC的功能变化来探索使用B7-DC交联抗体的调制。 从处理和转基因动物中分离的T细胞和通过过继转移操纵的细胞 致敏或NATve宿主。对病理性肺调控机制的认识 这种人类抗体的炎症将为未来对人类患者的研究提供基础。

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.