Blocking airway inflammation with B7-DC cross-linking Ab

描述（由申请人提供）：树突状细胞（DC）是炎症的调节因子，可用于预防过敏性哮喘和慢性肺损伤。我们已经鉴定了一种人单克隆抗体，其交联由小鼠和人DC表达的B7-DC共刺激分子，诱导细胞内信号，导致两个物种中调节抗原呈递和免疫激活功能的信号传导分子和决定簇的表达发生重要变化。与其他DC活化处理如CpG-ODN、CD 40-配体、TNF-α或LPS相反，交联B7-DC不会导致DC成熟，并且事实上，可以改变用传统DC调节剂活化的细胞的表型。在抗原再激发致敏动物时给予我们的抗体完全阻断气道肺部炎症的发展和伴随的哮喘症状，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，不强调促炎细胞因子的产生和致病细胞进入肺部的募集，这通常发生在致敏个体的过敏原暴露后。该抗体改变树突状细胞的活化状态，调节产生的细胞因子、趋化因子和趋化因子受体的概况以及这些免疫中枢调节因子的共刺激特性。将通过评估从经处理和遗传修饰的动物中分离的DC和T细胞的功能变化以及通过将操作的细胞过继转移到致敏或naTve宿主中来探索使用B7-DC交联抗体进行免疫调节的潜在机制。了解这种人抗体调节病理性肺部炎症的机制将为未来在人类患者中的研究提供基础。

DESCRIPTION (provided by applicant): 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.