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。我们已经鉴定出一种人源单克隆抗体，它交联小鼠和人DC表达的B7-DC共刺激分子，诱导细胞内信号，导致两种物种中调节抗原提呈和免疫激活功能的信号分子和决定因子的表达发生重要变化。与其他DC激活处理（如CpG-ODN、cd40配体、TNF-a或LPS）不同，交联B7-DC不会导致DC成熟，事实上，它可以改变传统DC调节剂激活的细胞的表型。在致敏动物的抗原再挑战时给予我们的抗体，完全阻断气道肺部炎症的发展和伴随的哮喘症状，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，从而减少促炎细胞因子的产生和致病性细胞进入肺部的募集，这通常发生在过敏个体暴露于过敏原后。该抗体改变树突状细胞的激活状态，调节细胞因子、趋化因子和趋化因子受体的分布以及这些免疫中枢调节因子的共刺激特性。利用B7-DC交联抗体进行免疫调节的潜在机制将通过评估从处理过的和转基因动物中分离的DC和T细胞的功能变化，以及通过过继性地将处理过的细胞转移到致敏宿主或原生宿主中来探索。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.