Blocking airway inflammation with B7-DC cross-linking Ab

使用 B7-DC 交联抗体阻断气道炎症

• 批准号: 7544476
• 负责人: LARRY R PEASE
• 金额: $ 36.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544476
• 关键词: Adoptive Transfer; Allergens; Allergic; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Asthma; Biological; CD40 Ligand; Cell physiology; Cells; Chickens; Chronic; Dendritic Cells; Development; Extrinsic asthma; Future; Genetically Modified Animals; Human; Immune; Immunity; Individual; Inflammation; Inflammatory; Intravenous Immunoglobulins; Lead; Leucocytic infiltrate; Lung; Lung Inflammation; Lung diseases; Modeling; Mus; Ovalbumin; Pathologic; Patients; Phenotype; Production; Property; Scheme; Signal Transduction; Signaling Molecule; Surface; Symptoms; T memory cell; T-Cell Activation; T-Lymphocyte; Time; Toxic effect; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; antigen challenge; base; chemokine; chemokine receptor; crosslink; cytokine; human monoclonal antibodies; immune function; immunoregulation; lymph nodes; methacholine; novel; prevent; response

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.

树突状细胞（DC）是炎症的调节因子，可以被操纵来预防过敏性哮喘和