Immune Mechanisms of Alloinjury

同种异体损伤的免疫机制

• 批准号: 8810687
• 负责人: JOHN A BELPERIO
• 金额: $ 44.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810687
• 关键词: Acute; Alloantigen; Allografting; Animals; Antigen-Presenting Cells; Biological; Biology; Bronchiolitis; Bronchiolitis Obliterans; CCL17 gene; CCL22 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical; Clinical Trials; Data; Development; Functional disorder; Future; Generations; Goals; Helper-Inducer T-Lymphocyte; Home environment; Homing; Human; Human Biology; Immune; Inflammatory; Interleukin-12; Lead; Licensing; Ligands; Lung; Lung Transplantation; Lymphoid Tissue; Maintenance; Mediating; Memory; Modeling; Mus; Nature; Nodal; Observational Study; Pathogenesis; Patients; Pharmacologic Substance; Population; Process; Prognostic Marker; Risk Factors; Role; Secondary to; Syndrome; T memory cell; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic Trials; Tissues; Translating; Transplant Recipients; Transplantation; Viral Tumor Antigens; allograft rejection; arm; base; improved; insight; lung allograft; novel; pre-clinical; prevent; programs; prospective; response; trafficking; translational study

DESCRIPTION (provided by applicant): Chronic lung allograft rejection, also known as bronchiolitis obliterans syndrome (BOS), is an inflammatory process that ends in fibro-obliteration of the allograft airways; however the exact mechanism(s) involved are unknown. Our preliminary data demonstrates that CCR4/ligands (CCL17 and CCL22) interaction is important for both the afferent and efferent arms of allograft rejection. Specifically, CCR4/ligand biological axis in the afferent arm of alloreactivity orchestrates allosensitization by promoting: ) the homing of naive CD4 and CD8 T cells to secondary lymphoid tissues and 2) the intranodal interactions between CD4 helper T cell and antigen presenting cells (APC) which licenses the APC to generate allospecific CD8 T cells. The CCR4/ligand biological axis in the efferent arm of alloreactivity promotes: 1) CD4 helper T cells to maintain clonal populations of CD8 memory cells and enhances the recruitment of allospecific CD8 T cells to the allograft that eventually leads to chronic lung allograft dysfunction. Discoveries generated by this proposal will be the basis for future therapeutic trials of pharmaceutical agents that inhibit CCR4/ligands interaction with the goal of preventing/treating BOS post-lung transplantation.

描述（由申请人提供）：慢性肺同种异体移植排斥，也称为细支气管炎闭塞综合征（BOS），是一种炎症过程，以同种异体移植气道的纤维融合结束。但是，涉及的确切机制尚不清楚。我们的初步数据表明，CCR4/配体（CCL17和CCL22）相互作用对于同种异体移植排斥的传入和传出臂都很重要。具体来说，CCR4/配体 同种异体反应性传入臂中的生物轴通过促进通过：）将幼稚的CD4和CD8 T细胞归为二次淋巴样组织，以及2）CD4辅助T细胞和抗原呈现细胞（APC）之间的摩s内相互作用（APC），该细胞（APC）许可APC生成APC产生同种种体外CD8 T细胞。同种异体反应性的传出臂中的CCR4/配体生物轴促进：1）CD4辅助T细胞维持CD8记忆细胞的克隆群体，并增强同种异体移植物的同种型CD8 T细胞的募集，最终导致慢性肺同种异体移植功能障碍。该提案产生的发现将是对抑制CCR4/配体相互作用的药物治疗试验的基础，目的是预防/治疗BOS后肺后移植。