Innate Recognition of Allogeneic Non-Self

对同种异体非自我的本能认知

• 批准号: 8897251
• 负责人: Fadi G. Lakkis
• 金额: $ 38.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897251
• 关键词: Accounting; Acute; Address; Alloantigen; Allogenic; Allografting; Antigen-Presenting Cells; Applications Grants; B-Lymphocytes; Cell Death; Cell Maturation; Cell Transplantation; Cells; Chronic; Clinical; Critical Pathways; Cutaneous; Dendritic Cells; Equilibrium; Event; Genes; Genetic; Genome; Graft Rejection; Heart Transplantation; Immune response; Immune system; Immunodeficient Mouse; Immunoglobulins; Infection; Interruption; Knockout Mice; Lead; Manuscripts; Mediating; Microbe; Modeling; Molecular; Mouse Strains; Mus; Natural Immunity; Natural Killer Cells; Organ Transplantation; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Physiological; Reperfusion Injury; Role; Signal Transduction; Solid; Splenocyte; System; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Thinking; Time; Transgenic Organisms; Transplantation; abstracting; adaptive immunity; cell type; immune activation; in vivo; innovation; insight; isoimmunity; microbial; monocyte; novel; receptor; response; tool

Abstract The innate immune system is responsible for the early non-self recognition events that lead to adaptive immunity. Although the mechanisms by which the innate immune system recognizes microbial non-self have been well defined, it is not known how the innate immune system senses allogeneic non-self. We have discovered that monocytes mount a specific response to allogeneic non-self independent of T, B, and NK cels. This response leads to persistent monocyte differentiation to mature dendritic cells (DC) after transplantation and is responsible for indirect alloantigen presentation. In this grant application we propose to define (1) the role of innate allorecognition by monocytes in acute and chronic rejection, and (2) the mechanisms by which monocytes sense allogeneic non-self. To accomplish these aims we will utilize transgenic and gene-knockout mice in which specific cell types and molecular pathways can be tracked or deleted. Genetic tools to identify mechanisms of innate allorecognition will also be employed. The proposed studies are innovative and significant because they represent a shift in our thinking about the innate immune response to transplanted organs and could yield novel targets for interrupting innate immune activation in a specific and safe manner.

摘要 先天免疫系统负责早期的非我识别事件，导致 适应性免疫。尽管先天免疫系统识别 微生物的非我已经被很好地定义了，还不知道先天免疫系统是如何 感觉同种异体的非我。我们已经发现单核细胞对 不依赖T、B和NK细胞的同种异体非自体。此响应导致持久化 移植后单核细胞分化为成熟树突状细胞(DC)及其机制 用于间接呈现同种异体抗原。在这项赠款申请中，我们建议定义(1) 急、慢性排斥反应中单核细胞的天然同种异体识别； 哪个单核细胞能感觉到异体异体。为了实现这些目标，我们将利用 转基因和基因敲除小鼠，在其中特定的细胞类型和分子途径可以 已跟踪或已删除。识别先天同种异体识别机制的遗传工具也将是 受雇的。拟议的研究具有创新性和重大意义，因为它们代表了一种转变 在我们对移植器官的先天免疫反应的思考中，可能会产生新的 以特定和安全的方式干扰天然免疫激活的靶点。