Innate Recognition of Allogeneic Non-Self

对同种异体非自我的本能认知

• 批准号: 10177841
• 负责人: Fadi G. Lakkis
• 金额: $ 41.85万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177841
• 关键词: Acute; Adaptive Immune System; Affinity; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Applications Grants; Binding; CD47 gene; Cell Maturation; Cells; Chromosome Mapping; Chronic; Clinical; Clonal Expansion; Data; Dendritic Cells; Epigenetic Process; Family member; Funding; Generations; Genetic Polymorphism; Goals; Half-Life; Homologous Transplantation; Immunocompetent; Infection; Infiltration; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-12; Knowledge; Lead; Ligands; Link; Mediating; Memory; Microbe; Minor; Minor Histocompatibility Antigens; Molecular; Organ Survival; Organ Transplantation; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Proteins; Role; SHPS-1 protein; Solid; Source; Specificity; Stimulus; System; T-Lymphocyte; Testing; Time; Tissues; Toll-like receptors; Transplantation; adaptive immune response; adaptive immunity; allograft rejection; experimental study; immune activation; immunoglobulin receptor; in vivo; memory recall; microbial; monocyte; novel; novel therapeutics; pathogen; prevent; receptor; response; tissue injury; Acute; Adaptive Immune System; Affinity; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Applications Grants; Binding; CD47 gene; Cell Maturation; Cells; Chromosome Mapping; Chronic; Clinical; Clonal Expansion; Data; Dendritic Cells; Epigenetic Process; Family member; Funding; Generations; Genetic Polymorphism; Goals; Half-Life; Homologous Transplantation; Immunocompetent; Infection; Infiltration; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-12; Knowledge; Lead; Ligands; Link; Mediating; Memory; Microbe; Minor; Minor Histocompatibility Antigens; Molecular; Organ Survival; Organ Transplantation; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Proteins; Role; SHPS-1 protein; Solid; Source; Specificity; Stimulus; System; T-Lymphocyte; Testing; Time; Tissues; Toll-like receptors; Transplantation; adaptive immune response; adaptive immunity; allograft rejection; experimental study; immune activation; immunoglobulin receptor; in vivo; memory recall; microbial; monocyte; novel; novel therapeutics; pathogen; prevent; receptor; response; tissue injury

Abstract Despite significant reduction in acute rejection rates, long-term allograft survival remains stagnant, hovering at around a half-life of 10 years for most transplanted organs. A principal cause of poor long-term graft outcomes is persistent host immune activation leading to chronic rejection. We propose here that persistent immune activation is driven by the innate immune system, specifically by monocytes which recognize allogeneic non-self and acquire memory to it. Monocytes sense non-MHC and MHC polymorphisms on allogeneic tissues and acquire the ability to mount an enhanced recall response specific to donor MHC. This response results in sustained graft infiltration by mature, IL-12+, monocyte-derived DCs that maintain an inflammatory Th1 response and are critical for allograft rejection. The goal of this grant application is to investigate in Aim 1 the molecular and cellular mechanisms of monocyte memory generation and specificity to allogeneic MHC, and to determine in Aim 2 the contribution of monocyte memory to chronic allograft rejection. Completion of the proposed studies is likely to have a significant impact on organ transplantation by uncovering novel innate immune system targets to prevent or treat rejection.

抽象的 尽管急性排斥率显着降低，但长期同种异体移植存活仍然存在 停滞不前，大多数移植器官的半衰期约为10年。校长 长期移植结果不良的原因是持续的宿主免疫激活导致慢性 拒绝。我们在这里建议，持续的免疫激活是由先天免疫驱动的 系统，特别是单核细胞，这些单核细胞识别同种异体非自我并获得记忆 它。单核细胞在同种异体组织上感知非MHC和MHC多态性并获得 能够安装特定于供体MHC的增强召回响应。这种响应导致 通过成熟的IL-12+，单核细胞衍生的DC持续的移植浸润 炎症性Th1反应，对同种异体移植排斥至关重要。这笔赠款的目标 应用是在AIM 1中调查单核细胞的分子和细胞机制 对同种异体MHC的记忆产生和特异性，并确定目标2 单核细胞记忆对慢性同种异体移植排斥的贡献。拟议的完成 研究可能会通过发现新的先天物来对器官移植产生重大影响 免疫系统的目标是防止或治疗排斥。