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

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.

摘要 尽管急性排斥反应发生率显著降低， 停滞，大多数移植器官的半衰期徘徊在10年左右。一个主要 长期移植结果不佳的原因是持续的宿主免疫激活导致慢性 排斥反应我们在这里提出，持续的免疫激活是由先天免疫驱动的， 系统，特别是单核细胞识别同种异体非自我和获得记忆， 了单核细胞感知同种异体组织上的非MHC和MHC多态性， 能够对供体MHC特异性地进行增强的回忆反应。这种反应导致 通过成熟的IL-12+单核细胞来源的DC持续的移植物浸润， 炎性Th 1应答，并且是同种异体移植排斥反应的关键。这项资助的目的是 目的1是研究单核细胞的分子和细胞机制， 记忆产生和对同种异体MHC的特异性，并确定在Aim 2中， 单核细胞记忆在慢性同种异体移植排斥反应中的作用完成建议 研究可能会对器官移植产生重大影响， 免疫系统靶点以预防或治疗排斥。