Ischemia-Reperfusion Injury in Human Liver Transplantation: Reciprocal Regulation of Innate/Adaptive Immune Responses

人肝移植中的缺血再灌注损伤：先天/适应性免疫反应的相互调节

• 批准号: 9975701
• 负责人: ELAINE F REED
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975701
• 关键词: Acute; Acute Liver Failure; Adaptive Immune System; Allografting; Antigens; Biopsy; CD4 Positive T Lymphocytes; CEACAM1; Cells; Chronic; Clinical; Data; Donor person; Endothelial Cells; Feedback; Flushing; Frequencies; Generations; Genes; Goals; Hepatocellular Damage; Hepatocyte; Human; Immune; Immunologic Memory; In Situ; Inflammation; Inflammatory; Injury; Kupffer Cells; Lead; Liver; Liver diseases; MHC antigen; Mediating; Molecular; Monitor; Mus; Myeloid Cell Activation; Myeloid Cells; Natural Immunity; Organ; Organ Preservation; Organ Transplantation; Outcome; Pathologic; Pathway interactions; Pattern; Pattern Recognition; Pattern recognition receptor; Phenotype; Play; Process; Production; Receptor Signaling; Regulation; Reperfusion Injury; Research; Risk; Role; Seminal; Signal Transduction; Specimen; Stress; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Intervention; Tissues; Transplant Recipients; Transplantation; adaptive immune response; adaptive immunity; cell injury; clinically relevant; cytokine; immune activation; immunoregulation; improved; insight; isoimmunity; liver allograft; liver injury; liver ischemia; liver transplantation; monocyte; mouse model; novel; novel therapeutics; post-transplant; recruit; response; tissue injury; transcriptome

PROJECT III - SUMMARY/ABSTRACT Orthotropic human liver transplantation is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia and reperfusion injury (IRI), the inevitable consequence of the transplant process, is a key limitation. The cellular damage incurred by IRI occurs in about 20% of cases and can lead to primary non-function necessitating re-transplantation. Liver IRI also predisposes the recipient to both acute and chronic rejection and graft loss, as well as, decreasing the pool of transplantable organs. Seminal observations in murine models indicate that liver IRI is mediated by both the innate and adaptive immune systems. Little is known whether similar mechanisms are at play in human liver transplantation. Our central hypothesis is that identifying the continuum of innate and adaptive immune phenotypes during human liver transplant IRI will permit us to select, monitor and refine the practice of therapeutic interventions and hence improve liver transplant outcomes. Under Aim 1 we will determine the role of DAMP/Pattern Recognition Receptor (PRR) signaling in the activation of innate and adaptive immune responses in human OLT IRI. We hypothesize that IRI-stressed hepatocytes release the endogenous DAMPs that trigger TLR and other PRR signaling on innate myeloid cells, which then induce adaptive immunity via T cell activation. We will investigate whether effluents from IRI+ allografts trigger innate myeloid cell activation through TLR/PRR signaling. Furthermore, we will define the role of DAMPs within the IRI effluent in triggering myeloid cell activation and see if DAMPs alter T cell activation and polarization. Under Aim 2 we will delineate the pathological signature of human liver transplant IRI. We hypothesize that IRI leads to activation of hepatocytes and resident Kupffer cells and LSECs, and recruitment/activation of myeloid cells and circulating T cells in human liver allografts, and this pathological cascade will perpetuate damage to the graft. To prove this concept, we will establish a “transcriptome” profile for IRI biopsies to better understand mechanisms of injury and characterize the acute and long-term pro-inflammatory profile of IRI and elucidate interactions between innate and adaptive immune cells in situ. Under Aim 3 we will determine the crosstalk between alloimmunity and IRI. We postulate memory T cells enhance inflammation and tissue injury in human liver transplant through antigen-dependent and antigen-independent mechanisms. We will therefore determine if allospecific T memory cells augment human liver IRI and also determine if IRI potentiates alloreactivity. Detailed insights into the interactions of the innate and adaptive immune system in human liver transplantation IRI will generate novel concepts to better understand the mechanistic underpinnings and to develop novel therapeutics to treat this major clinical problem.

项目III-摘要/摘要 正性人肝移植是终末期肝病和急性肝衰竭的主要疗法。 但是，缺血和再灌注损伤（IRI）是移植过程的必然结果，是关键 局限性。 IRI产生的细胞损伤发生在约20％的病例中，可能导致主要无功能 必要的重新转移。肝脏IRI还使接受者患有急性和慢性排斥和 移植物损失以及减少了可移植器官的池。鼠模型中的开创性观察 表明肝脏IRI是由先天和适应性免疫系统介导的。鲜为人知是否 类似的机制在人肝移植中也发挥了作用。我们的核心假设是确定 人肝移植IRI期间先天和适应性免疫型的连续性将使我们能够选择， 监测和完善热干预措施的实践，从而改善肝脏移植结果。在下面 AIM 1我们将确定潮湿/模式识别受体（PRR）信号在激活中的作用 人类OLT IRI中的先天和适应性免疫回报。我们假设IRI压力肝细胞 释放触发TLR和其他PRR信号在先天髓样细胞上的内源性潮湿，然后 通过T细胞激活诱导适应性免疫学。我们将研究IRI+同种异体移植物的影响是否触发 先天髓样细胞通过TLR/PRR信号传导激活。此外，我们将定义潮湿的作用 IRI在触发髓样细胞激活中的效应，看看潮湿是否改变了T细胞的激活和极化。 在AIM 2下，我们将描述人肝移植IRI的病理特征。我们假设IRI 导致肝细胞的激活和居民Kupffer细胞和LSEC，并募集/激活髓样 人肝移植中的细胞和循环T细胞，这种病理级联会使损害永久存在 移植。为了证明这一概念，我们将建立IRI活检的“转录组”配置文件，以更好地理解 损伤机制并表征了IRI和阐明的急性和长期促炎的特征 先天性和适应性免疫小球之间的相互作用。在AIM 3下，我们将确定串扰 在AlloMunity和IRI之间。我们假设记忆T细胞增强了人类的炎症和组织损伤 通过抗原依赖和抗原独立的机制进行肝移植。因此，我们将确定 如果同种特异性T记忆细胞增强人类肝脏IRI，并且还确定IRI是否具有同种反应性。详细的 对人肝移植中先天和适应性免疫系统相互作用的见解将 产生新颖的概念，以更好地了解机械基础并开发新的疗法 治疗这一主要临床问题。