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.

项目三-概要/摘要 人原位肝移植是治疗终末期肝病和急性肝功能衰竭的主要方法。 然而，缺血和再灌注损伤（IRI），移植过程中不可避免的后果，是一个关键， 限制. IRI引起的细胞损伤发生在约20%的病例中，并可导致原发性无功能 需要再次移植。肝脏IRI也使受体易于发生急性和慢性排斥反应， 移植物损失，以及减少可移植器官的池。小鼠模型中的精液观察 表明肝脏IRI由先天性和适应性免疫系统介导。很少有人知道， 类似的机制在人类肝移植中起作用。我们的中心假设是， 人肝移植过程中先天性和适应性免疫表型的连续性IRI将允许我们选择， 监测和完善治疗干预措施的实践，从而改善肝移植结果。下 目的1：我们将确定DAMP/模式识别受体（PRR）信号转导在激活细胞中的作用。 人奥尔特IRI中的先天性和适应性免疫应答。我们假设IRI应激的肝细胞 释放内源性DAMP，其触发先天性骨髓细胞上的TLR和其他PRR信号传导， 通过T细胞活化诱导适应性免疫。我们将研究IRI+同种异体移植物的流出物是否触发 通过TLR/PRR信号传导的先天性骨髓细胞活化。此外，我们将定义DAMP的作用， IRI流出物在触发骨髓细胞活化中作用，并观察DAMP是否改变T细胞活化和极化。 在目标2下，我们将描述人肝移植IRI的病理特征。我们假设IRI 导致肝细胞和驻留库普弗细胞和LSEC的活化，以及骨髓细胞的募集/活化。 细胞和循环T细胞，这种病理级联反应将使人类肝脏移植物的损伤永久化， 移植物为了证明这一概念，我们将建立IRI活检的“转录组”图谱，以更好地了解 损伤的机制，表征IRI的急性和长期促炎特征，并阐明 先天性和适应性免疫细胞之间的相互作用。根据目标3，我们将确定串扰 同种免疫和IRI之间的联系我们假设记忆性T细胞增强人类炎症和组织损伤， 肝移植通过抗原依赖性和抗原非依赖性机制。因此我们将决定 同种异体特异性T记忆细胞是否增加人肝IRI，并确定IRI是否增强同种异体反应性。详细 深入了解人类肝移植中先天免疫系统和适应性免疫系统的相互作用 产生新的概念，以更好地理解机制基础，并开发新的治疗方法 来治疗这个重大的临床问题。