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--摘要/摘要 正交异性人肝移植是治疗终末期肝病和急性肝衰竭的主要方法。 然而，移植过程的必然结果--缺血再灌注损伤(IRI)是一个关键 限制。IRI引起的细胞损伤发生在大约20%的病例中，并可能导致原发的无功能 需要再次移植。肝脏IRI还使受体容易发生急性和慢性排斥反应， 移植物丢失，以及可移植器官池的减少。小鼠模型的精液观察 提示肝脏IRI受先天免疫系统和获得性免疫系统的双重调节。目前尚不清楚 类似的机制也在人类肝移植中发挥作用。我们的中心假设是，确定 在人类肝脏移植中，先天性和获得性免疫表型的连续体IRI将允许我们选择， 监测和改进治疗干预的做法，从而改善肝脏移植的结果。在……下面 目的1我们将确定DAMP/模式识别受体(PRR)信号在激活 人原位肝移植IRI的先天和获得性免疫反应。我们假设IRI应激的肝细胞 释放内源性阻滞剂，触发固有髓系细胞上的TLR和其他PRR信号，然后 通过T细胞活化诱导获得性免疫。我们将调查IRI+异体移植物的流出物是否会引发 天然髓系细胞通过TLR/PRR信号激活。此外，我们还将定义阻尼器在 IRI在触发髓系细胞激活过程中流出，看看阻滞剂是否会改变T细胞的激活和极化。 在目标2下，我们将描述人类肝移植IRI的病理特征。我们假设IRI 导致肝细胞、常驻Kupffer细胞和LSECs的激活，以及髓系的募集/激活 人同种异体肝移植中的细胞和循环T细胞，这种病理性级联反应将使损伤永久化 移植物。为了证明这一概念，我们将建立IRI活组织检查的“转录组”配置文件，以便更好地理解 IRI的损伤机制、急性和长期促炎性特征及其阐明 先天免疫细胞和获得性免疫细胞在原位的相互作用。在目标3下，我们将确定串扰 在同种免疫和IRI之间。我们假设记忆T细胞增强人类的炎症和组织损伤 通过抗原依赖和非抗原依赖机制进行肝移植。因此，我们将决定 如果同种异体特异性T记忆细胞增强人类肝脏IRI，也可以确定IRI是否增强同种异体反应。详细 对人肝移植先天免疫系统和获得性免疫系统相互作用的见解IRI Will 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。