Approaches To Immunological Intervention In Schistosomiasis

血吸虫病的免疫干预方法

• 批准号: 9354751
• 负责人: Thomas Wynn
• 金额: $ 81.56万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354751
• 关键词: Acute; Affect; Allergens; Allergic Disease; Allergic inflammation; Area; Basophils; Behavior; Bile Duct Epithelium; Bile fluid; Biliary; Cells; Cessation of life; Cholangiocarcinoma; Chronic; Clinical; Development; Disease; Disease Progression; Epithelial Cells; Etiology; Exhibits; Family; Fibroblasts; Fibrosis; Goals; Granuloma; Granulomatous; Helminths; Hepatic; Hepatobiliary; Hepatocyte; Homeostasis; Human; Immune response; Immunity; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interferons; Interleukin 4 Receptor; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-9; Intestines; Knockout Mice; Lead; Lipids; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Lung; Lymphoid Cell; Malignant Neoplasms; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Natural regeneration; Necrosis; Organ; Outcome; Parasites; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Population; Portal Hypertension; Portal Venous System; Process; Production; Prognostic Marker; Proliferating; Reaction; Regulation; Research; Risk; Role; Schistosoma mansoni; Schistosomiasis; Series; Signal Transduction; Source; Stem cells; T-Lymphocyte; TNF gene; Th2 Cells; Tissues; Transgenic Mice; Work; base; bile duct; cell type; cholangiocyte; chronic liver disease; cytokine; egg; eosinophil; gastrointestinal; immunological intervention; injured; liver injury; macrophage; mast cell; mortality; mouse model; neutralizing monoclonal antibodies; novel; novel strategies; progenitor; programs; receptor; repaired; research study; response; senescence; stem cell population; tissue regeneration; tissue repair

In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseases. Our work is focused on elucidating the mechanisms of granulomatous inflammation, fibrosis, portal hypertension, and death following infection with S. mansoni and to devise novel strategies to slow or reverse the progression of liver fibrosis. Progress was made in the following areas: 1. The liver is remarkable in its ability to regenerate despite repeated injury. Different from many other organs that utilize stem cell populations to replace tissues, the liver relies heavily upon hepatocytes and cholangiocytes to exit quiescence and divide. Recent studies have demonstrated distinct hepatocyte subsets, which contribute to hepatocyte turnover during homeostasis and during mild chronic injury. However, during severe chronic injury, damaged hepatocytes can lose the ability to divide, and in response, a population of putative hepatobiliary progenitor cells (HPCs) expands. Although several studies have questioned the source of HPCs and whether HPCs exhibit bipotent progenitor capacity, other recent studies have demonstrated that these cells can completely repopulate the liver after injuries that induce hepatocellular senescence. These differences in behavior and potency of HPCs may be explained by differences in the etiology of liver injury; nevertheless, it has been well established that the dysregulated signaling microenvironment of the injured liver can lead to aberrant proliferation of both HPCs and existing cholangiocytes (bile duct epithelial cells), together facilitating a disorganized expansion of bile ducts and recruitment of inflammatory cells known as ductular reaction (DR). DRs are encountered in virtually every acute and chronic liver disorder in which there is organ-wide liver damage and cell loss. Proliferating ductules derived from HPCs or existing cholangiocytes may fail to drain bile contents properly, leading to local necrosis and progression toward cancers such as hepatocellular or cholangiocarcinoma. Furthermore, it has been well documented that the presence of DRs is highly correlated with the progression of hepatic fibrosis and emergence of lipid abnormalities, although the mechanisms behind these correlations are debated and not well understood. Thus, the presence of DRs is an important prognostic marker of advanced liver disease, with patients exhibiting DRs generally having poor clinical outcomes. The mechanisms that govern tissue regeneration versus pathological type 2 cytokine-driven fibrosis remain unclear. Although previous studies have implicated M2 macrophages in repair and fibrosis, other cells including hepatocytes, cholangiocytes, HPCs, and fibroblasts also express functional IL-4 and IL-13 receptors, yet their roles in the progression of liver disease, steatosis, fibrosis, DRs, and liver regeneration during chronic type 2 cytokine-driven inflammatory responses were unclear. Therefore, we generated a series of cell-specific genetically ablated mice in which IL-4 receptor alpha chain (IL-4R), an essential receptor component for both IL-4 and IL-13 signaling, was targeted for deletion in biliary cells (defined as both HPCs and existing cholangiocytes), hepatocytes, and fibroblasts to elucidate the cellular pathways instructed by IL-13 that regulate the emergence of DRs and fibrosis during schistosomiasis. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. 2. Type 2 cytokine responses, defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9, and IL-13, and type 1 responses characterized by IL-12 and IFN-gamma (IFN-g) play distinct roles in immunity, inflammation, and fibrosis, and both responses undergo significant cross-regulation or suppression by the opposing pathway. In addition to suppressing type 1-driven inflammatory responses, type 2 cytokine responses are intimately involved in the activation of allergic inflammation, anti-helminth immunity, and tissue repair. In particular, the type 2 cytokine IL-13, produced by a variety of cell types including CD4+ Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, basophils, and NK T cells, has emerged as a key cytokine in numerous type 2-driven diseases including schistosomasis. In addition to their well-defined roles in allergic disease and immunity to gastrointestinal parasites, chronic IL-13 responses are also directly involved in the development of pathological fibrosis. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis and tissue remodeling remain unclear. Some studies have suggested that IL-13 directly activates the pro-fibrotic functions of macrophages and myofibroblasts. Alternatively, because IFN-g exhibits potent anti-fibrotic activity, and type 2 cytokines antagonize IFN- effector function, compensatory increases in IFN-g expression or activity following IL-13 blockade might also contribute to the reduction in fibrosis. To investigate the potential protective role of IFN-g in the development of IL-13-dependent fibrosis, we developed novel IL-13/IFN-g double cytokine-deficient mice and examined disease progression in two pulmonary and hepatic models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN- production and activity in the tissues of IL-13-deficient mice, suggesting that the protective anti-fibrotic effects of IL-13 deficiency might indeed be in part due to the increased IFN- response. Surprisingly, however, we observed an even greater reduction in fibrosis in the IL-13/IFN-g double deficient mice, particularly in the livers of chronically infected mice. The increased protection observed in IL-13/IFN-g mice was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA in the tissues; reduced inflammation; and suppression of other pro-inflammatory mediators such as TNF-alpha. Moreover, studies conducted with neutralizing mAbs to IFN-g and IL-13 confirmed these findings. Together, these studies demonstrate that the protective anti-fibrotic activity observed in IL-13-deficient mice is completely independent from increased IFN-g activity. Instead, our findings suggest that by reducing compensatory increases in type 1-associated inflammation, simultaneous reductions in IL-13 and IFN-g signaling might confer greater protection from pathological fibrosis than IL-13 blockade alone.

在血吸虫病和与2型免疫相关的其他疾病中，由慢性感染或慢性过敏原暴露引起的病理主要由宿主免疫反应引起。慢性2型免疫反应最终会触发明显的纤维化，这是许多慢性传染病和炎症性疾病中发病率和死亡率的主要原因。我们的工作重点是阐明肉芽肿性炎症，纤维化，门静脉高压和死亡的机制，并在感染了曼氏链球菌后死亡，并制定了新的策略，以减缓或逆转肝纤维化的进展。在以下领域取得了进展： 1。尽管反复受伤，但肝脏的再生能力很显着。与许多其他利用干细胞群替代组织的器官不同，肝脏严重依赖肝细胞和胆管细胞来退出静止和分裂。 最近的研究表明，在体内稳态期间和轻度慢性损伤期间有助于肝细胞更换，这表明了明显的肝细胞亚群。但是，在严重慢性损伤期间，受损的肝细胞可能会失去分裂的能力，并且反应响应，推定的肝副祖细胞（HPC）群体会扩大。尽管有几项研究质疑HPC的来源以及HPC是否表现出二元祖细胞的能力，但最近的其他研究表明，这些细胞可以在诱导肝细胞衰老的损伤后完全重新填充肝脏。 HPC的行为和效力上的这些差异可以通过肝损伤病因的差异来解释。然而，已经有充分的确定是，受伤的肝脏的信号传导微环境失调会导致HPC和现有的胆管细胞（胆管上皮细胞）的异常增殖，从而促进胆管膨胀和募集的膨胀性膨胀，并促进胆管的膨胀和募集的疾病，并促进了已知的无效反应。 在几乎每种急性和慢性肝脏疾病中都遇到了DRS，其中有器材范围内的肝脏损伤和细胞损失。源自HPC或现有胆管细胞的增殖导管可能无法正确排出胆汁含量，从而导致局部坏死和向癌细胞的进展，例如肝细胞癌或胆管癌。此外，已经有充分的文献证明，DR的存在与肝纤维化的进展和脂质异常的出现高度相关，尽管这些相关性背后的机制是有争议的，并且不太了解。因此，DRS的存在是晚期肝病的重要预后标记，患者表现出临床结局较差。控制组织再生与2型细胞因子驱动纤维化的机制尚不清楚。尽管以前的研究已经在修复和纤维化中涉及M2巨噬细胞，但其他细胞，包括肝细胞，胆管细胞，HPC和成纤维细胞，也表达功能性的IL-4和IL-13受体，但它们在肝病，纤维化，纤维化，纤维化，Drs和liver typer pernersision drerniseralsissiperssiperssiperss中的发展中的作用。 Therefore, we generated a series of cell-specific genetically ablated mice in which IL-4 receptor alpha chain (IL-4R), an essential receptor component for both IL-4 and IL-13 signaling, was targeted for deletion in biliary cells (defined as both HPCs and existing cholangiocytes), hepatocytes, and fibroblasts to elucidate the cellular pathways由IL-13指示，该IL-13调节血吸虫病期间DR和纤维化的出现。总之，这些研究表明，这些机制是同时控制的，但由白介素13信号传导明显调节。因此，在不产生病理纤维化的情况下，可能有可能促进白介素13依赖性的肝膨胀。 2。2型细胞因子反应，由细胞因子介绍列鲁金4（IL-4），IL-5，IL-9和IL-13以及以IL-12和IFN-GAMMA（IFN-G）为特征的1型反应在免疫，炎症，纤维化以及抗纤维化的抑制作用中，由IL-12和IFN-GAMMA（IFN-G）（IFN-G）（IFN-G）（IFN-G）的作用都起作用。除了抑制1型1型驱动炎症反应外，2型细胞因子反应还与过敏性炎症，抗抑制免疫和组织修复的激活密切相关。特别是，由多种细胞类型产生的2型细胞因子IL-13，包括CD4+ TH2细胞，2型先天淋巴样细胞，嗜酸性粒细胞，肥大细胞，嗜碱性粒细胞和NK T细胞，在包括schistosomasis在内的许多类型2驱动疾病中已成为关键细胞因子。 除了它们在过敏性疾病中定义明确的作用和对胃肠道寄生虫的免疫力外，慢性IL-13反应还直接参与病理纤维化的发展。然而，IL-13封锁导致纤维化和组织重塑的改善的机制尚不清楚。一些研究表明，IL-13直接激活巨噬细胞和肌纤维细胞的促纤维化功能。另外，由于IFN-G表现出有效的抗纤维化活性，并且2型细胞因子拮抗IFN效应功能，因此IL-13封锁后IFN-G表达或活性的补偿性增加也可能有助于减少纤维化。为了研究IFN-G在IL-13依赖性纤维化发展中的潜在保护作用，我们开发了新型IL-13/IFN-G双重细胞因子缺陷小鼠，并检查了两种2型型纤维化的两种肺和肝模型中的疾病进展。如预测的那样，我们表明肺和肝脏中的纤维化都高度依赖于IL-13。我们还观察到在IL-13缺陷型小鼠组织中的IFN产生和活性增加，这表明IL-13缺乏的保护性抗纤维化作用确实可能部分是由于IFN反应增加。然而，令人惊讶的是，我们观察到IL-13/IFN-G双重缺陷小鼠的纤维化的降低更大，尤其是在慢性感染小鼠的肝脏中。在IL-13/IFN-G小鼠中观察到的保护增加与组织中TGFB1，MMP12和TIMP1 mRNA的明显降低有关。减少炎症；并抑制其他促炎性介体（例如TNF-Alpha）。此外，对IFN-G和IL-13进行中和MAB进行的研究证实了这些发现。总之，这些研究表明，在IL-13缺陷型小鼠中观察到的保护性抗纤维化活性完全独立于IFN-G活性。取而代之的是，我们的发现表明，通过减少1型相关炎症的补偿性增加，IL-13的同时减少和IFN-G信号传导可能比单独的IL-13阻滞更大。