Immune Functions of the Vascular Endothelium in Health and Disease

血管内皮在健康和疾病中的免疫功能

• 批准号: 9130444
• 负责人: CHRISTOPHER V CARMAN
• 金额: $ 46.76万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-11 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130444
• 关键词: Address; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Arthritis; Atherosclerosis; Autoimmune Process; B-Lymphocytes; Bioavailable; Biological Models; Biopsy; Blood Cells; Blood Circulation; Blood Vessels; CD1d antigen; CD4 Antigens; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell Communication; Cell physiology; Cells; Crohn' s disease; Dendritic Cells; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Drug or chemical Tissue Distribution; Employee Strikes; Endothelial Cells; Endothelium; Extravasation; Goals; Health; Hematopoietic; Heterogeneity; Home environment; Human; Hypoxia; Image; Immune; Immune response; Immune system; Immunity; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-2; Intervention; Investigation; Knock-out; Knowledge; Link; Lipids; Lupus; Lymphocyte; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Memory; Modeling; Multiple Sclerosis; Mus; Myocarditis; Natural Killer Cells; Pathologic; Pathology; Peptides; Peripheral; Phase; Plastics; Play; Positioning Attribute; Process; Psoriasis; Research; Rest; Role; Sepsis; Series; Sirolimus; Site; Staging; Stimulus; Structure; Surface; Synapses; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Vascular Endothelial Cell; Vascular Endothelium; Vasculitis; adaptive immunity; allograft rejection; base; behavior influence; cell type; cytokine; immune function; immunological synapse; immunoregulation; improved; in vitro Model; in vivo; inhibitor/antagonist; insight; interstitial; killer T cell; lymph nodes; monocyte; neutrophil; novel; pathogen; response; vascular bed

DESCRIPTION (provided by applicant): The basic premise of this study is that the vascular endothelium represents an important, yet understudied and therapeutically untapped, subset of peripheral, non-hematopoietic 'semi-professional' antigen presenting cells (APCs). Similar to hematopoietic 'professional' APCs (but distinct from most other cell types) endothelial cells constitutively express essential peptide (MHC-I, MHC-II) and lipid (CD1d) antigen presentation molecules, along with critical co-stimulators and co-inhibitors. However, they lack the co-stimulators (CD80, CD86) essential for initiating adaptive immune responses (i.e., for priming of naive T cells). Thus endothelial APC functions would seem to be geared for later effector/memory/tolerogenic stages of responses within the periphery. Indeed, a range of in vitro and in vivo studies have supported this hypothesis and implicated endothelial APC function in autoimmune/inflammatory/cardiovascular pathologies such as atherosclerosis, arthritis, lupus, multiple sclerosis, diabetes, Crohn's disease, allograft rejection and myocarditis. However, overall contributions of endothelial cells as APCs has remained poorly appreciated, controversial and in many cases completely ignored. This is striking given their ubiquitous tissue distribution, constitutive interaction with circulating lymphocytes and that they, in fact, outnumber professional hematopoietic APCs (conservatively) by ~1000-fold. The central objective of this study is to build the first systematic framework for understanding roles for endothelial APCs in adaptive immune responses and inflammatory pathology, with the ultimate goal of harnessing this knowledge to improve on emerging and exciting APC-dependent immune-modulatory therapeutic strategies. Our preliminary studies have established in vitro model systems that confirm the ability of endothelial cells to activate CD4+ and CD8+ effector/memory cells and that demonstrate for the first time that endothelial cells can effectivel present lipid antigen to, and activate NKT cells. Additionally, we have defined novel endothelial cell-lymphocyte immunological synapse structures that mediate these interactions. Furthermore, we have generated novel endothelial-specific MHC-II and CD1d murine knockout strains, and with the former, generated the first evidence of an unambiguous role for endothelium in adaptive immunity in vivo. This proposal will extend these preliminary studies, focusing on the potent and interrelated CD4+ T helper and NKT cytokine-driven antigen responses. A series of in vitro studies will delineate basic roles of endothelial APCs, their heterogeneous function in distinct vascular beds, their plasticity in response to critical pathologic stimuli and their sensitivity to pharmacologic-/antibody-based intervention. Finally, murine transplant and infection models will be employed, along with our endothelial MHC-II and CD1d knockout strains, to i) generate expanded proof-of-principle demonstration of endothelial APC-specific functions in adaptive immunity and ii) to evaluate the critical translational potential of endothelial cells in mediatingin vivo immunomodulatory effects of emerging therapeutics. These studies will be highly significant in that they will open fundamental new avenues for understanding and for pharmacologically addressing broad ranging inflammatory/cardiovascular diseases.

描述（由申请人提供）：这项研究的基本前提是血管内皮代表了一个重要的，但本研究的，治疗效果未开发的，是周围，非杂质的“半专业”抗原呈现细胞（APC）的子集。类似于造血“专业” APC（但与大多数其他细胞类型不同）的内皮细胞组成型表达必需肽（MHC-I，MHC-II）和脂质（CD1D）抗原表现分子，以及关键的共刺激剂和抑制剂。但是，他们缺乏启动适应性免疫反应至关重要的共刺激剂（CD80，CD86）（即，对于幼稚T细胞的启动）。因此，内皮APC函数似乎是为了以后的效应子/记忆/耐受性阶段的响应阶段。实际上，一系列体外和体内研究支持了这一假设，并暗示了内皮APC功能在自身免疫性/炎症/心血管病理中，例如动脉粥样硬化，关节炎，狼疮，多发性硬化症，糖尿病，糖尿病，克罗恩病，克罗恩病，同性疾病，同种异体移植和心肌炎。但是，作为APC的内皮细胞的总体贡献仍然受到良好的欣赏，有争议的，并且在许多情况下完全被忽略。鉴于其无处不在的组织分布，与循环淋巴细胞的组成型相互作用，实际上它们的数量超过了专业的造血APC（保守地）约1000倍。这项研究的核心目的是建立第一个系统框架，以了解内皮APC在适应性免疫反应和炎症病理学中的作用，其最终目标是利用这一知识来改善新兴和令人兴奋的APC依赖性免疫调节性治疗策略。我们的初步研究已经建立了体外模型系统，这些系统确认了内皮细胞激活CD4+和CD8+效应子/记忆细胞的能力，并首次证明内皮细胞可以有效脂质抗原对和激活NKT细胞。此外，我们定义了介导这些相互作用的新型内皮细胞 - 淋巴细胞免疫突触结构。此外，我们已经产生了新型的内皮特异性MHC-II和CD1D鼠敲除菌株，并且与前者有关，这是内皮在体内适应性免疫中发挥明确作用的第一个证据。该建议将扩展这些初步研究，重点是有效且相互关联的CD4+ T助手和NKT细胞因子驱动的抗原反应。一系列的体外研究将描述内皮APC的基本作用，它们在不同的血管床中的异质功能，它们对关键病理刺激的可塑性以及对它们的敏感性 基于药理/抗体的干预措施。 Finally, murine transplant and infection models will be employed, along with our endothelial MHC-II and CD1d knockout strains, to i) generate expanded proof-of-principle demonstration of endothelial APC-specific functions in adaptive immunity and ii) to evaluate the critical translational potential of endothelial cells in mediatingin vivo immunomodulatory effects of emerging therapeutics.这些研究将非常重要，因为它们将开辟基本的新途径，用于理解和在药理学上解决广泛的炎症/心血管疾病。