Role of Macrophages in ocular GVHD

巨噬细胞在眼 GVHD 中的作用

• 批准号: 10577351
• 负责人: Ajay Sharma
• 金额: $ 34.2万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577351
• 关键词: Acute; Affect; Allogeneic Bone Marrow Transplantation; Antigens; Area; Attenuated; Binding; Biological; Bone Marrow; Bone Marrow Transplantation; Categories; Cell Proliferation; Cells; Chimerism; Chronic; Chronic Phase; Complication; Cornea; Data; Environmental Exposure; Excision; Exhibits; Eye; Fibroblasts; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Genes; Goals; Goblet Cells; Hematopoietic Stem Cell Transplantation; Immune; Immunologist; Immunology; Immunophenotyping; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-13; Keratopathy; Knowledge; Lacrimal gland structure; Macrophage; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Marrow; Mediating; Mediator; Modeling; Morbidity - disease rate; Mucins; Mucous Membrane; Mus; Myofibroblast; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Perforation; Phenotype; Positioning Attribute; Prevention; Refractory; Role; Sampling; Sentinel; Steroids; Stimulus; Surface; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Tissues; Visual; chemokine; chemotherapy; chronic graft versus host disease; conditioning; conjunctiva; disorder control; eye dryness; graft vs host disease; inhibitor; irradiation; lacrimal; mouse model; nano-string; new therapeutic target; novel therapeutic intervention; ocular surface; paracrine; pharmacologic; prevent; profibrotic cytokine; receptor; recruit; tissue injury; transdifferentiation; wound healing; Acute; Affect; Allogeneic Bone Marrow Transplantation; Antigens; Area; Attenuated; Binding; Biological; Bone Marrow; Bone Marrow Transplantation; Categories; Cell Proliferation; Cells; Chimerism; Chronic; Chronic Phase; Complication; Cornea; Data; Environmental Exposure; Excision; Exhibits; Eye; Fibroblasts; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Genes; Goals; Goblet Cells; Hematopoietic Stem Cell Transplantation; Immune; Immunologist; Immunology; Immunophenotyping; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-13; Keratopathy; Knowledge; Lacrimal gland structure; Macrophage; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Marrow; Mediating; Mediator; Modeling; Morbidity - disease rate; Mucins; Mucous Membrane; Mus; Myofibroblast; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Perforation; Phenotype; Positioning Attribute; Prevention; Refractory; Role; Sampling; Sentinel; Steroids; Stimulus; Surface; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Tissues; Visual; chemokine; chemotherapy; chronic graft versus host disease; conditioning; conjunctiva; disorder control; eye dryness; graft vs host disease; inhibitor; irradiation; lacrimal; mouse model; nano-string; new therapeutic target; novel therapeutic intervention; ocular surface; paracrine; pharmacologic; prevent; profibrotic cytokine; receptor; recruit; tissue injury; transdifferentiation; wound healing

Project Summary/Abstract Graft versus host disease (GVHD) is an immune-mediated condition affecting many organs. It is categorized into acute and chronic subtypes. Eyes are affected in 60-90% of the patients with chronic GVHD resulting in significant visual morbidity. About half of the ocular GVHD (oGVHD) patients develop steroid- refractory conjunctival and lacrimal fibrosis and severe dry eye, sometimes with ocular perforation and loss of globe. Pathophysiology of oGVHD remains incompletely understood. The current proposal will investigate the role of host and donor macrophages, their phenotypic changes, and their crosstalk with fibroblasts and goblet cells as mechanisms underlying oGVHD-associated ocular surface damage, fibrosis, and dry eye. The long- term goal is to understand the immune-mediated pathophysiological basis of oGVHD for its prevention and better therapeutic management. This proposal will use two mouse models of allogeneic bone marrow transplantation to induce oGVHD. These models recapitulate many features of GVHD-associated ocular surface damage, including a decrease in tear volume, signs of corneal keratopathy, conjunctival fibrosis, and loss of goblet cells. Aim 1 will investigate whether irradiation, host macrophage activation, and the influx of donor marrow-derived macrophages initiate and perpetuate ocular surface injury in oGVHD. Aim 2 will identify whether profibrotic mediators released by macrophages cause transdifferentiation of conjunctival and lacrimal gland fibroblasts to elicit oGVHD-associated fibrosis. Aim 2 will also test the role of the fibroblast-mediated release of macrophage colony-stimulating factor-1 (CSF-1) and other chemokines in recruiting donor macrophages to the ocular surface. Furthermore, aim 2 will evaluate whether pexidartinib, a CSF-1 receptor inhibitor, can attenuate oGVHD by depleting conjunctival and lacrimal gland macrophages. Aim 3 will investigate whether rescue of goblet cell loss by IL-13 can mitigate oGVHD-associated dry eye. Aim 3 will also identify the macrophage receptors involved in mediating the biological effects of goblet cell mucins. The results of this study will provide data on the role of host-donor macrophages, their interaction with fibroblasts and goblet cells as underlying mechanisms in oGVHD pathology and will potentially identify novel therapeutic approaches for the management of oGVHD.

项目摘要/摘要 移植与宿主疾病（GVHD）是影响许多器官的免疫介导的疾病。这是 分为急性和慢性亚型。慢性GVHD患者中有60-90％的眼睛受到影响 导致明显的视觉发病率。大约一半的眼球GVHD（OGVHD）患者发展了类固醇 难治性结膜和泪纤维化和严重的干眼，有时还带有眼睛穿孔和丧失 地球。 OGVHD的病理生理学尚不完全理解。当前的提议将调查 宿主和供体巨噬细胞的作用，表型变化以及与成纤维细胞和杯状的串扰 细胞作为OGVHD相关的眼表损伤，纤维化和干眼的机制。长期 术语目标是了解OGVHD的免疫介导的病理生理基础，以预防和 更好的治疗管理。该建议将使用两个同种异体骨髓的鼠标模型 移植以诱导OGVHD。这些模型概括了与GVHD相关眼的许多特征 表面损伤，包括撕裂量减少，角膜角膜病的迹象，结膜纤维化和 杯状细胞的丢失。 AIM 1将研究辐射，宿主巨噬细胞激活和流入是否 供体骨髓来源的巨噬细胞在OGVHD中引发和永久性眼表面损伤。 AIM 2将确定 巨噬细胞释放的纤维纤维化介质是否会导致结膜和泪液的转变 腺成纤维细胞可引起与OGVHD相关的纤维化。 AIM 2还将测试成纤维细胞介导的作用 在招募供体中，巨噬细胞刺激因子1（CSF-1）和其他趋化因子的释放 巨噬细胞到眼表。此外，AIM 2将评估Pexidartinib，CSF-1受体是否是否 抑制剂可以通过耗尽结膜和泪腺巨噬细胞来减弱OGVHD。目标3意志 调查IL-13挽救杯状细胞损失是否可以减轻与OGVHD相关的干眼。 AIM 3也将 确定涉及介导杯状细胞粘蛋白的生物学作用的巨噬细胞受体。结果 这项研究将提供有关宿主 - 唐纳巨噬细胞作用的数据，它们与成纤维细胞的相互作用和 杯状细胞作为OGVHD病理学中的潜在机制，并有可能识别新型治疗性 OGVHD管理的方法。