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

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.

项目概要/摘要 移植物抗宿主病（GVHD）是一种影响许多器官的免疫介导疾病。这是 分为急性亚型和慢性亚型。 60-90% 的慢性 GVHD 患者的眼睛受到影响 导致严重的视觉疾病。大约一半的眼部 GVHD (oGVHD) 患者会出现类固醇- 难治性结膜和泪腺纤维化以及严重干眼，有时伴有眼穿孔和视力丧失 地球。 oGVHD 的病理生理学仍不完全清楚。目前的提案将调查 宿主和供体巨噬细胞的作用、它们的表型变化以及它们与成纤维细胞和杯状细胞的串扰 细胞作为 oGVHD 相关眼表损伤、纤维化和干眼的潜在机制。长- 长期目标是了解 oGVHD 的免疫介导的病理生理学基础，以预防和预防 oGVHD。 更好的治疗管理。该提案将使用两种同种异体骨髓小鼠模型 移植诱导oGVHD。这些模型概括了 GVHD 相关眼部的许多特征 表面损伤，包括泪液量减少、角膜病变、结膜纤维化和 杯状细胞损失。目标 1 将研究辐射、宿主巨噬细胞激活和巨噬细胞的流入是否 供体骨髓来源的巨噬细胞在 oGVHD 中引发并维持眼表损伤。目标 2 将确定 巨噬细胞释放的促纤维化介质是否引起结膜和泪腺的转分化 腺体成纤维细胞引发 oGVHD 相关纤维化。目标 2 还将测试成纤维细胞介导的作用 招募供体时释放巨噬细胞集落刺激因子-1 (CSF-1) 和其他趋化因子 巨噬细胞到达眼表。此外，目标 2 将评估 Pexidartinib（一种 CSF-1 受体）是否 抑制剂，可以通过消耗结膜和泪腺巨噬细胞来减弱 oGVHD。目标3将 研究通过 IL-13 挽救杯状细胞损失是否可以减轻 oGVHD 相关的干眼症。目标3也将 鉴定参与介导杯状细胞粘蛋白生物效应的巨噬细胞受体。结果 这项研究将提供有关宿主供体巨噬细胞的作用、它们与成纤维细胞的相互作用以及 杯状细胞作为 oGVHD 病理学的潜在机制，并将有可能识别新的治疗方法 oGVHD 的管理方法。