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.

项目总结/摘要 移植物抗宿主病（GVHD）是一种免疫介导的疾病，影响许多器官。是 分为急性和慢性亚型。60-90%的慢性GVHD患者的眼睛受到影响 导致明显的视觉病态。大约一半的眼部GVHD（oGVHD）患者发展为类固醇- 难治性结膜和泪纤维化和严重干眼症，有时伴有眼穿孔和眼内分泌丧失。 地球仪。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、表型变化及其与成纤维细胞和杯状细胞的相互作用 细胞作为oGVHD相关的眼表面损伤、纤维化和干眼的潜在机制。很长的- 长期目标是了解免疫介导的oGVHD的病理生理学基础， 更好的治疗管理。这项建议将使用两个小鼠模型的同种异体骨髓 移植以诱导oGVHD。这些模型概括了GVHD相关的眼部免疫缺陷的许多特征。 表面损伤，包括泪液量减少、角膜病变体征、结膜纤维化，以及 杯状细胞丢失。目的1将研究是否辐射，宿主巨噬细胞活化，和流入的 供体骨髓来源的巨噬细胞在oGVHD中引发并维持眼表面损伤。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 腺成纤维细胞以引发oGVHD相关的纤维化。Aim 2还将测试成纤维细胞介导的 巨噬细胞集落刺激因子-1（CSF-1）和其他趋化因子在招募供体中的释放 巨噬细胞进入眼表。此外，目的2将评价Pexidartinib（一种CSF-1受体） 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拯救杯状细胞损失是否可以减轻oGVHD相关干眼。Aim 3还将 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 本研究的结果将提供关于宿主-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，并将潜在地确定新的治疗方法。 管理oGVHD的方法。