Role of Macrophages in ocular GVHD

项目摘要/摘要 移植物抗宿主病(GVHD)是一种免疫调节的疾病，影响许多器官。它是 分为急性亚型和慢性亚型。60%-90%的慢性移植物抗宿主病患者的眼睛受到影响 导致严重的视觉障碍。大约一半的眼部移植物抗宿主病(OGVHD)患者发生类固醇- 难治性结膜和泪膜纤维化和严重的干眼症，有时伴有眼球穿孔和泪液丢失。 环球网。OGVHD的病理生理学机制尚不完全清楚。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高脚杯的相互作用 细胞作为oGVHD相关眼表损伤、纤维化和干眼的机制。长的- 学期目标是了解免疫介导的oGVHD的病理生理学基础，以便预防和治疗 更好的治疗管理。该提案将使用两种异基因骨髓的小鼠模型 移植诱发移植物抗宿主病。这些模型概括了GVHD相关眼的许多特征 表面损伤，包括泪量减少，角膜病变迹象，结膜纤维化，以及 杯状细胞丢失。目的1将研究辐射、宿主巨噬细胞激活以及 供体骨髓来源的巨噬细胞在oGVHD中启动并持续眼表损伤。目标2将确定 巨噬细胞释放的促纤维化介质是否导致结膜和泪膜的转分化 腺体成纤维细胞诱导移植物抗宿主病相关纤维化。AIM 2还将测试成纤维细胞介导的 招募供者巨噬细胞集落刺激因子-1等趋化因子的释放 巨噬细胞进入眼表。此外，Aim 2将评估pexidartinib，一种csf-1受体 抑制剂可通过耗尽结膜和泪腺巨噬细胞来减轻oGVHD。目标3将 研究IL-13挽救杯状细胞丢失是否可以缓解oGVHD相关性干眼。Aim 3也将 鉴定参与介导杯状细胞粘蛋白生物学效应的巨噬细胞受体。结果是 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和 杯状细胞是oGVHD病理的潜在机制，可能会发现新的治疗方法 OGVHD的管理方法。

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.