Immune Mechanisms in Ocular Graft versus Host Disease

眼移植物抗宿主病的免疫机制

• 批准号: 9747598
• 负责人: Robert Benjamin Levy
• 金额: $ 45.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9747598
• 关键词: Address; Adoptive Transfer; Agonist; Allogeneic Bone Marrow Transplantation; Allogenic; Animal Model; Anti-inflammatory; Antibodies; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Bone Marrow; CD4/CD8 ratio procedure; CD8B1 gene; Caring; Cells; Chimeric Proteins; Clinical; Complex; Corneal Ulcer; Data; Detection; Development; Disease; Dry Eye Syndromes; Educational workshop; Effector Cell; Exhibits; Eye; Eye diseases; Failure; Frequencies; Future; Genetic Diseases; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; ITGAM gene; Immune; Immune System Diseases; Immune response; Immunologic Deficiency Syndromes; Immunologics; Immunotherapy; Individual; Infiltration; Inflammatory; Injury; Interferons; Interleukin-2; Keratopathy; Kinetics; Knockout Mice; Label; Life; Liver; MEKs; Microscopy; Mission; Modeling; Mus; Organ; Pain; Palliative Care; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patient Care; Patients; Perforation; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Prevention approach; Quality of life; Quantitative Reverse Transcriptase PCR; Reaction; Research; Resources; Role; Sjogren' s Syndrome; Skin; Stains; Survival Rate; Symptoms; T-Lymphocyte; TNF gene; Testing; Thymectomy; Thymus Gland; Time; Tissues; Transgenic Organisms; United States; Universities; Vision; base; central tolerance; chemokine; congenic; conjunctiva; cytokine; enhanced green fluorescent protein; experimental study; eye dryness; graft vs host disease; improved; in vivo evaluation; inhibitor/antagonist; macrophage; medical schools; multidisciplinary; neutralizing antibody; novel; ocular surface; pre-clinical; prevent; public health relevance; recruit; standard of care; translational approach; translational impact

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of several life-threatening hematologic malignancies as well as certain immunodeficiency diseases. Unfortunately, as the survival rate of patients with these diseases is improved, the quality of life is negatively impacted by the development of Graft vs. Host Disease (GVHD). GVHD is a complex, multi-organ disorder arising from an immunological attack by donor allo-reactive (rx) T cells that result in damage to vital organs including the liver, skin, hematopoietic compartment and the ocular surface of the eye. Ocular GVHD occurs in >60% of these patients and is characterized by dry eye, conjunctiva damage, punctate keratopathy, corneal ulceration and perforation. Patients with ocular GVHD suffer and are incapacitated because of severe ocular discomfort, pain and poor vision. Despite the high frequency of eye involvement in patients undergoing GVHD, little is known regarding the underlying immune mechanisms responsible for ocular GVHD, limiting the ophthalmic care of these patients to palliative therapies and global anti-inflammatory drugs. Even though major advances have been made in the understanding of immune dysregulation in systemic GVHD, a critical question in the field is to understand the relationship between systemic and organ specific GVHD. More specifically, a central unanswered question regarding GVHD and subsequent damage in various tissues is the involvement of not only allo-rx, but also self-rx T cells. This is relevant as autoimmune "like" clinical and pathological symptoms occur in GVHD, including Sjogrens and dry eye syndrome. To understand the immune mechanisms of ocular GVHD, our group has developed a unique pre-clinical animal model, in which lethally irradiated C3H.SW mice (H2b) infused with C57BL6 (H2b) T cells + bone marrow, results in the development of systemic and ocular GVHD with kinetics of onset similar to that observed in patients who develop eye complications. Our preliminary data clearly demonstrate for the first time that ocular disease correlates with the presence of donor T cells in eye tissue and is also associated with the infiltration of macrophages (m$). Importantly, in contrast to the CD8>CD4 systemic GVHD immune phenotype, the CD4>CD8 ratio immune phenotype in the ocular compartment is distinct. Furthermore, the detection of IFN-y and TNF-a, suggests that Th1 effector allo-rx cells and M1 inflammatory m$ are involved in ocular GVHD. Interesting, these mice also exhibit thymic damage and therefore the possibility for the potential involvement of donor and/or host pathogenic T cells with self-reactivity to ocular antigens. Based on these results, we propose in Aims 1 and 2 to test the hypothesis that both allo-rx donor T cells and/ or "self-rx" T cells infiltrate the ocular surface and are responsible for orchestrating the recruitmet of inflammatory M1 m$ that contribute to the ocular damage. Moreover in Aim 3, we will locally regulate the T cells and m$ using antibody/cytokine conjugates, fusion proteins and novel small biomolecules to prevent and treat ocular GVHD.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）已成为治疗几种危及生命的血液恶性肿瘤以及某些免疫缺陷疾病的护理标准。不幸的是，随着患有这些疾病的患者的生存率提高，生活质量却受到移植物抗宿主病（GVHD）的发展的负面影响。 GVHD 是一种复杂的多器官疾病，由供体同种异体反应性 (rx) T 细胞的免疫攻击引起，导致 损害重要器官，包括肝脏、皮肤、造血室和眼睛的眼表面。超过 60% 的患者会发生眼部 GVHD，其特征是干眼、结膜损伤、点状角膜病变、角膜溃疡和穿孔。眼部 GVHD 患者因严重的眼部不适、疼痛和视力不佳而遭受痛苦并丧失行为能力。尽管接受 GVHD 的患者眼部受累的频率很高，但人们对眼部 GVHD 的潜在免疫机制知之甚少，这将这些患者的眼科护理限制在姑息治疗和整体抗炎药物上。尽管在了解系统性 GVHD 中的免疫失调方面已经取得了重大进展，但该领域的一个关键问题是了解系统性和器官特异性 GVHD 之间的关系。更具体地说，关于 GVHD 和随后的各种组织损伤的一个核心问题是，不仅涉及同种异体接受 T 细胞，还涉及自体接受 T 细胞。这是相关的，因为 GVHD 中会出现自身免疫“类似”临床和病理症状，包括干燥症和干眼综合征。为了了解眼部GVHD的免疫机制，我们小组开发了一种独特的临床前动物模型，其中经致死照射的C3H.SW小鼠（H2b）注入C57BL6（H2b）T细胞+骨髓，导致全身性GVHD的发生。和眼 GVHD 的发病动力学与在出现眼部并发症的患者中观察到的相似。我们的初步数据首次清楚地证明，眼部疾病与眼组织中供体 T 细胞的存在相关，并且还与巨噬细胞的浸润相关 (m$)。重要的是，与CD8>CD4全身GVHD免疫表型相比，眼部CD4>CD8比率免疫表型是不同的。此外，IFN-γ和TNF-a的检测表明Th1效应器allo-rx细胞和M1炎症m$参与眼GVHD。有趣的是，这些小鼠还表现出胸腺损伤，因此可能涉及对眼抗原具有自身反应的供体和/或宿主致病性 T 细胞。基于这些结果，我们在目标 1 和 2 中建议检验以下假设：allo-rx 供体 T 细胞和/或“self-rx”T 细胞浸润眼表并负责协调炎症 M1 m$ 的募集。导致眼睛损伤。此外，在目标 3 中，我们将使用抗体/细胞因子缀合物、融合蛋白和新型小生物分子局部调节 T 细胞和 m$，以预防和治疗眼部 GVHD。