Immune Mechanisms in Ocular Graft versus Host Disease

眼移植物抗宿主病的免疫机制

基本信息

批准号：
8714813
负责人：
Robert Benjamin Levy
金额：
$ 61.4万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714813
关键词：
Address Adoptive Transfer Agonist Allogeneic Bone Marrow Transplantation Allogenic Animal Model Anti-Inflammatory Agents 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 Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hereditary Disease ITGAM gene Immune Immune response Immunologic Deficiency Syndromes Immunotherapy Infiltration Inflammatory Injury Interferons Interleukin-2 Keratopathy Kinetics Knockout Mice Label Life Liver MEKs Microscopy Mission Modeling Mus Organ Pain Palliative Care Pathogenesis Pathway interactions Patient Care Patients Perforation Pharmaceutical Preparations Phenotype Pre-Clinical Model Prevention Quality of life Reaction Research Resources Role Sjogren&apos s Syndrome Skin Staining method Stains Survival Rate Symptoms T-Lymphocyte TNF gene Testing Thymectomy Time Tissues Transgenic Organisms United States Universities Vision base central tolerance chemokine congenic conjunctiva cytokine enhanced green fluorescent protein eye dryness graft vs host disease improved in vivo inhibitor/antagonist interest macrophage medical schools multidisciplinary neutralizing antibody novel ocular surface pre-clinical prevent public health relevance research study standard of care translational approach

项目摘要

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）已成为治疗几种威胁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，随着这些疾病患者的存活率得到了提高，其生活质量受到移植与宿主疾病（GVHD）的发展的负面影响。 GVHD是一种复杂的多器官疾病，是由供体异种反应（RX）T细胞的免疫学攻击引起的在损害包括肝脏，皮肤，造血室和眼睛的眼表面在内的重要器官的损害。眼球GVHD发生在这些患者中> 60％以上，其特征是干眼症，结膜损伤，点状角膜病，角膜溃疡和穿孔。眼睛GVHD患者因严重的眼部不适，疼痛和视力差而遭受痛苦并无能为力。尽管在接受GVHD的患者中的眼睛参与频率很高，但对于负责眼球GVHD的潜在免疫机制知之甚少，限制了这些患者的眼科护理来姑息治疗和全球抗炎药。尽管在理解系统性GVHD的免疫失调方面已经取得了重大进展，但该领域的关键问题是了解系统性和器官特定GVHD之间的关系。更具体地说，关于GVHD和随后在各种组织中的损害的中心未解决的问题不仅是Allo-RX的参与，而且还参与了Self-Rx T细胞。这与自身免疫性“像”临床症状和病理症状相关，包括Sjogrens和干眼综合征。 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.我们的初步数据清楚地证明了眼部疾病与眼组织中的供体T细胞的存在相关，并且也与巨噬细胞的浸润有关（M $）。重要的是，与CD8> CD4全身GVHD免疫表型相反，眼室中的CD4> CD8比率免疫表型与众不同。此外，检测IFN-Y和TNF-A，表明Th1效应子Allo-RX细胞和M1炎性M $参与眼球GVHD。有趣的是，这些小鼠还表现出胸腺损伤，因此具有对眼部抗原的自我反应性的供体和/或宿主致病性T细胞潜在参与的可能性。基于这些结果，我们在目标1和2中提出，以检验以下假设：Allo-RX供体T细胞和/或“ Self-Rx” T细胞都渗透了眼表，并负责策划有助于Ocular损害的炎症M1 M $的募集。此外，在AIM 3中，我们将使用抗体/细胞因子结合物，融合蛋白和新型的小型生物分子在本地调节T细胞和M $，以预防和治疗眼球GVHD。