Characterization of Chronic Graft-Versus-Host Disease in the Canine Model

犬模型中慢性移植物抗宿主病的特征

• 批准号: 8445126
• 负责人: SCOTT Stoll GRAVES
• 金额: $ 20.92万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-13 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445126
• 关键词: Accounting; Acute; Acute Graft Versus Host Disease; Adrenal Cortex Hormones; Affect; Allogenic; Anemia; Animal Disease Models; Animal Model; Animals; Biological; Biology; Canis familiaris; Cells; Cessation of life; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Communities; Complication; Consensus; Data; Development; Diagnosis; Disease; Future; Genetic Variation; Goals; Hematological Disease; Hematopoietic Neoplasms; Histologic; Human; Immune; Immunologic Deficiency Syndromes; Immunology; Individual; Inherited; Institution; Investigation; Lead; Lesion; Long-Term Survivors; Malignant - descriptor; Modeling; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Malignant; Organ Transplantation; Outcome; Pathway interactions; Patients; Phase III Clinical Trials; Plant Roots; Play; Pre-Clinical Model; Prevention; Prevention therapy; Protocols documentation; Quality of life; Randomized Clinical Trials; Reaction; Reagent; Regulatory T-Lymphocyte; Research; Role; Solid; T-Lymphocyte; Testing; Tissues; Translations; Transplant Recipients; Transplantation; Transplantation Tolerance; United States National Institutes of Health; base; chronic graft versus host disease; clinically relevant; disability; effective therapy; experience; graft vs host disease; hematopoietic cell transplantation; human disease; improved; insight; mortality; mouse model; novel; novel strategies; pre-clinical; prevent; prophylactic; public health relevance; success

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (HCT) is increasingly widely used to treat blood cancers and non-malignant blood diseases (such as hereditary anemias and immunodeficiencies), and as a platform to facilitate solid-organ transplants. However, graft-vs.-host disease (GVHD), caused by a reaction of donor immune cells against normal host tissues, is a major complication of HCT. GVHD occurs in two forms: acute and chronic. There has been substantial progress in preventing and treating the acute form of GVHD. In contrast, chronic GVHD remains a major cause of illness and death, and the major determinant of quality of life, in long-term survivors of HCT. In contrast to acute GVHD, chronic GVHD remains poorly understood on a biological level, and efforts to devise novel and effective treatments have been almost uniformly unsuccessful. Thus, the lack of effective approaches to chronic GVHD limits the application and success of allogeneic HCT. There are several factors accounting for the decades-long lack of progress against chronic GVHD. Primary among these is the lack of relevant preclinical animal models of the disease. Several mouse models of chronic GVHD have been described, but each suffers from serious limitations and fails to mirror critical aspects of human disease. Despite extensive investigation, these models have not led to the translation of novel approaches to chronic GVHD. Without a preclinical means to investigate the biology of chronic GVHD and rapidly screen treatment approaches, Phase III clinical trials of novel agents in humans have been uniformly disappointing. Thus, a desperate need exists for new and clinically relevant animal models of chronic GVHD. The dog has been used extensively as a model organism in allogeneic HCT, from the earliest days of investigation in the field. The canine model offers numerous advantages over the murine model, including greater genetic diversity, closer analogy to human immunology, and a long track record of successful translation of novel GVHD treatment approaches to the clinic. However, chronic GVHD has not been modeled or studied in the dog to this point. We have observed pathological and clinical evidence of chronic GVHD in individual dogs transplanted on various protocols at our institution. We therefore believe that chronic GVHD exists in the dog. This proposal aims to systematically develop a clinically relevant, logistically feasible, reproducible canine model of chronic GVHD. Such a model would be enormously useful in gaining biological and mechanistic insights into chronic GVHD and in rapidly testing and optimizing treatment approaches before moving to clinical trials. Ultimately, our goal is to produce a novel animal model to fill a major unmet scientific need and to facilitate research into chronic GVHD. If successful, we believe that such a model would be widely useful in studying and improving treatments for blood cancers (NCI), non-malignant blood disorders (NHLBI), and potentially solid-organ transplantation and tolerance (NIDDK, NIAID).

描述(申请人提供)：异基因造血细胞移植(HCT)越来越广泛地用于治疗血癌和非恶性血液疾病(如遗传性贫血和免疫缺陷)，并作为促进实体器官移植的平台。然而，移植物抗宿主病(GVHD)是HCT的主要并发症，由供者免疫细胞对正常宿主组织的反应引起。移植物抗宿主病有两种形式：急性和慢性。在预防和治疗急性移植物抗宿主病方面取得了实质性进展。相比之下，慢性移植物抗宿主病仍然是导致疾病和死亡的主要原因，也是长期接受高血球移植的幸存者生活质量的主要决定因素。与急性GVHD相比，慢性GVHD在生物学水平上仍然知之甚少，设计新的有效治疗方法的努力几乎一致失败。因此，缺乏治疗慢性移植物抗宿主病的有效方法限制了同种异体血细胞移植的应用和成功。几十年来，在防治慢性GVHD方面缺乏进展，原因有几个。其中最主要的是缺乏相关的临床前动物模型。已经描述了几种慢性GVHD的小鼠模型，但每一种模型都存在严重的局限性，未能反映人类疾病的关键方面。尽管进行了广泛的研究，但这些模型并没有导致慢性GVHD的新方法的转化。由于没有临床前手段来研究慢性移植物抗宿主病的生物学和快速筛选治疗方法，新药在人类身上的第三阶段临床试验一直令人一致失望。因此，迫切需要新的和临床相关的慢性移植物抗宿主病动物模型。从最早的现场调查开始，狗就被广泛用作同种异体红细胞移植的模式生物。与小鼠模型相比，犬模型具有许多优势，包括更大的遗传多样性，更接近人类免疫学，以及成功将新的GVHD治疗方法转化为临床的长期记录。然而，到目前为止，慢性GVHD还没有在狗身上进行建模或研究。我们观察了在我们机构按不同方案移植的单个犬慢性移植物抗宿主病的病理和临床证据。因此，我们认为狗体内存在慢性移植物抗宿主病。这项建议旨在系统地发展一种临床相关的、逻辑上可行的、可重复性的慢性移植物抗宿主病犬模型。这种模型在获得对慢性GVHD的生物学和机械学见解以及在进入临床试验之前快速测试和优化治疗方法方面将非常有用。最终，我们的目标是创造一种新的动物模型，以满足一个重大的未得到满足的科学需求，并促进慢性GVHD的研究。如果成功，我们相信这样的模型将广泛用于研究和改进血癌(NCI)、非恶性血液病(NHLBI)的治疗，以及潜在的实体器官移植和耐受(NIDDK，NIAID)。