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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：同种异体造血细胞移植（HCT）越来越广泛地用于治疗血液癌和非恶性血液疾病（例如遗传性贫血和免疫缺陷），并作为促进固体轨道移植物的平台。然而，由供体免疫细胞与正常宿主组织的反应引起的移植物vs.-host疾病（GVHD）是HCT的主要并发症。 GVHD以两种形式出现：急性和慢性。在预防和治疗GVHD的急性形式方面取得了重大进展。相反，在HCT的长期幸存者中，慢性GVHD仍然是疾病和死亡的主要原因，也是生活质量的主要决定因素。与急性GVHD相反，慢性GVHD在生物学水平上仍然很糟糕，而设计新颖有效治疗的努力几乎均无成功。因此，缺乏有效的慢性GVHD方法限制了同种异体HCT的应用和成功。数十年来，针对慢性GVHD缺乏进展，有几个因素。其中的主要是缺乏该疾病的相关临床前动物模型。已经描述了几种慢性GVHD的小鼠模型，但每个小鼠都有严重的局限性，并且无法反映人类疾病的关键方面。尽管进行了广泛的研究，但这些模型并未导致慢性GVHD的新方法的翻译。没有临床前的手段来研究慢性GVHD的生物学和快速筛查治疗方法，人类新型药物的III期临床试验令人失望。因此，迫切需要慢性GVHD的新的和临床相关的动物模型。从该领域的最早研究开始，该狗已被广泛用作同种异体HCT的模型生物。犬种模型比鼠模型具有许多优势，包括更大的遗传多样性，与人类免疫学更紧密的类比以及新型GVHD治疗方法成功翻译为诊所的长期记录。但是，到目前为止，尚未在狗中对慢性GVHD进行建模或研究。我们已经观察到在我们机构的各种方案中移植的个体狗中慢性GVHD的病理和临床证据。因此，我们认为狗中存在慢性GVHD。该建议旨在系统地开发出临床上相关的，可行的，可再现的慢性GVHD犬模型。这种模型将在获得慢性GVHD的生物学和机理见解以及在进行临床试验之前迅速测试和优化治疗方法方面非常有用。最终，我们的目标是生产一种新型的动物模型来满足主要的未满足的科学需求，并促进对慢性GVHD的研究。如果成功，我们认为这种模型将在研究和改善血液癌（NCI），非恶性血液疾病（NHLBI）以及潜在的固体器官移植和耐受性（NIDDK，NIAID）方面广泛有用。