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

描述（由申请人提供）：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vs.-由供体免疫细胞对正常宿主组织的反应引起的宿主病（GVHD）是HCT的主要并发症。GVHD有两种形式：急性和慢性。在预防和治疗急性形式的GVHD方面取得了实质性进展。相反，慢性GVHD仍然是HCT长期存活者的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知之甚少，并且设计新颖和有效治疗的努力几乎都不成功。因此，缺乏治疗慢性GVHD的有效方法限制了同种异体HCT的应用和成功。 有几个因素导致了数十年来对慢性GVHD缺乏进展。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，但每种模型都有严重的局限性，不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GVHD的生物学和快速筛选治疗方法，人类新药的III期临床试验一直令人失望。因此，迫切需要新的和临床相关的慢性GVHD动物模型。 从该领域研究的最早期起，犬已被广泛用作同种异体HCT的模式生物。犬模型提供了许多优于鼠模型的优势，包括更大的遗传多样性，更接近人类免疫学，以及将新型GVHD治疗方法成功转化为临床的长期记录。然而，慢性GVHD尚未在犬中建模或研究。 我们已经观察到慢性GVHD的病理和临床证据在个别狗移植在我们的机构的各种协议。因此，我们认为慢性GVHD存在于狗中。该提案旨在系统地开发一种临床相关的、后勤可行的、可重复的慢性GVHD犬模型。这样的模型在获得慢性GVHD的生物学和机制方面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，我们的目标是产生一种新的动物模型，以填补一个主要的未满足的科学需求，并促进慢性GVHD的研究。如果成功，我们相信这种模型将广泛用于研究和改善血癌（NCI），非恶性血液病（NHLBI）和潜在的实体器官移植和耐受（NIDDK，NIAID）的治疗。

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).