An Animal Model of Chronic Oral Inflammation for Stem Cell-Based Therapy

描述（由申请人提供）：我们建议开发一种自然发生的猫模型，通过给予基于干细胞的再生药物来解决慢性粘膜炎症。间充质干细胞（MSCs）在治疗免疫介导的炎症性疾病的临床试验中得到了广泛的应用。然而，缺乏研究MSC治疗这些疾病的相关动物模型继续限制了这种治疗选择的发展。这些疾病通常表现为口腔黏膜的损害。口腔黏膜丘疹褶皱和溃疡样溃疡是克罗恩病的共同特征，25-70%的移植物抗宿主病（GVHD）患者存在自身免疫性膀胱溃疡性口腔病变，寻常型天疱疮除了影响患者的皮肤外，还会影响患者的口腔黏膜。虽然这些疾病的病因多种多样，但所有这些慢性和衰弱性粘膜疾病都是不适当的

DESCRIPTION (provided by applicant): We propose to develop a naturally-occurring feline model for the resolution of chronic mucosal inflammation through the administration of stem cell-based regenerative medicine. Mesenchymal stem cells (MSCs) are being investigated in several clinical trials for the treatment of immune- mediated inflammatory diseases. However, a lack of relevant animal models for studying MSC therapy in these disorders continues to limit the development of this therapeutic option. These disorders frequently manifest themselves as lesions of the oral mucosa. Papular folds and aphthous-like ulcers in the oral mucosa are a common feature of Crohn's disease, auto-immune vesci ulo-ulcerative oral lesions are present in 25-70% of patients with graft-versus-host disease (GVHD) and pemphigus vulgaris can affect the patient's oral mucosa in addition to their skin. While these diseases arise from a diverse etiology, all of these chronic and debilitating mucosal diseases are the result of an inappropriate immune response to auto-antigens. Feline chronic gingivostomatitis (FCGS) is a naturally occurring, painful and debilitating, immune-mediated inflammatory disorder with a possible multi-factorial etiology. The disease symptoms are also the result of an inappropriate immune response to antigens that manifests itself in severe oral ulcerative and proliferative mucosal lesions and in systemic signs of inflammation. Exciting preliminary data demonstrate that systemic MSC administration in cats with FCGS results in disease remission and normalization of systemic biomarkers of inflammation. This disease model is ideal to study MSC-immune system interactions as both the oral cavity and local/systemic immune system are readily imaged and sampled. Our overarching hypothesis is that this novel, naturally occurring animal disease can be used as a model to study MSC treatment of immune-mediated inflammatory disorders. The proposed study will enhance our fundamental understanding of MSC-based immunomodulation, the systemic impact of MSC therapy in the context of a naturally occurring immune- mediated inflammatory disease, and generate novel regenerative therapies. To develop this animal model we will characterize the surface protein phenotype of the MSCs using flow cytometry. We will then fully elucidate the migration and homing of technetium-labeled MSCs following transplantation into cats afflicted with CGS via scintigraphy. In conjunction to tracking the MSCs we will monitor changes in blood leukocytes, lymph node cell subsets, serum proteins, and salivary proteins to determine the best practices to treat mucosal lesions. In addition to biomarkers, regular examinations by blinded, board certified veterinary dentists will monitor changes in clinical symptoms of inflammation in the oral mucosa. We will also compare the pathology of human and feline oral lesions to determine their histological and immunohistochemical similarities. Finally, we will determine if humans with chronic oral inflammatory diseases share the alterations in measurable biomarkers, including circulating lymphocyte subsets and serum proteins, noted in cats with FCGS.