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

用于干细胞治疗的慢性口腔炎症动物模型

• 批准号: 8747852
• 负责人: DORI L. BORJESSON
• 金额: $ 15.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8747852
• 关键词: Adipose tissue; Affect; Animal Diseases; Animal Model; Antigens; Autologous; B-Lymphocytes; Biological Markers; Blinded; CD4/CD8 ratio procedure; Cell Therapy; Cells; Chronic; Clinical; Clinical Treatment; Clinical Trials; Crohn' s disease; Data; Dentists; Disease; Disease Outcome; Disease model; Disease remission; Etiology; Family Felidae; Felis catus; Flow Cytometry; Future; Gingiva; Health; Histology; Home environment; Homing; Human; Human Pathology; IL17 gene; Image; Immune; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Investigation; Label; Lesion; Leukocytes; Lymphocyte; Lymphocyte Subset; Measurable; Measures; Mediating; Membrane Proteins; Mesenchymal Stem Cells; Modeling; Monitor; Mucositis; Nitric Oxide; Oral; Oral cavity; Oral mucous membrane structure; Pain; Pathology; Patients; Pemphigus Vulgaris; Phenotype; Radionuclide Imaging; Regenerative Medicine; Regulatory T-Lymphocyte; Resolution; Salivary; Salivary Proteins; Sampling; Serum Proteins; Skin; Stem cells; Stomatitis; Surface; Symptoms; Systemic disease; T-Lymphocyte; T-Lymphocyte Subsets; Technetium; Testing; Tissues; Transplantation; Tumor Necrosis Factor-alpha; Ulcer; Work; base; clinical remission; cytokine; graft vs host disease; human disease; immunoregulation; improved; indexing; lymph nodes; meetings; migration; neutrophil; novel; oral lesion; public health relevance; regenerative therapy; response; stem cell therapy; therapeutic development; therapy development

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.

描述（由申请人提供）：我们建议开发一种自然出现的猫科动物模型，以通过基于干细胞的再生医学来解决慢性粘膜炎症。在几项临床试验中，正在研究间充质干细胞（MSC），以治疗免疫介导的炎症性疾病。但是，缺乏研究这些疾病中MSC治疗的相关动物模型继续限制这种治疗选择的发展。这些疾病经常表现为口腔粘膜病变。口腔粘膜中的丘疹褶皱和类似圆锥形的溃疡是克罗恩病的常见特征，在25-70％的患有嫁接的抗抗菌病（GVHD）患者中，有25-70％的自动免疫性口服疾病（GVHD）患者以及Pemphigus dulgaris可能会影响他们的患者或其他乳muccosa muccosa brincea。尽管这些疾病源于多样化的病因，但所有这些慢性和衰弱的粘膜疾病都是对自身抗原的不当免疫反应的结果。猫慢性牙龈炎（FCGS）是一种天然发生的，痛苦和令人衰弱的，免疫介导的炎症疾病，可能具有多因素病因。疾病症状也是对抗原的不当免疫反应的结果，该反应表现出严重的口腔溃疡性和增殖性粘膜病变以及全身性炎症迹象。令人兴奋的初步数据表明，具有FCGS的猫的全身MSC给药会导致疾病缓解和炎症的全身生物标志物的正常化。由于口腔和局部/全身免疫系统都很容易成像和采样，因此该疾病模型是研究MSC-免疫系统相互作用的理想选择。我们的总体假设是，这种新颖的自然发生的动物疾病可以用作研究免疫介导的炎症性疾病的MSC治疗的模型。拟议的研究将增强我们对基于MSC的免疫调节的基本了解，MSC治疗在天然发生的免疫介导的炎症性疾病的背景下的系统性影响，并产生新的再生疗法。为了开发这种动物模型，我们将使用流式细胞术表征MSC的表面蛋白表型。然后，我们将通过Scintraphy移植到CGS中的猫后，充分阐明Technetium标记的MSC的迁移和归宿。结合跟踪MSC，我们将监视血清细胞，淋巴结细胞亚群，血清蛋白和唾液蛋白的变化，以确定治疗粘膜病变的最佳实践。除生物标志物外，经过盲目认证的兽医牙医的定期检查还将监测口腔粘膜炎症临床症状的变化。我们还将比较人类和猫口腔病变的病理学，以确定其组织学和免疫组织化学相似性。最后，我们将确定患有慢性口腔炎症性疾病的人是否共享可测量的生物标志物的改变，包括循环淋巴细胞亚群和血清蛋白，在患有FCGS的猫中指出。