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.

Public Health Relevance

The oral lesions associated with chronic inflammatory diseases such as Crohn's disease, graft-versus-host disease, and pemphigus vulgaris are painful and debilitating. We have discovered a novel cell-based therapy that results in clinical cure in cats suffering from chronic oral inflammatory lesions that mimic those seen in human beings. The purpose of this study is to fully develop this relevant, large animal model for stem cell- based regenerative medicine to improve human health and develop therapies for patients for chronic inflammatory diseases.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Lumelsky, Nadya L
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University of California Davis
United States
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Clark, Kaitlin C; Fierro, Fernando A; Ko, Emily Mills et al. (2017) Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome. Stem Cell Res Ther 8:69
Arzi, Boaz; Clark, Kaitlin C; Sundaram, Ayswarya et al. (2017) Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis. Stem Cells Transl Med 6:1710-1722
Arzi, Boaz; Mills-Ko, Emily; Verstraete, Frank J M et al. (2016) Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats. Stem Cells Transl Med 5:75-86
Kol, Amir; Arzi, Boaz; Athanasiou, Kyriacos A et al. (2015) Companion animals: Translational scientist's new best friends. Sci Transl Med 7:308ps21