title: Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.
abstract: Mesenchymal stem cells (MSCs) are a promising therapy for immune-mediated and inflammatory disorders, because of their potent immunomodulatory properties. In this study, we investigated the use of fresh, autologous, adipose-derived MSCs (ASCs) for feline chronic gingivostomatitis (FCGS), a chronic, debilitating, idiopathic, oral mucosal inflammatory disease. Nine cats with refractory FCGS were enrolled in this pilot study. Each cat received 2 intravenous injections of 20 million autologous ASCs, 1 month apart. Oral biopsies were taken before and at 6 months after the first ASC injection. Blood immune cell subsets, serum protein, and cytokine levels were measured at 0, 1, 3, and 6 months after treatment to assess immunomodulatory effects. Seven of the 9 cats completed the study. Five cats responded to treatment by either complete clinical remission (n=3) or substantial clinical improvement (n=2). Two cats were nonresponders. Cats that responded to treatment also exhibited systemic immunomodulation demonstrated by decreased numbers of circulating CD8+ T cells, a normalization of the CD4/CD8 ratio, decreased neutrophil counts, and interferon-γ and interleukin (IL)-1β concentration, and a temporary increase in serum IL-6 and tumor necrosis factor-α concentration. No clinical recurrence has occurred following complete clinical remission (follow-up of 6-24 months). In this study, cats with <15% cytotoxic CD8 T cells with low expression of CD8 (CD8lo) cells were 100% responsive to ASC therapy, whereas cats with >15% CD8lo cells were nonresponders. The relative absence of CD8lo cells may be a biomarker to predict response to ASC therapy, and may shed light on pathogenesis of FCGS and mechanisms by which ASCs decrease oral inflammation and affect T-cell phenotype.
  
  
  CONCLUSIONS
  This study is the first to demonstrate the safety and efficacy of fresh, autologous, adipose-derived stem cell systemic therapy for a naturally occurring, chronic inflammatory disease in cats. The findings demonstrate that this therapy resulted in complete clinical and histological resolution or reduction in clinical disease severity and immune modulation in most cats. This study also identified a potentially useful biomarker that could dictate patient enrollment and shed light on immune modulation mechanism. As a naturally occurring animal model, FCGS also provides a strategic platform for potentially translatable therapy for the treatment of human oral inflammatory disease.
authors.affiliation: Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, USA barzi@ucdavis.edu.
authors.forename: Boaz
authors.initials: B
authors.lastname: Arzi
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Mills-Ko
authors.affiliation: Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, USA.
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: Verstraete
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Kol
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Walker
authors.affiliation: William R. Pritchard Veterinary Medical Teaching Hospital, University of California, Davis, Davis, California, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Badgley
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Nasim
authors.initials: N
authors.lastname: Fazel
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Davis, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, California, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vapniarsky
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Dori L
authors.initials: DL
authors.lastname: Borjesson
mesh_terms: D000818:Animals; D064592:Autografts; D002371:Cat Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002415:Cats; D005260:Female; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D013280:Stomatitis / Q000276:immunology / Q000473:pathology / Q000628:therapy / Q000662:veterinary
keywords: Adipose-derived stem cells; Autologous; Cats; Fresh; Gingivostomatitis; Immunomodulation; Oral mucosa