Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats

• Published in: Stem cells translational medicine 2016-01, Vol.5 (1), p.75-86
• Main Authors: Arzi, Boaz, Mills-Ko, Emily, Verstraete, Frank J.M., Kol, Amir, Walker, Naomi J., Badgley, Megan R., Fazel, Nasim, Murphy, William J., Vapniarsky, Natalia, Borjesson, Dori L.
• Format: Article
• Language: English
• Subjects: Adipose-derived stem cells; Animal models; Animals; Autografts; Autologous; Biomarkers; Blood; Cat Diseases - immunology; Cat Diseases - pathology; Cat Diseases - therapy; Cats; CD4 antigen; CD8 antigen; Cell growth; Clinical trials; Cytokines; Cytotoxicity; Data analysis; Disease; Enabling Technologies for Cell-Based Clinical Translation; Female; Fresh; Gingivostomatitis; Humans; Immunomodulation; Inflammation; Inflammatory diseases; Interferon; Intravenous administration; Lymphocytes; Lymphocytes T; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stromal Cells - immunology; Mesenchymal Stromal Cells - pathology; Mesenchyme; Mouth; Mucosa; Oral mucosa; Pathogenesis; Phenotypes; Remission; Stem cell transplantation; Stem cells; Stomatitis - immunology; Stomatitis - pathology; Stomatitis - therapy; Stomatitis - veterinary; Veterinary medicine
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2015-0127

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% 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. Significance 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. The use of f