1. Boaz Arzi^a,
2. Emily Mills-Ko^b,
3. Frank J.M. Verstraete^a,
4. Amir Kol^b,
5. Naomi J. Walker^b,
6. Megan R. Badgley^c,
7. Nasim Fazel^d,
8. William J. Murphy^d,
9. Natalia Vapniarsky^e and
10. Dori L. Borjesson^b

Author Affiliations

1. ^aDepartment of Surgical and Radiological Sciences, University of California, Davis, Davis, California, USA
2. ^bDepartment of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
3. ^cWilliam R. Pritchard Veterinary Medical Teaching Hospital, University of California, Davis, Davis, California, USA
4. ^dDepartment of Dermatology, School of Medicine, University of California, Davis, Davis, California, USA
5. ^eDepartment of Biomedical Engineering, University of California, Davis, Davis, California, USA
6. Correspondence: Boaz Arzi, D.V.M., Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, One Shield Avenue, Davis, California 95616, USA. Telephone: 530-752-2470; E-Mail: barzi@ucdavis.edu

• Received June 12, 2015.
• Accepted September 28, 2015.
• Published online before print November 18, 2015.

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 (CD8^lo) cells were 100% responsive to ASC therapy, whereas cats with >15% CD8^lo cells were nonresponders. The relative absence of CD8^lo 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.