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

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.

doi:10.5966/sctm.2015-0127

Cited by 107 publications

(209 citation statements)

References 66 publications

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“…Our previous work demonstrated that cats with FCGS have increased percentages of blood CD81 T cells with a resultant decreased CD4/ CD8 T cell ratio [1]. The cats in this study generally recapitulated this phenotype (Fig.…”

Section: Allogenic Asc Administration Did Not Predictably Alter Bloodsupporting

confidence: 78%

“…E) as measured by BrdU incorporation. There was no difference in lymphocyte suppressive ability between the three SPF allogenic ASC lines used in this study and the autologous ASC lines used in the previous study .…”

Section: Resultsmentioning

confidence: 52%

“…We found that systemically administered, fresh, allogeneic ASCs were safe and could achieve cure, or a substantial reduction in the inflammation associated with FCGS, resulting in regeneration of the oral mucosa and improved clinical signs. However, although patient numbers are low, the efficacy of allogeneic ASCs may be lower as compared to autologous ASC therapy for the treatment of FCGS [57% (4/7) cats in current study, compared to 71% (5/7 cats) in the autologous study] . This potential reduction in efficacy for allogeneic ASCs was particularly noted in cats with the most severe inflammation, as measured by blood neutrophil number, serum globulin concentration and serum IFNγ concentration.…”

Section: Discussionmentioning

confidence: 71%

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Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Arzi

Clark

Sundaram

et al. 2017

Stem Cells Translational Medicine

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115

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Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune‐mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose‐derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti‐fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine 2017;6:1710–1722

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Section: Allogenic Asc Administration Did Not Predictably Alter Bloodsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 71%

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Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Arzi

Clark

Sundaram

et al. 2017

Stem Cells Translational Medicine

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115

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“…Cats are a particularly important translational model for a number of diseases that are similar in cats and humans, including FIV (HIV) [61], T cell-mediated oral mucosa inflammation [24], chronic renal failure [29], asthma [25], chronic enteropathy [26], and osteoarthritis. The goal of this work was to profile feline ASCs and directly compare their phenotypic, cellular, and immunomodulatory profiles with human ASCs to deepen our understanding of MSC-based therapies as we move towards mechanism-of-action studies in animals and people.…”

Section: Discussionmentioning

confidence: 99%

Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome

Clark

Fierro

et al. 2017

Stem Cell Res Ther

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BackgroundAdipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular, and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs, with an emphasis on their immunomodulatory capacity and transcriptome.MethodsHuman and feline ASCs were evaluated for phenotype, immunomodulatory profile, and transcriptome. Additionally, transwells were used to determine the role of cell-cell contact in ASC-mediated inhibition of lymphocyte proliferation in both humans and cats.ResultsSimilar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity, and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen-activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern, including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta, and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of three unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis; 2) cell adhesion; 3) response to oxidative stress; and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs.ConclusionsFindings suggest that feline ASCs modulate lymphocyte proliferation using soluble mediators that mirror the human ASC secretion pattern. Uninduced feline ASCs have similar gene expression profiles to uninduced human ASCs, as revealed by transcriptome analysis. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0528-z) contains supplementary material, which is available to authorized users.

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“…The contribution of Th17 cells and the cytokine IL-17 in the pathogenesis of some infectious diseases in some of the non-rodent animals has been described (116, 121). However, most of these studies are observational, and cells were isolated from peripheral blood samples only.…”

Section: Comparison Of Treg and Th17 Response In Humans Rodents Andmentioning

confidence: 99%

Interplay of Regulatory T Cell and Th17 Cells during Infectious Diseases in Humans and Animals

Sehrawat

Rouse

2017

Front. Immunol.

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It is now clear that the outcome of an inflammatory process caused by infections depends on the balance of responses by several components of the immune system. Of particular relevance is the interplay between regulatory T cells (Tregs) and CD4+ T cells that produce IL-17 (Th17 cells) during immunoinflammatory events. In addition to discussing studies done in mice to highlight some unresolved issues in the biology of these cells, we emphasize the need to include outbred animals and humans in analyses. Achieving a balance between Treg and Th17 cells responses represents a powerful approach to control events during immunity and immunopathology.

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

Cited by 107 publications

References 66 publications

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome

Interplay of Regulatory T Cell and Th17 Cells during Infectious Diseases in Humans and Animals

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