Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.
Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats.
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DOI：
10.5966/sctm.2015-0127
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发表时间：
2016-01
影响因子：
6
通讯作者：
Borjesson DL
中科院分区：
文献类型：
--
作者：
Arzi B;Mills-Ko E;Verstraete FJ;Kol A;Walker NJ;Badgley MR;Fazel N;Murphy WJ;Vapniarsky N;Borjesson DL
采用新鲜的、自体的、脂肪来源的间充质干细胞(ASCs)治疗猫科慢性牙周炎。猫接受自体ASCs，并评估免疫调节效果。对治疗有反应的五只猫也表现出全身免疫调节。对ASC治疗的反应仅见于拥有15%CD8lo细胞的猫，这表明相对缺乏CD8lo细胞可能是治疗反应的一个生物标志物。间充质干细胞(MSCs)具有强大的免疫调节特性，有望成为治疗免疫介导性和炎症性疾病的一种有效方法。在这项研究中，我们研究了新鲜的、自体的、脂肪来源的间充质干细胞(ASCs)在猫慢性牙周炎(FCGS)中的应用。FCGS是一种慢性、衰弱、特发性的口腔黏膜炎症性疾病。9只患有难治性FCGS的猫参加了这项初步研究。每只猫每只接受2次静脉注射2000万个自体ASCs，间隔1个月。分别在第一次注射ASC前和注射后6个月进行口腔活检。在治疗后0、1、3和6个月检测血液免疫细胞亚群、血清蛋白和细胞因子水平，以评估免疫调节效果。9只猫中有7只完成了这项研究。5只猫在治疗后临床完全缓解(n=3)或临床显著改善(n=2)。有两只猫没有反应。对治疗有反应的猫也表现出全身免疫调节，表现为循环中CD8+T细胞数量减少，CD_4/CD_8比值正常化，中性粒细胞计数下降，干扰素-γ和白介素1β浓度下降，血清IL-6和肿瘤坏死因子-α浓度暂时升高。临床完全缓解后(随访6~24个月)无临床复发。在这项研究中，拥有15%细胞毒性CD8 T细胞且CD8(CD8lo)细胞低表达的猫对ASC治疗有100%的反应，而拥有15%CD8lo细胞的猫则无反应。CD8lo细胞的相对缺失可能是预测ASC治疗反应的一个生物标志物，并可能有助于阐明FCGS的发病机制，以及ASCs减轻口腔炎症和影响T细胞表型的机制。这项研究首次证明了新鲜的、自体的、脂肪来源的干细胞系统治疗猫的一种自然发生的慢性炎症性疾病的安全性和有效性。结果表明，这种疗法在大多数猫的临床和组织学上完全缓解或降低了临床疾病的严重性和免疫调节。这项研究还确定了一个潜在有用的生物标记物，可以决定患者的登记情况，并阐明免疫调节机制。作为一种自然发生的动物模型，FCGS也为治疗人类口腔炎症性疾病提供了一个潜在的可翻译治疗的战略平台。
The use of fresh, autologous, adipose-derived mesenchymal stem cells (ASCs) was studied for treatment of feline chronic gingivostomatitis. Cats received autologous ASCs, and immunomodulatory effects were assessed. The five cats that responded to treatment also exhibited systemic immunomodulation. Response to ASC therapy was seen only in cats with <15% CD8lo cells, suggesting relative absence of CD8lo cells may be a biomarker of treatment response. 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. 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.