TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions
TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions
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DOI：
10.1128/jvi.01391-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Rouse, Barry T.
中科院分区：
文献类型：
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作者：
Reddy, Pradeep B. J.;Schreiber, Taylor H.;Rouse, Barry T.
单纯疱疹病毒 1 (HSV-1) 眼部感染会导致角膜出现慢性免疫炎症反应，该反应主要由 CD4(+) T 细胞精心策划。因此，针对促炎性 CD4(+) T 细胞或增加调节其功能的细胞的代表性是一种相关的治疗策略。在本报告中，我们证明在单一疗法无效的情况下，可以通过组合方法实现有效的治疗控制。我们使用方便且高效的单克隆抗体 (MAb) 方法和 MAbT25 来扩增表达肿瘤坏死因子受体超家族成员 25 (TNFRSF25) 的细胞。在幼稚动物中，这些细胞主要是 Foxp3 阳性调节 T 细胞。在初次 HSV 感染之前或同时进行 MAbT25 治疗是减轻随后基质性角膜炎病变严重程度的有效手段。然而，如果在感染后 6 天进行 MAbT25 治疗则无效，因为它会扩增也表达 TNFRSF25 的促炎效应 T 细胞。因此，MAbT25 程序与半乳糖凝集素 9 (Gal-9) 相结合，这种方法会损害参与组织损伤的 T 细胞的活性。与其中一种治疗相比，联合疗法提供了高效的病变控制。联合疗法的有益结果归因于调节性 T 细胞群的扩张，这些细胞还表达了进入炎症部位所需的激活标记物，例如 CD103。此外，负责协调组织损伤的产生CD4（+）γ干扰素的效应T细胞显着减少。除了基质角膜炎（人类失明的重要原因）之外，我们描述的方法还具有控制多种炎症性疾病的潜在应用。
Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4(+) T cells. Hence, targeting proinflammatory CD4(+) T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naive animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4(+) gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.