Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease.
Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease.
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MyD88 信号传导缺陷导致小鼠庞贝病中对腺相关病毒载体的抗体反应降低。
DOI：
10.1089/biores.2012.0217
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发表时间：
2012
影响因子：
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通讯作者：
Koeberl,DwightD
中科院分区：
文献类型：
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作者：
Zhang,Ping;Luo,Xiaoyan;Bird,Andrew;Li,Songtao;Koeberl,DwightD
我们之前已经证明，抗体和 T 细胞反应限制了含有通用活性巨细胞病毒增强子/鸡 β-肌动蛋白调节盒 (AAV2/8-CBhGAA) 的腺相关病毒 (AAV) 假型 8 (2/8) 载体治疗小鼠庞贝病的功效。然而，对 AAV2/8-CBhGAA 的先天免疫反应很大程度上未知。在这项研究中，我们研究了 AAV2/8-CBhGAA 的急性免疫反应以及 MyD88/TRIF 信号通路在形成对该载体的适应性免疫反应中的作用。我们在此表明，注射 AAV2/8-CBhGAA 6 小时后，酸性 α-葡萄糖苷酶敲除 (GAAKO) 小鼠的肝脏中 CXCL-1 和 IL-1β 表达出现小幅短暂增加。注射该载体的野生型小鼠对 GAA 产生了强烈的抗体反应。相比之下，MyD88KO 小鼠中的抗 GAA IgG1 反应减弱，并且 TRIFKO 小鼠中的抗 GAA IgG1 反应呈减弱趋势。此外，与野生型肝脏相比，MyD88KO 肝脏中的载体基因组和 GAA 活性显着较高，表明细胞毒性 T 细胞反应减少。重要的是，免疫组织化学检测到 MyD88KO 肝脏中 CD4+T 细胞升高。当过继转移至野生型小鼠时，这些 CD4+T 细胞能够抑制针对 AAV2/8-CBhGAA 的抗体反应，并防止针对 rhGAA 的进一步免疫。我们的研究表明，MyD88 缺陷会导致对 AAV2/8-CBhGAA 有害免疫反应的抑制，这对庞贝病的基因治疗具有重要意义。
We have previously shown that antibody and T cell responses limit the efficacy of an adeno-associated virus (AAV) pseudotype 8 (2/8) vector containing the universally active cytomegalovirus enhancer/chicken β-actin regulatory cassette (AAV2/8-CBhGAA) in treating murine Pompe disease. However, the innate immune responses to AAV2/8-CBhGAA are largely unknown. In this study, we investigated acute immune responses to AAV2/8-CBhGAA and the role of MyD88/TRIF signaling pathway in shaping adaptive immune responses to this vector. We showed here that a small and transient increase in CXCL-1 and IL-1β expression in livers of acid-α-glucosidase knockout (GAAKO) mice 6 h following injection with AAV2/8-CBhGAA. There was a robust antibody response to GAA in wild-type mice injected with this vector. In contrast, the anti-GAA IgG1 response was diminished in MyD88KO mice, and showed a trend toward a decrease in TRIFKO mice. In addition, the vector genome and GAA activity were significantly higher in MyD88KO livers compared with wild-type livers, suggesting reduced cytotoxic T cell responses. Importantly, elevated CD4+T cells were detected by immunohistochemistry in MyD88KO livers. When adoptively transferred to wild-type mice, these CD4+T cells have an ability to suppress antibody responses against AAV2/8-CBhGAA and to prevent further immunization against rhGAA. Our study suggests that the MyD88 deficiency leads to the suppression of deleterious immune responses to AAV2/8-CBhGAA, which has implications for gene therapy in Pompe disease.