中科院武汉病毒研究所胡勤学学科组在HIV免疫应答研究中取得新进展,相关结果作为封面论文于2013年8月发表在免疫学领域期刊The Journal of Immunology上。
HIV疫苗的研究经历近三十年,但目前仍没有有效的HIV疫苗问世。HIV包膜糖蛋白(Env)是预防性疫苗的首选靶标,然而,多种形式的Env均不能诱导机体产生高水平的广谱中和能力。增强抗原免疫原性的手段之一是选用合适的佐剂。胡勤学学科组研究了三个质粒型细胞因子:pAPRIL、pCCL19和pCCL28,作为分子佐剂对HIV疫苗候选抗原gp140的免疫增强作用及其潜在分子机制。
研究结果表明,pCCL19和pCCL28均能够显著增强系统性以及黏膜部位的抗原特异性的抗体水平,而pAPRIL则未表现出明显的免疫增强作用。此外,血清和黏膜部位增强的抗体水平具有更好的中和同源以及异源HIV的能力,其中和能力分别与血清中抗原特异性的IgG以及黏膜部位抗原特异性IgA水平正相关。进一步的实验表明,pCCL19和pCCL28能够平衡地增强Th1/Th2细胞免疫应答水平以及增加免疫小鼠直肠黏膜表面的IgA+细胞数目。pCCL19能够招募CCR7+DC细胞迁移至肠系膜淋巴结以及招募CCR7+DC细胞和CCR7+T细胞迁移至脾脏;而pCCL28则能够招募CCR10+B细胞迁移至脾脏和肠系膜淋巴结。以上结果表明,pCCL19和pCCL28能够增强HIVEnv特异性的系统性以及黏膜部位的抗体应答水平和T细胞免疫应答水平,这种增强效果可能与它们能够招募特定免疫细胞迁移至二级淋巴器官和黏膜组织相关。
以上发现对定向诱导针对HIV抗原的免疫应答特别是黏膜免疫应答具有指导意义。该项研究受到科技部和国家自然科学基金委等的支持。(生物谷 Bioon.com)
生物谷推荐的英文摘要
J. Immunol. doi: 10.4049/?jimmunol.1300120
CCL19 and CCL28 Augment Mucosal and Systemic Immune Responses to HIV-1 gp140 by Mobilizing Responsive Immunocytes into Secondary Lymph Nodes and Mucosal Tissue
Kai Hu*,†, Sukun Luo*,†, Lina Tong*, Xin Huang*,†, Wei Jin*,†, Wenjie Huang*, Tao Du*,†, Yan Yan*,†, Siyi He*,†, George E. Griffin‡, Robin J. Shattock§ and Qinxue Hu*,‡
Induction of broad and potent neutralizing Abs at the mucosal portals of entry remains a primary goal for most vaccines against mucosally acquired viral infections. Selection of appropriate adjuvants capable of promoting both systemic and mucosal responses will be crucial for the development of effective immunization strategies. In this study, we investigated whether plasmid codelivery of cytokines APRIL, CCL19, or CCL28 can enhance Ag-induced immune responses to HIV-1 gp140. Our results demonstrated that pCCL19 and pCCL28, but not pAPRIL, significantly enhanced Ag-specific systemic and mucosal Ab responses. gp140-specific Abs in serum enhanced by pCCL19 or pCCL28 were broadly distributed across all four IgG subclasses, of which IgG1 was predominant. The enhanced systemic and mucosal Abs showed increased neutralizing activity against both homologous and heterologous HIV-1, and potency correlated with gp140-specific serum IgG and vaginal IgA levels. Measurement of gp140-specific cytokines produced by splenocytes demonstrated that pCCL19 and pCCL28 augmented balanced Th1/Th2 responses. pCCL19 and pCCL28 also increased IgA+ cells in colorectal mucosal tissue. pCCL19 codelivery resulted in an increase of CCR7+ CD11c+ cells in mesenteric lymph nodes and both CCR7+ CD11c+ cells and CCR7+ CD3e+ cells in spleen, whereas pCCL28 codelivery resulted in an augment of CCR10+ CD19+ cells in both spleen and mesenteric lymph nodes. Together, our data indicate that pCCL19 and pCCL28 can enhance HIV-1 envelope–specific systemic and mucosal Ab responses, as well as T cell responses. Such enhancements appear to be associated with mobilization of responsive immunocytes into secondary lymphoid organs and mucosal tissues through interactions with corresponding receptors.