Mucosal Humoral Immune Response to SIVmac239∆nef Vaccination and Vaginal Challenge.
Mucosal Humoral Immune Response to SIVmac239∆nef Vaccination and Vaginal Challenge.
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DOI：
10.4049/jimmunol.1500156
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Haase AT
中科院分区：
文献类型：
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作者：
Zeng M;Smith AJ;Shang L;Wietgrefe SW;Voss JE;Carlis JV;Li Q;Piatak M Jr;Lifson JD;Johnson RP;Haase AT
减毒活疫苗，如nef基因缺失的SIV（SIVmac 239 Δnef），在HIV-1传播给女性的SIV-恒河猴（RM）模型中，对随后的野生型（WT）SIV阴道攻击提供了最稳健的保护。因此，识别这种保护的相关性可以设计有效的HIV-1疫苗。一种这样的保护阴道免受攻击的攻击前相关物最近被鉴定为具有三个组分的系统：1）与病毒包膜糖蛋白三聚体gp 41（gp 41 t）反应的IgG抗体; 2）由外宫颈和阴道中粘膜下层和异位三级淋巴滤泡中的浆细胞产生;和3）集中在病毒通过覆盖上皮中的新生儿Fc受体进入的路径上。我们现在检查阴道激发后该系统的抗体组分的粘膜产生。我们发现，阴道的挑战立即elaborated显着增加浆细胞不仅在女性生殖道，但也在其他粘膜网站，这些增加与低，但持续复制粘膜网站。我们描述了阴道异位卵泡，其结构和功能组织像次级淋巴器官中的卵泡，并为女性生殖道上皮在促进抗体产生、亲和力成熟和类转换重组中的关键作用提供了推论证据。因此，疫苗接种进入女性生殖道中的上皮免疫系统轴，以响应暴露于粘膜病原体。设计模仿这种系统的策略可以促进有效的HIV-1疫苗的开发。
Live attenuated vaccines such as SIV with a deleted nef gene (SIVmac239Δnef) have provided the most robust protection against subsequent vaginal challenge with wild type (WT) SIV in the SIV-rhesus macaque (RM) model of HIV-1 transmission to women. Hence, identifying correlates of this protection could enable design of an effective HIV-1 vaccine. One such pre-challenge correlate of protection from vaginal challenge has recently been identified as a system with three components: 1) IgG antibodies reacting with the viral envelope glycoprotein, trimeric gp41 (gp41t); 2) produced by plasma cells in the submucosa and ectopic tertiary lymphoid follicles in the ectocervix and vagina; and 3) concentrated on the path of virus entry by the neonatal Fc receptor in the overlying epithelium. We now examine the mucosal production of antibody component of this system post-vaginal challenge. We show that vaginal challenge immediately elicits striking increases in plasma cells not only in the female reproductive tract but also at other mucosal sites, and that these increases correlate with low but persistent replication at mucosal sites. We describe vaginal ectopic follicles that are structurally and functionally organized like follicles in secondary lymphoid organs, and provide inferential evidence for a key role of the female reproductive tract epithelium in facilitating antibody production, affinity maturation and class switch recombination. Vaccination thus accesses an epithelial-immune system axis in the female reproductive tract to respond to exposure to mucosal pathogens. Designing strategies to mimic this system could advance development of an effective HIV-1 vaccine.