Belyakov I M, Moss B, Strober W, Berzofsky J A
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4512-7. doi: 10.1073/pnas.96.8.4512.
Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.
克服成年人群中对痘苗病毒预先存在的免疫力是开发其他方面有效的重组痘苗疫苗的关键要求。基于我们的观察，即皮下接种痘苗仅在全身淋巴组织而非黏膜部位诱导对痘苗的细胞免疫和抗体免疫，我们推测黏膜免疫系统对痘苗仍保持幼稚状态，因此尽管先前接触过痘苗，仍适合用重组痘苗载体进行免疫。我们发现，用表达HIV gp160的重组痘苗对已免疫痘苗的BALB/c小鼠进行黏膜免疫，可诱导特异性血清抗体和强烈的HIV特异性细胞毒性T淋巴细胞反应。这些反应不仅发生在黏膜组织，也发生在全身淋巴组织，而在这些情况下全身免疫无效。在此背景下，直肠内免疫比鼻内免疫更有效。通过黏膜途径用第二剂重组痘苗加强免疫也更有效。在黏膜部位共同给予IL-12可增强全身HIV特异性细胞毒性T淋巴细胞反应。这些结果还证明了黏膜免疫系统与全身免疫系统的独立分隔以及淋巴细胞在它们之间的不对称迁移。这种规避先前痘苗免疫的方法可能有助于在因天花疫苗接种而对痘苗具有预先存在免疫力的大量人群中诱导针对传染病和癌症的保护性免疫。
