Epstein S L, Lo C Y, Misplon J A, Lawson C M, Hendrickson B A, Max E E, Subbarao K
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
J Immunol. 1997 Feb 1;158(3):1222-30.
Immunity that is cross-protective between different influenza A virus subtypes (termed heterosubtypic immunity) can be demonstrated readily in some animals but only rarely in humans. Induction of heterosubtypic immunity in humans by vaccines would provide public health benefit, perhaps offering some protection against pandemics or other new influenza A strains. Therefore, we studied mechanisms mediating heterosubtypic immunity in mice. Immunization with either A/H1N1 or A/H3N2 virus protected mice against mortality following heterosubtypic challenge while providing modest reductions in lung virus titers. No cross-protection was seen with distantly related type B influenza virus. Depletion of CD4+ or CD8+ T cells or both around the time of challenge had no significant effect on survival, indicating that these cells are not required at the effector stage. beta2-microglobulin knockout mice could be protected readily against heterosubtypic challenge, confirming that class I-restricted T cells are not required. In beta2-microglobulin -/- mice, depletion of CD4+ T cells partially abrogated heterosubtypic immunity, showing that they play a role in these mice. Passive transfer of Abs to naive recipients protected against subsequent challenge with homologous but not heterosubtypic virus. Because a role for secretory Abs has been suggested, we studied dependence on the J chain, which is required for polymeric Ig receptor-mediated IgA transport. J chain knockout mice were readily protected by heterosubtypic immunity, indicating that polymeric Ig receptor-mediated transport is not required. Better understanding of heterosubtypic immunity should be valuable in analyzing new vaccines, including peptide and DNA vaccines, intended to induce broadly cross-reactive immunity.
在不同甲型流感病毒亚型之间具有交叉保护作用的免疫（称为异源亚型免疫）在某些动物中很容易得到证实，但在人类中却很少见。通过疫苗在人类中诱导异源亚型免疫将为公共卫生带来益处，或许能提供一些针对大流行或其他新型甲型流感病毒株的保护。因此，我们研究了介导小鼠异源亚型免疫的机制。用A/H1N1或A/H3N2病毒免疫小鼠，可使其在受到异源亚型攻击后免受死亡，同时肺部病毒滴度略有降低。与远缘相关的乙型流感病毒未见交叉保护作用。在攻击前后耗竭CD4⁺或CD8⁺T细胞或两者，对生存没有显著影响，这表明在效应阶段不需要这些细胞。β2-微球蛋白基因敲除小鼠很容易受到异源亚型攻击的保护，这证实了不需要I类限制性T细胞。在β2-微球蛋白基因敲除小鼠中，耗竭CD4⁺T细胞部分消除了异源亚型免疫，表明它们在这些小鼠中发挥作用。将抗体被动转移给未免疫的受体可保护其免受同源病毒而非异源亚型病毒的后续攻击。由于有人提出分泌性抗体起作用，我们研究了对J链的依赖性，J链是聚合免疫球蛋白受体介导的IgA转运所必需的。J链基因敲除小鼠很容易受到异源亚型免疫的保护，这表明不需要聚合免疫球蛋白受体介导的转运。更好地理解异源亚型免疫对于分析旨在诱导广泛交叉反应性免疫的新疫苗（包括肽疫苗和DNA疫苗）应该是有价值的。
