Alexander J, Oseroff C, Sidney J, Wentworth P, Keogh E, Hermanson G, Chisari F V, Kubo R T, Grey H M, Sette A
Cytel Corporation, San Diego, CA 92121, USA.
J Immunol. 1997 Nov 15;159(10):4753-61.
Transgenic mice expressing chimeric human (alpha1 and alpha2 HLA-A11 domains) and murine (alpha3, transmembrane, and cytoplasmic H-2Kb domains) class I molecules were derived. These mice were used as a model system to study the immunogenicity of human CTL epitopes and also to examine the aspects of Ag processing differences of mice vs man. Immunization of these mice with seven known HLA-A11-restricted CTL epitopes emulsified in IFA resulted in vigorous specific CTL responses. A larger panel of 45 A11-binding peptides was used to examine the relationship between immunogenicity in the HLA-A11/Kb transgenic mice and HLA-A11 binding capacity. Twenty-one of 28 (75%) peptides with high binding affinities (50% inhibitory concentration (IC50), 2-50 nM) and 7 of 13 (54%) intermediate binding peptides (IC50, 50-500 nM range) were immunogenic. In parallel, 19 of these peptides were used for in vitro primary immunizations of PBMC derived from HLA-A11 healthy human donors. It was found that 8 of 8 peptides that were able to elicit CTL in primary human in vitro cultures were also immunogenic in HLA-A11/Kb mice. Finally, HLA-A11/Kb transgenic mice were found to generate an A11/Kb restricted CTL response following immunization with influenza virus A/PR/8/34, suggesting that, at least to some extent, A11 epitopes are generated by transgenic mice as a result of natural in vivo processing and presentation.
构建了表达嵌合型人（α1和α2 HLA - A11结构域）和鼠（α3、跨膜和胞质H - 2Kb结构域）I类分子的转基因小鼠。这些小鼠被用作模型系统来研究人CTL表位的免疫原性，并考察小鼠与人在抗原加工差异方面的情况。用在不完全弗氏佐剂中乳化的7种已知HLA - A11限制性CTL表位免疫这些小鼠，可引发强烈的特异性CTL反应。使用一组更大的45种A11结合肽来考察HLA - A11/Kb转基因小鼠中的免疫原性与HLA - A11结合能力之间的关系。28种高结合亲和力肽（50%抑制浓度（IC50），2 - 50 nM）中有21种（75%）以及13种中等结合肽（IC50，50 - 500 nM范围）中有7种（54%）具有免疫原性。同时，其中19种肽用于对来自HLA - A11健康人类供体的外周血单个核细胞进行体外初次免疫。结果发现，在原代人体外培养中能够引发CTL的8种肽在HLA - A11/Kb小鼠中也具有免疫原性。最后，发现用甲型流感病毒A/PR/8/34免疫后，HLA - A11/Kb转基因小鼠产生了A11/Kb限制性CTL反应，这表明至少在一定程度上，A11表位是转基因小鼠在体内自然加工和呈递的结果。
