Generation of human MHC (HLA-A11/DR1) transgenic mice for vaccine evaluation

• Published in: Human vaccines & immunotherapeutics 2016-03, Vol.12 (3), p.829-836
• Main Authors: Zeng, Yang, Gao, Tongtong, Zhao, Guangyu, Jiang, Yuting, Yang, Yi, Yu, Hong, Kou, Zhihua, Lone, Yuchun, Sun, Shihui, Zhou, Yusen
• Format: Article
• Language: English
• Subjects: AIDS Vaccines - administration & dosage; AIDS Vaccines - immunology; Animals; Crosses, Genetic; Drug Evaluation, Preclinical - methods; Hepatitis B Antibodies - blood; Hepatitis B Vaccines - administration & dosage; Hepatitis B Vaccines - immunology; HIV Antibodies - blood; HLA; HLA-A11 Antigen - genetics; HLA-A11/DR1 transgenic mice; HLA-DR1 Antigen - genetics; Homozygote; Humans; Interferon-gamma - secretion; MHC; MHC-restricted epitopes; Mice, Transgenic; Models, Animal; Research Papers; T-Lymphocytes - immunology; Vaccine
• ISSN: 2164-5515; 2164-554X
• DOI: 10.1080/21645515.2015.1103405

The rapid occurrence of emerging infectious diseases demonstrates an urgent need for a new preclinical experimental model that reliably replicates human immune responses. Here, a new homozygous humanized human leukocyte antigen (HLA)-A11/DR1 transgenic mouse (HLA-A11 +/+ /DR01 +/+ /H-2-β 2m −/− /IAβ −/− ) was generated by crossing HLA-A11 transgenic (Tg) mice with HLA-A2 +/+ /DR01 +/+ /H-2-β 2m −/− /IAβ −/− mice. The HLA-A11-restricted immune response of this mouse model was then examined. HLA-A11 Tg mice expressing a chimeric major histocompatibility complex (MHC) molecule comprising the α1, α2, and β 2 m domains of human HLA-A11 and the α3 transmembrane and cytoplasmic domains of murine H-2D b were generated. The correct integration of HLA-A11 and HLA-DR1 into the genome of the HLA-A11/DR1 Tg mice (which lacked the expression of endogenous H-2-I/II molecules) was then confirmed. Immunizing mice with a recombinant HBV vaccine or a recombinant HIV-1 protein resulted in the generation of IFN-γ-producing cytotoxic T lymphocyte (CTL) and antigen-specific antibodies. The HLA-A11-restricted CTL response was directed at HLA immunodominant epitopes. These mice represent a versatile animal model for studying the immunogenicity of HLA CTL epitopes in the absence of a murine MHC response. The established animal model will also be useful for evaluating and optimizing T cell-based vaccines and for studying differences in antigen processing between mice and humans.