title: Development of a humanized HLA-A2.1/DP4 transgenic mouse model and the use of this model to map HLA-DP4-restricted epitopes of HBV envelope protein.
abstract: A new homozygous humanized transgenic mouse strain, HLA-A2.1(+/+)HLA-DP4(+/+) hCD4(+/+)mCD4(-/-)IAβ(-/-)β2m(-/-) (HLA-A2/DP4), was obtained by crossing the previously characterized HLA-A2(+/+)β2m(-/-) (A2) mouse and our previously created HLA-DP4(+/+) hCD4(+/+)mCD4(-/-)IAβ(-/-) (DP4) mouse. We confirmed that the transgenes (HLA-A2, HLA-DP4, hCD4) inherited from the parental A2 and DP4 mice are functional in the HLA-A2/DP4 mice. After immunizing HLA-A2/DP4 mice with a hepatitis B DNA vaccine, hepatitis B virus-specific antibodies, HLA-A2-restricted and HLA-DP4-restricted responses were observed to be similar to those in naturally infected humans. Therefore, the present study demonstrated that HLA-A2/DP4 transgenic mice can faithfully mimic human cellular responses. Furthermore, we reported four new HLA-DP4-restricted epitopes derived from HBsAg that were identified in both vaccinated HLA-A2/DP4 mice and HLA-DP4-positive human individuals. The HLA-A2/DP4 mouse model is a promising preclinical animal model carrying alleles present to more than a quarter of the human population. This model should facilitate the identification of novel HLA-A2- and HLA-DP4-restricted epitopes and vaccine development as well as the characterization of HLA-DP4-restricted responses against infection in humans.
authors.affiliation: State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Ru
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xiao
authors.forename: Anthony
authors.initials: A
authors.lastname: Pajot
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Kou
authors.forename: Shihui
authors.initials: S
authors.lastname: Sun
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhao
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lone
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018604:Epitope Mapping / Q000379:methods*; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D006720:Homozygote; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D019444:Vaccines, DNA / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D015789:HLA-A2 Antigen; D059868:HLA-DP beta-Chains; C056284:HLA-DPw4 antigen; D006514:Hepatitis B Surface Antigens; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014765:Viral Vaccines