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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.

Ru Z, Xiao W, Pajot A, Kou Z, Sun S, Maillere B, Zhao G, Ojcius DM, Lone YC, Zhou Y - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.

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.

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Related in: MedlinePlus

HBs-specific antibody and proliferative response.(A) The titers of antibody (IgG) from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) against HBs particles and the preS2109–134 peptide were determined using an ELISA assay (Figure 5A). (B) The HLA-DP4-restricted proliferation of CD4+ T cells from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) after stimulation with HBs particles, the previously described HBV DP4 restricted peptide, S181–S192, or the control HLA-DP4-restricted epitope, Mag-3243–258 (Figure 5B).
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pone-0032247-g005: HBs-specific antibody and proliferative response.(A) The titers of antibody (IgG) from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) against HBs particles and the preS2109–134 peptide were determined using an ELISA assay (Figure 5A). (B) The HLA-DP4-restricted proliferation of CD4+ T cells from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) after stimulation with HBs particles, the previously described HBV DP4 restricted peptide, S181–S192, or the control HLA-DP4-restricted epitope, Mag-3243–258 (Figure 5B).

Mentions: To evaluate the behavior of CD4+ T cells in HLA-A2/DP4 mice, we immunized the mice with a hepatitis B virus DNA vaccine, pCMV-S2.S, by intramuscular injection. H2-class II-deficient mice were used as a control [33]. As shown in Figure 5A, HBs protein- and PreS2 antigen-specific antibodies were induced in HLA-A2/DP4 transgenic mice (solid column) at 10 days after the third immunization. Conversely, no antigen-specific antibodies were detected in H2-class II-deficient mice. This result demonstrates that potent humoral responses require the help of CD4+ T cells.


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.

Ru Z, Xiao W, Pajot A, Kou Z, Sun S, Maillere B, Zhao G, Ojcius DM, Lone YC, Zhou Y - PLoS ONE (2012)

HBs-specific antibody and proliferative response.(A) The titers of antibody (IgG) from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) against HBs particles and the preS2109–134 peptide were determined using an ELISA assay (Figure 5A). (B) The HLA-DP4-restricted proliferation of CD4+ T cells from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) after stimulation with HBs particles, the previously described HBV DP4 restricted peptide, S181–S192, or the control HLA-DP4-restricted epitope, Mag-3243–258 (Figure 5B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293898&req=5

pone-0032247-g005: HBs-specific antibody and proliferative response.(A) The titers of antibody (IgG) from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) against HBs particles and the preS2109–134 peptide were determined using an ELISA assay (Figure 5A). (B) The HLA-DP4-restricted proliferation of CD4+ T cells from HLA-A2/DP4 transgenic mice (solid bar) and H-2 class II-deficient mice (hollow bar) after stimulation with HBs particles, the previously described HBV DP4 restricted peptide, S181–S192, or the control HLA-DP4-restricted epitope, Mag-3243–258 (Figure 5B).
Mentions: To evaluate the behavior of CD4+ T cells in HLA-A2/DP4 mice, we immunized the mice with a hepatitis B virus DNA vaccine, pCMV-S2.S, by intramuscular injection. H2-class II-deficient mice were used as a control [33]. As shown in Figure 5A, HBs protein- and PreS2 antigen-specific antibodies were induced in HLA-A2/DP4 transgenic mice (solid column) at 10 days after the third immunization. Conversely, no antigen-specific antibodies were detected in H2-class II-deficient mice. This result demonstrates that potent humoral responses require the help of CD4+ T cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.

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.

Show MeSH
Related in: MedlinePlus