Limits...
Age at Mycobacterium bovis BCG Priming Has Limited Impact on Anti-Tuberculosis Immunity Boosted by Respiratory Mucosal AdHu5Ag85A Immunization in a Murine Model.

Damjanovic D, Khera A, Afkhami S, Lai R, Zganiacz A, Jeyanathan M, Xing Z - PLoS ONE (2015)

Bottom Line: Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB.Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection.However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre and Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans.

No MeSH data available.


Related in: MedlinePlus

Multifunctional profile of CD4+ T cells in the lung of infant and adult mice following BCG immunization.Infant and adult mice were immunized s.c. with BCG and sacrificed at 4 (A), 8 (B), or 16 (C) weeks following immunization. Cells from the lung were stimulated with M.tb CF + crude BCG for 24h or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Average proportions displayed in pie chart are of the CD4 T cells expressing specific cytokine combinations. Absolute numbers of CD4+ T cells in the tissues were calculated and displayed in bar graphs. Results are from one independent experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4476612&req=5

pone.0131175.g002: Multifunctional profile of CD4+ T cells in the lung of infant and adult mice following BCG immunization.Infant and adult mice were immunized s.c. with BCG and sacrificed at 4 (A), 8 (B), or 16 (C) weeks following immunization. Cells from the lung were stimulated with M.tb CF + crude BCG for 24h or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Average proportions displayed in pie chart are of the CD4 T cells expressing specific cytokine combinations. Absolute numbers of CD4+ T cells in the tissues were calculated and displayed in bar graphs. Results are from one independent experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.

Mentions: Since deficient T cell multifunctionality has been reported among infants, primarily in the CD4 T cell compartment [30, 31], next we investigated the multifunctional profile among Ag-specific T cells. Generally, Ag-specific CD4 T cells induced by BCG immunization were positive for a single cytokine regardless of age at immunization (Fig 2). Only a small proportion of Ag-specific CD4 T cells were multifunctional in each group, which remained unchanged throughout the post-immunization period (Fig 2A–2C). Detailed analysis of multi-cytokine expression combinations at 4 weeks post-immunization revealed almost equal proportions of cells that express either IFN-γ or TNF-α or IL-2 in mice immunized as infants, as opposed to predominantly IFN-γ-expressing cells in mice immunized as adults (Fig 2A). Furthermore, mice immunized as infants had significantly increased numbers of IFN-γ, TNF-α, and IL-2 single-cytokine-positive cells and IFN-γ+TNF-α+ cells, compared to mice immunized as adults (Fig 2A). However, multi-cytokine functionality was comparable at 16 weeks post-immunization except for IL-2 single-cytokine-positive cells (Fig 2C). The proportion of IL-2-producing Ag-specific CD4 T cells was significantly increased in mice immunized as adults (Fig 2C). The above data suggest that although there were transient differences in the multi-cytokine functionality of Ag-specific CD4 T cells, such variations became minimal later after immunization.


Age at Mycobacterium bovis BCG Priming Has Limited Impact on Anti-Tuberculosis Immunity Boosted by Respiratory Mucosal AdHu5Ag85A Immunization in a Murine Model.

Damjanovic D, Khera A, Afkhami S, Lai R, Zganiacz A, Jeyanathan M, Xing Z - PLoS ONE (2015)

Multifunctional profile of CD4+ T cells in the lung of infant and adult mice following BCG immunization.Infant and adult mice were immunized s.c. with BCG and sacrificed at 4 (A), 8 (B), or 16 (C) weeks following immunization. Cells from the lung were stimulated with M.tb CF + crude BCG for 24h or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Average proportions displayed in pie chart are of the CD4 T cells expressing specific cytokine combinations. Absolute numbers of CD4+ T cells in the tissues were calculated and displayed in bar graphs. Results are from one independent experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476612&req=5

pone.0131175.g002: Multifunctional profile of CD4+ T cells in the lung of infant and adult mice following BCG immunization.Infant and adult mice were immunized s.c. with BCG and sacrificed at 4 (A), 8 (B), or 16 (C) weeks following immunization. Cells from the lung were stimulated with M.tb CF + crude BCG for 24h or left unstimulated as a control. Cells were stained and analyzed by flow cytometry. Average proportions displayed in pie chart are of the CD4 T cells expressing specific cytokine combinations. Absolute numbers of CD4+ T cells in the tissues were calculated and displayed in bar graphs. Results are from one independent experiment per timepoint, n = 4-5/group/timepoint. Data are expressed as Mean ± SEM. *, p < 0.05; **, p < 0.005; ***, p < 0.0005.
Mentions: Since deficient T cell multifunctionality has been reported among infants, primarily in the CD4 T cell compartment [30, 31], next we investigated the multifunctional profile among Ag-specific T cells. Generally, Ag-specific CD4 T cells induced by BCG immunization were positive for a single cytokine regardless of age at immunization (Fig 2). Only a small proportion of Ag-specific CD4 T cells were multifunctional in each group, which remained unchanged throughout the post-immunization period (Fig 2A–2C). Detailed analysis of multi-cytokine expression combinations at 4 weeks post-immunization revealed almost equal proportions of cells that express either IFN-γ or TNF-α or IL-2 in mice immunized as infants, as opposed to predominantly IFN-γ-expressing cells in mice immunized as adults (Fig 2A). Furthermore, mice immunized as infants had significantly increased numbers of IFN-γ, TNF-α, and IL-2 single-cytokine-positive cells and IFN-γ+TNF-α+ cells, compared to mice immunized as adults (Fig 2A). However, multi-cytokine functionality was comparable at 16 weeks post-immunization except for IL-2 single-cytokine-positive cells (Fig 2C). The proportion of IL-2-producing Ag-specific CD4 T cells was significantly increased in mice immunized as adults (Fig 2C). The above data suggest that although there were transient differences in the multi-cytokine functionality of Ag-specific CD4 T cells, such variations became minimal later after immunization.

Bottom Line: Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB.Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection.However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization.

View Article: PubMed Central - PubMed

Affiliation: McMaster Immunology Research Centre and Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans.

No MeSH data available.


Related in: MedlinePlus