Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i>
Extensively drug-resistant tuberculosis (XDR-TB) is a public health concern as drug resistance is outpacing the drug development pipeline. Alternative immunotherapeutic approaches are needed. Peripheral blood mononuclear cells (PBMCs) were isolated from pre-XDR/XDR-TB (<i>n</i> = 25) pat...
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2025-02-01
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| author | Rolanda Londt Lynn Semple Aliasgar Esmail Anil Pooran Richard Meldau Malika Davids Keertan Dheda Michele Tomasicchio |
| author_facet | Rolanda Londt Lynn Semple Aliasgar Esmail Anil Pooran Richard Meldau Malika Davids Keertan Dheda Michele Tomasicchio |
| author_sort | Rolanda Londt |
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| description | Extensively drug-resistant tuberculosis (XDR-TB) is a public health concern as drug resistance is outpacing the drug development pipeline. Alternative immunotherapeutic approaches are needed. Peripheral blood mononuclear cells (PBMCs) were isolated from pre-XDR/XDR-TB (<i>n</i> = 25) patients and LTBI (<i>n</i> = 18) participants. Thereafter, monocytic-derived dendritic cells (mo-DCs) were co-cultured with <i>M. tb</i> antigens, with/without a maturation cocktail (interferon-γ, interferon-α, CD40L, IL-1β, and TLR3 and TLR7/8 agonists). Two peptide pools were evaluated: (i) an ECAT peptide pool (ESAT6, CFP10, Ag85B, and TB10.4 peptides) and (ii) a PE/PPE peptide pool. Sonicated lysate of the <i>M. tb</i> HN878 strain served as a control. Mo-DCs were assessed for DC maturation markers, Th1 cytokines, and the ability of the DC-primed PBMCs to restrict the growth of <i>M. tb</i>-infected monocyte-derived macrophages. In pre-XDR/XDR-TB, mo-DCs matured with <i>M. tb</i> antigens (ECAT or PE/PPE peptide pool, or HN878 lysate) + cocktail, compared to mo-DCs matured with <i>M. tb</i> antigens only, showed higher upregulation of co-stimulatory molecules and IL-12p70 (<i>p</i> < 0.001 for both comparisons). The matured mo-DCs had enhanced antigen-specific CD8<sup>+</sup> T-cell responses to ESAT-6 (<i>p</i> = 0.05) and Ag85B (<i>p</i> = 0.03). Containment was higher with mo-DCs matured with the PE/PPE peptide pool cocktail versus mo-DCs matured with the PE/PPE peptide pool (<i>p</i> = 0.0002). Mo-DCs matured with the PE/PPE peptide pool + cocktail achieved better containment than the ECAT peptide pool + cocktail [50%, (IQR:39–75) versus 46%, (IQR:15–62); <i>p</i> = 0.02]. In patients with pre-XDR/XDR-TB, an effector response primed by mo-DCs matured with an ECAT or PE/PPE peptide pool + cocktail was capable of restricting the growth of <i>M. tb</i> in vitro. |
| format | Article |
| id | doaj-art-25795f32343c4149adf5f2183f1c40f5 |
| institution | DOAJ |
| issn | 2076-2607 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-25795f32343c4149adf5f2183f1c40f52025-08-20T03:12:15ZengMDPI AGMicroorganisms2076-26072025-02-0113234510.3390/microorganisms13020345Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i>Rolanda Londt0Lynn Semple1Aliasgar Esmail2Anil Pooran3Richard Meldau4Malika Davids5Keertan Dheda6Michele Tomasicchio7Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine, University of Cape Town and UCT Lung Institute, Cape Town 7925, South AfricaExtensively drug-resistant tuberculosis (XDR-TB) is a public health concern as drug resistance is outpacing the drug development pipeline. Alternative immunotherapeutic approaches are needed. Peripheral blood mononuclear cells (PBMCs) were isolated from pre-XDR/XDR-TB (<i>n</i> = 25) patients and LTBI (<i>n</i> = 18) participants. Thereafter, monocytic-derived dendritic cells (mo-DCs) were co-cultured with <i>M. tb</i> antigens, with/without a maturation cocktail (interferon-γ, interferon-α, CD40L, IL-1β, and TLR3 and TLR7/8 agonists). Two peptide pools were evaluated: (i) an ECAT peptide pool (ESAT6, CFP10, Ag85B, and TB10.4 peptides) and (ii) a PE/PPE peptide pool. Sonicated lysate of the <i>M. tb</i> HN878 strain served as a control. Mo-DCs were assessed for DC maturation markers, Th1 cytokines, and the ability of the DC-primed PBMCs to restrict the growth of <i>M. tb</i>-infected monocyte-derived macrophages. In pre-XDR/XDR-TB, mo-DCs matured with <i>M. tb</i> antigens (ECAT or PE/PPE peptide pool, or HN878 lysate) + cocktail, compared to mo-DCs matured with <i>M. tb</i> antigens only, showed higher upregulation of co-stimulatory molecules and IL-12p70 (<i>p</i> < 0.001 for both comparisons). The matured mo-DCs had enhanced antigen-specific CD8<sup>+</sup> T-cell responses to ESAT-6 (<i>p</i> = 0.05) and Ag85B (<i>p</i> = 0.03). Containment was higher with mo-DCs matured with the PE/PPE peptide pool cocktail versus mo-DCs matured with the PE/PPE peptide pool (<i>p</i> = 0.0002). Mo-DCs matured with the PE/PPE peptide pool + cocktail achieved better containment than the ECAT peptide pool + cocktail [50%, (IQR:39–75) versus 46%, (IQR:15–62); <i>p</i> = 0.02]. In patients with pre-XDR/XDR-TB, an effector response primed by mo-DCs matured with an ECAT or PE/PPE peptide pool + cocktail was capable of restricting the growth of <i>M. tb</i> in vitro.https://www.mdpi.com/2076-2607/13/2/345dendritic cell vaccinepre-extensively drug-resistant tuberculosisextensively drug-resistant tuberculosisdrug-resistant tuberculosiscellular vaccinemonocytic-derived dendritic cells |
| spellingShingle | Rolanda Londt Lynn Semple Aliasgar Esmail Anil Pooran Richard Meldau Malika Davids Keertan Dheda Michele Tomasicchio Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> Microorganisms dendritic cell vaccine pre-extensively drug-resistant tuberculosis extensively drug-resistant tuberculosis drug-resistant tuberculosis cellular vaccine monocytic-derived dendritic cells |
| title | Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> |
| title_full | Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> |
| title_fullStr | Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> |
| title_full_unstemmed | Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> |
| title_short | Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to <i>Mycobacterium tuberculosis</i> |
| title_sort | autologous human dendritic cells from xdr tb patients polarize a th1 response which is bactericidal to i mycobacterium tuberculosis i |
| topic | dendritic cell vaccine pre-extensively drug-resistant tuberculosis extensively drug-resistant tuberculosis drug-resistant tuberculosis cellular vaccine monocytic-derived dendritic cells |
| url | https://www.mdpi.com/2076-2607/13/2/345 |
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