Autologous Human Dendritic Cells from XDR-TB Patients Polarize a Th1 Response Which Is Bactericidal to

Overview

Journal Microorganisms

Specialty Microbiology

Date 2025 Feb 26

PMID 40005712

Authors

Rolanda Londt

Lynn Semple

Aliasgar Esmail

Anil Pooran

Richard Meldau

Malika Davids

Keertan Dheda

Michele Tomasicchio

Affiliations

Soon will be listed here.

Abstract

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 ( = 25) patients and LTBI ( = 18) participants. Thereafter, monocytic-derived dendritic cells (mo-DCs) were co-cultured with 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 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 -infected monocyte-derived macrophages. In pre-XDR/XDR-TB, mo-DCs matured with antigens (ECAT or PE/PPE peptide pool, or HN878 lysate) + cocktail, compared to mo-DCs matured with antigens only, showed higher upregulation of co-stimulatory molecules and IL-12p70 ( < 0.001 for both comparisons). The matured mo-DCs had enhanced antigen-specific CD8 T-cell responses to ESAT-6 ( = 0.05) and Ag85B ( = 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 ( = 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); = 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 in vitro.

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