Increased Frequency of Myeloid-derived Suppressor Cells during Active Tuberculosis and after Recent<i>Mycobacterium tuberculosis</i>Infection Suppresses T-Cell Function

Plessis, Nelita du; Loebenberg, Laurianne; Kriel, Magdalena; Groote-Bidlingmaier, Florian von; Ribechini, Eliana; Loxton, André G.; Helden, Paul D. van; Lutz, Manfred B.; Walzl, Gerhard

doi:10.1164/rccm.201302-0249oc

Cited by 148 publications

(242 citation statements)

References 69 publications

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“…136 Mesenchymal stromal cells (MSC) are nonhematopoietic progenitor cells with immunomodulatory and antibacterial properties, [137][138] that improve immune responses and lung pathology in human and murine TB. [139][140] Another immunotherapeutic approach involves modulation of immune regulatory cells, specifically myeloid-derived suppressor cells (MDSC) [141][142] MDSC are increased in TB, display T-cell immunosuppressive properties, [143][144][145] and harbour Mtb, suggesting that MDSC-targeting strategies should also be considered in TB HDT design. The promise of use T-cell therapy, with or without T-cell receptor (TCR) manipulations to increase affinity for antigen has shown promise for CMV treatment, and could be beneficial in TB.…”

Section: Cellular Therapymentioning

confidence: 99%

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tiberi

Plessis

Walzl

et al. 2018

The Lancet Infectious Diseases

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308

275

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Tuberculosis (TB) remains the top killer from an infectious globally causing an estimated 1.674.000 million deaths worldwide. In 2016, WHO estimates 600.000 cases of rifampicin-resistant TB of which 490.000 had multidrug-resistant (MDR) and less than half of them survive after receiving currently recommended WHO treatment regimens, illustrating weaknesses in current treatment approaches. We review progress and advances in the development of new and repurposed TB drugs, treatment trials and host-directed therapies. Updates are provided on phase 3 trials of the new compounds bedaquiline, delamanid, pretomanid; phase 2 trials of sutezolid, SQ-109, LCB01-0371, PBTZ-169; and five new drugs in phase 1 development. Approved or repurposed drugs undergoing further testing are rifampicin, rifapentine, clofazimine, and linezolid. Update on ongoing clinical trials, which aim to shorten TB treatment and improve treatment outcome is given. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR-TB, and five antimicrobial drug candidates are in phase 1 (Q203, TBI-166, OPC-167832, GSK 070, TBA-7371) and 5 in pre-clinical studies. Specific issues of safety and toxicity; drug-drug interactions; Therapeutic Drug Monitoring are reviewed. A wide range of candidate host-directed therapies (HDTs) and immune-based treatments are being investigated to accelerate the eradication of M.tb infection and for use as adjunctive therapy in shortening duration of treatment, preventing permanent lung injury and improving treatment outcomes of MDR-TB. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented.5

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Section: Cellular Therapymentioning

confidence: 99%

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tiberi

Plessis

Walzl

et al. 2018

The Lancet Infectious Diseases

Self Cite

308

275

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show abstract

“…MDSC-like cells have previously been described during TB disease in susceptible mouse models (24,37) and early during disease in TB patients (38). Both in experimental models and humans, accumulation of MDSCs is associated with increased TB disease severity, and depletion of MDSCs reverses TB disease severity in Mtb-susceptible mice (24,38). Consistent with these studies, our data show that IL-17 depletion results in increased HIF1α-expressing myeloid cells and accumulation of large numbers of MDSCs within TB granulomas, coinciding with increased disease severity and suppression of T cell responses.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

Domingo-Gonzalez¹,

Das²,

Griffiths³

et al. 2017

JCI Insight

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“…In this regard, expansion and activation of MDSC were described to be involved in the establishment of chronic viral infections (45). MDSC also were reported to be induced in individuals infected with Mycobacterium tuberculosis and are suggested to contribute to the inability of the host to eradicate the pathogen because they impair protective T cell responses (46). MDSC accumulate in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa and correlate with disease activity (27).…”

Section: Discussionmentioning

confidence: 99%

A Major Role for Myeloid-Derived Suppressor Cells and a Minor Role for Regulatory T Cells in Immunosuppression during Staphylococcus aureus Infection

Tebartz

Horst

Sparwasser

et al. 2015

The Journal of Immunology

138

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Staphylococcus aureus can cause difficult-to-treat chronic infections. We recently reported that S. aureus chronic infection was associated with a profound inhibition of T cell responses. In this study, we investigated the mechanisms responsible for the suppression of T cell responses during chronic S. aureus infection. Using in vitro coculture systems, as well as in vivo adoptive transfer of CFSE-labeled OT-II cells, we demonstrated the presence of immunosuppressive mechanisms in splenocytes of S. aureus–infected mice that inhibited the response of OT-II cells to cognate antigenic stimulation. Immunosuppression was IL-10/TGF-β independent but required cell–cell proximity. Using DEREG and Foxp3gfp mice, we demonstrated that CD4+CD25+Foxp3+ regulatory T cells contributed, but only to a minor degree, to bystander immunosuppression. Neither regulatory B cells nor tolerogenic dendritic cells contributed to immunosuppression. Instead, we found a significant expansion of granulocytic (CD11b+Ly6G+Ly6Clow) and monocytic (CD11b+Ly6G−Ly6Chigh) myeloid-derived suppressor cells (MDSC) in chronically infected mice, which exerted a strong immunosuppressive effect on T cell responses. Splenocytes of S. aureus–infected mice lost most of their suppressive activity after the in vivo depletion of MDSC by treatment with gemcitabine. Furthermore, a robust negative correlation was observed between the degree of T cell inhibition and the number of MDSC. An increase in the numbers of MDSC in S. aureus–infected mice by adoptive transfer caused a significant exacerbation of infection. In summary, our results indicate that expansion of MDSC and, to a minor degree, of regulatory T cells in S. aureus–infected mice may create an immunosuppressive environment that sustains chronic infection.

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Increased Frequency of Myeloid-derived Suppressor Cells during Active Tuberculosis and after RecentMycobacterium tuberculosisInfection Suppresses T-Cell Function

Cited by 148 publications

References 69 publications

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

A Major Role for Myeloid-Derived Suppressor Cells and a Minor Role for Regulatory T Cells in Immunosuppression during Staphylococcus aureus Infection

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