Failure to induce enhanced protection against tuberculosis by increasing T‐cell‐dependent interferon‐γ generation

Leal, Irene S.; Smedegård, Birgitte; Andersen, Peter; Appelberg, Rui

doi:10.1046/j.1365-2567.2001.01305.x

Cited by 68 publications

(54 citation statements)

References 29 publications

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“…Finally, there are also implications in the design of vaccines which are frequently screened based on their ability to induce strong IFN-␥ responses. In this regard, we have shown that IFN-␥ may interfere with the development of protective immune responses to tuberculosis during vaccination with mycobacterial proteins (21).…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

et al. 2005

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Infection by virulent Mycobacterium avium caused progressive severe lymphopenia in C57BL/6 mice due to increased apoptosis rates. T-cell depletion did not occur in gamma interferon (IFN-␥)-deficient mice which showed increased T-cell numbers and proliferation; in contrast, deficiency in nitric oxide synthase 2 did not prevent T-cell loss. Although T-cell loss was IFN-␥ dependent, expression of the IFN-␥ receptor on T cells was not required for depletion. Similarly, while T-cell loss was optimal if the T cells expressed IFN-␥, CD8؉ T-cell depletion could occur in the absence of T-cell-derived IFN-␥. Depletion did not require that the T cells be specific for mycobacterial antigen and was not affected by deficiencies in the tumor necrosis factor receptors p55 or p75, the Fas receptor (CD95), or the respiratory burst enzymes or by forced expression of bcl-2 in hematopoietic cells.

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Section: Discussionmentioning

confidence: 99%

Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

et al. 2005

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“…However, it should be noted that increasing the expression of endogenous IFN-␥ does not necessarily lead to enhanced protection from mycobacterial infection (50). Quite to the contrary, IFN-␥ and NOS2 have also been implicated in modulating the local cellular response to mycobacterial infection by down-regulating lymphocyte activation and by driving T cells into apoptosis, which may ultimately lead to a deteriorated protective immune response (41,51,52).…”

Section: Discussionmentioning

confidence: 99%

The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis

Hölscher

Rückerl

et al. 2005

The Journal of Immunology

252

305

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IL-12 is a potent inducer of IFN-γ production and promotes a protective cell-mediated immune response after Mycobacterium tuberculosis infection. Recently, the IL-12-related cytokine IL-27 was discovered, and WSX-1 was identified as one component of the IL-27R complex. To determine the functional significance of IL-27/WSX-1 during tuberculosis, we analyzed the course of infection and the immune response in WSX-1-KO mice after aerosol infection with M. tuberculosis. In the absence of WSX-1, an increased production of the proinflammatory cytokines TNF and IL-12p40 resulted in elevated CD4+ T cell activation and IFN-γ production, which enhanced macrophage effector functions and reduced bacterial loads. This is the first occasion of a selectively gene-deficient mouse strain showing higher levels of protective immunity against M. tuberculosis infection than wild-type mice. However, a concomitantly increased chronic inflammatory response also accelerated death of infected WSX-1-KO mice. In vitro, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation. In conclusion, IL-27 both prevents optimal antimycobacterial protection and limits the pathological sequelae of chronic inflammation.

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“…Induction of Th1 responses may not be relevant, since M. tuberculosis rapidly does this anyway. Furthermore, in experimental animals, manipulations that increase the Th1 response still further than is achieved by BCG vaccine alone, do not provide any additional protection [29,30]. Enough Th1 is enough.…”

Section: Implications For Vaccine Designmentioning

confidence: 99%

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

Rook

Dheda

Zumla

2005

Vaccine

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Tuberculosis vaccine candidates are entering clinical studies in areas where BCG fails. This is a high risk strategy. We suggest that geographical variation in the efficacy of BCG is related to the presence in developing countries of a cross-reactive background Th2-like response, probably attributable to exposure of mother and infant to helminths and environmental mycobacteria. Such Th2-like activity can stop M. tuberculosis from being pushed into a latent state by the Th1 response, impair bactericidal functions and cause toxicity of TNF-α and pulmonary fibrosis. A successful vaccine, rather than driving a Th1 response, might need to suppress this pre-existing subversive Th2-like component.

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Failure to induce enhanced protection against tuberculosis by increasing T‐cell‐dependent interferon‐γ generation

Cited by 68 publications

References 29 publications

Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

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