The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection

Kindler, Vincent; Sappino, André‐Pascal; Grau, Georges E.; Piguet, P F; Vassalli, Pierre

doi:10.1016/0092-8674(89)90676-4

Cited by 1,172 publications

(732 citation statements)

References 33 publications

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“…Together, this indicates that lactoferrin could enhance generation of mycobacterial antigen responses towards the T H 1 phenotype. In addition to a more rapid upregulation in IFN-γ mRNA response, lactoferrin admixed to the BCG vaccine generated higher levels of TNF-α, which has the potential to synergize with IFN-γ to direct development of the protective granulomatous response during MTB infection [55][56][57]. Granulomas are the protective mechanism enabling containment of MTB infection and prolonging host survival [55,[58][59][60].…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Hwang

Wilk

Budnicka

et al. 2007

Vaccine

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant; IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-γ and IL-6, but only limited changes to proinflammatory mediators TNF-α or IL-1β from BCG stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology.

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Section: Discussionmentioning

confidence: 99%

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Hwang

Wilk

Budnicka

et al. 2007

Vaccine

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“…In animal models, TNFα plays an essential role in host defense against tuberculosis (TB), including granuloma formation and containment of disease [79][80][81]. It is therefore not surprising that TNFα blockade causes reactivation of TB in animal models [82].…”

Section: Mechanism Of Treatment-limiting Adverse Responsesmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

255

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…The amount of AFB within the various organs was significantly higher in the TNF␣-knockout mice compared with wild-type mice. TNF messenger RNA can be detected in granulomas in bacillus Calmette-Guérin (BCG)-infected mice (23). Furthermore, injection of anti-TNF IgG antibody significantly reduces the development of granulomas, which are mycobactericidal and play a major role in bacterial containment and elimination.…”

Section: Tnf␣ Inhibition and Sepsismentioning

confidence: 99%