Treatment With Anakinra, a Recombinant IL-1 Receptor Antagonist, Unlikely to Induce Lasting Remission in Patients With CGD Colitis

Hahn, Katherine; Ho, Nancy T.; Yockey, Lynne; Kreuzberg, Samantha A.; Daub, Janine; Rump, Amy; Marciano, Beatriz E.; Quezado, Martha; Malech, Harry L.; Holland, Steven M.; Heller, Theo; Zerbe, Christa S.

doi:10.1038/ajg.2015.135

Cited by 51 publications

(26 citation statements)

References 7 publications

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“…It has been suggested that the increased inflammasome activity in CGD patients is associated with the susceptibility to colitis . Treatment with the IL‐1R antagonist anakinra improved the colitis in two CGD patients, but no such beneficial effect is observed in other patients (Kuijpers et al. unpublished).…”

Section: Cytotoxicity: a Role For Cytokines?mentioning

confidence: 99%

How neutrophils kill fungi

Gazendam

Geer

Roos

et al. 2016

Immunological Reviews

123

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Neutrophils play a critical role in the prevention of invasive fungal infections. Whereas mouse studies have demonstrated the role of various neutrophil pathogen recognition receptors (PRRs), signal transduction pathways, and cytotoxicity in the murine antifungal immune response, much less is known about the killing of fungi by human neutrophils. Recently, novel primary immunodeficiencies have been identified in patients with a susceptibility to fungal infections. These human 'knock-out' neutrophils expand our knowledge to understand the role of PRRs and signaling in human fungal killing. From the studies with these patients it is becoming clear that neutrophils employ fundamentally distinct mechanisms to kill Candida albicans or Aspergillus fumigatus.

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Section: Cytotoxicity: a Role For Cytokines?mentioning

confidence: 99%

How neutrophils kill fungi

Gazendam

Geer

Roos

et al. 2016

Immunological Reviews

123

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“…For example, the monogenic immunodeficiency chronic granulomatous disease (CGD) caused by mutation in genes that code for the phagocyte NADPH oxidase and resulting in aberrant production of reactive oxygen species (ROS) is associated not only with increased susceptibility to infection but also with sterile inflammation in organs like the gastrointestinal tract, urogenital tract, and lungs (43–45). Normal levels of NADPH oxidase-derived ROS are likely to control inflammation (46), while dysregulation, causing for example, colitis, is responsive to IL-1 blockade (47, 48). Hence, CGD presents with a phenotype comprising increased susceptibility to infection due to deficiency in the innate immune system, in turn associated with autoinflammatory traits.…”

Section: The Expanding Disease Spectrum Of Autoinflammatory Diseasesmentioning

confidence: 99%

Toward an Inclusive, Congruent, and Precise Definition of Autoinflammatory Diseases

et al. 2017

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Autoinflammatory disease was introduced as a concept in 1999, demarcating an entirely new group of diseases in clinical, immunological, and conceptual terms. During recent years, the preconditions for the definition of autoinflammatory conditions have changed. This includes the recent discovery of a number of monogenic autoinflammatory conditions with complex phenotypes that combine autoinflammation with defects of the adaptive and/or innate immune system, resulting in the occurrence of infection, autoimmunity, and/or uncontrolled hyperinflammation in addition to autoinflammation. Further, there are strong indications that classical IL-1-driven autoinflammatory diseases are associated with activation of adaptive immunity. As suggested by this development, we are of the opinion that an all-encompassing definition of autoinflammatory diseases should regard autoinflammatory conditions and innate dysregulation as inseparable and integral parts of the immune system as a whole. Hence, in this article, we try to advance the conceptual understanding of autoinflammatory disease by, proposing a modification of the definition by Daniel Kastner et al., which allows for a congruent and precise description of conditions that expand the immunological spectrum of autoinflammatory disease.

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“…4,7 Because some experimental data have shown the potential benefit of IL-1 blockade with the receptor antagonist anakinra in patients with CGD, attempts have been made to treat patients with CGD presenting with inflammatory manifestations with the IL-1b receptor antagonist (anakinra), with mixed results. 6,7 Targeting the same pathway, we decided to evaluate the benefit of rapamycin treatment on CGD-related inflammation. Because rapamycin has been shown to act as an autophagy inducer through mTORC1 inhibition, 10 we reasoned that restoring the autophagy defect in patients with CGD might contribute to reversion of the biological inflammation observed in patients with CGD.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Because IL-1b blockade decreases the activation of inflammasome and restores autophagy in mice with CGD in vivo and in human cells in vitro, clinicians have been tempted to treat patients with CGD with the IL-1b receptor antagonist anakinra, with mixed results. 6,7 Rapamycin is a macrolide naturally produced by the bacterium Streptomyces hygroscopicus, which was initially developed as an antifungal agent. 8 However, rapamycin, a potent mammalian target of rapamycin (mTOR) inhibitor, has mainly been used in clinical care for its immunosuppressive properties.…”

mentioning

confidence: 99%