Exogenous Interferon-γ Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients

Armstrong‐James, Darius; Teo, Ian; Shrivastava, Seema; Petrou, Michael F.; Taube, David; Dorling, Anthony; Shaunak, Sunil

doi:10.1111/j.1600-6143.2010.03094.x

Cited by 86 publications

(57 citation statements)

References 44 publications

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“…The results of the present study show that macrophages are alternative sources of IFN-γ produced upon Dectin-1/MyD88 stimulation and ROS signaling, a finding suggesting that early production of IFN-γ by macrophages may occur in the relative absence of innate or adaptive immune cells and, as such, be exploitable in selected immunodeficiencies. Combined with antifungal drug therapy, immunotherapy with IFN-γ represents a treatment option in patients at risk for fungal infections (The International Chronic Granulomatous Disease Cooperative Study Group, 1991, Armstrong-James et al., 2010, Bodasing et al., 2002, Delsing et al., 2014, Dignani et al., 2005, Stevens et al., 2006). The results of the present study increase our understanding of the immunopharmacology of IFN-γ in infection treatment that now includes an activity on DAPK1.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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SummaryDefects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.

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Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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“…As such, it has been implicated as a treatment option in (invasive) fungal infections [20,21]. Moreover, limited evidence suggests that recombinant IFN-γ (rIFN-γ) has a beneficial effect on the outcome of fungal infections in patients with chronic granulomatous disease (CGD) [22], HIV [23-25], leukemia [26,27], and in patients receiving organ transplants [28]. However, it has not been investigated whether rIFN-γ actually enhances the immune response in these patients to explain these beneficial clinical effects.…”

Section: Introductionmentioning

confidence: 99%

Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series

et al. 2014

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BackgroundInvasive fungal infections are very severe infections associated with high mortality rates, despite the availability of new classes of antifungal agents. Based on pathophysiological mechanisms and limited pre-clinical and clinical data, adjunctive immune-stimulatory therapy with interferon-gamma (IFN-γ) may represent a promising candidate to improve outcome of invasive fungal infections by enhancing host defence mechanisms.MethodsIn this open-label, prospective case series, we describe eight patients with invasive Candida and/or Aspergillus infections who were treated with recombinant IFN-γ (rIFN-γ, 100 μg s.c., thrice a week) for 2 weeks in addition to standard antifungal therapy.ResultsRecombinant IFN-γ treatment in patients with invasive Candida and/or Aspergillus infections partially restored immune function, as characterized by an increased HLA-DR expression in those patients with a baseline expression below 50%, and an enhanced capacity of leukocytes from treated patients to produce proinflammatory cytokines involved in antifungal defence.ConclusionsThe present study provides evidence that adjunctive immunotherapy with IFN-γ can restore immune function in fungal sepsis patients, warranting future clinical studies to assess its potential clinical benefit.Trial registrationClinicalTrials.gov - NCT01270490

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“…Notably, increasing amounts of evidence from animal models of fungal infections suggest that recombinant human IFN-␥, GM-CSF, or G-CSF immunotherapies have utility in the treatment of invasive fungal infections, particularly in patients with impaired T-cell immunity (178,179). Given the fact that a failure to restore host immunity leads to worse outcomes of black yeast infections (91), further studies are required to evaluate the restoration of endogenous immunological responses through adjuvant immunotherapy for humans and animals in various immunosuppressive states.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Black Yeasts and Their Filamentous Relatives: Principles of Pathogenesis and Host Defense

et al. 2014

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SUMMARY Among the melanized fungi, the so-called “black yeasts” and their filamentous relatives are particularly significant as agents of severe phaeohyphomycosis, chromoblastomycosis, and mycetoma in humans and animals. The pathogenicity and virulence of these fungi may differ significantly between closely related species. The factors which probably are of significance for pathogenicity include the presence of melanin and carotene, formation of thick cell walls and meristematic growth, presence of yeast-like phases, thermo- and perhaps also osmotolerance, adhesion, hydrophobicity, assimilation of aromatic hydrocarbons, and production of siderophores. Host defense has been shown to rely mainly on the ingestion and elimination of fungal cells by cells of the innate immune system, especially neutrophils and macrophages. However, there is increasing evidence supporting a role of T-cell-mediated immune responses, with increased interleukin-10 (IL-10) and low levels of gamma interferon (IFN-γ) being deleterious during the infection. There are no standardized therapies for treatment. It is therefore important to obtain in vitro susceptibilities of individual patients' fungal isolates in order to provide useful information for selection of appropriate treatment protocols. This article discusses the pathogenesis and host defense factors for these fungi and their severity, chronicity, and subsequent impact on treatment and prevention of diseases in human or animal hosts.

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Exogenous Interferon-γ Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients

Cited by 86 publications

References 44 publications

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series

Black Yeasts and Their Filamentous Relatives: Principles of Pathogenesis and Host Defense

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