Interferon‐γ as an Antifungal

Stevens, David A.; Brummer, Elmer; Clemons, Karl V.

doi:10.1086/505357

Cited by 34 publications

(21 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Discussionmentioning

confidence: 99%

“…A few studies have reported direct killing of yeasts by CD8 + T cells [58,59]. Alternatively IFN-c or TNF-a, produced by activated CD8 + T cells, could enhance anti-fungal activity of macrophages and neutrophils [60], since IFN-c is used as therapy for fungal infections [61].Previously, we have shown that CD8 -DC can crosspresent immune complexes [36]. In CD8 -DC this process is dependent on the signaling FcR c-chain, whereas cross-presentation by CD8 + DC does not require the FcR c-chain.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

et al. 2008

View full text Add to dashboard Cite

Mouse splenic dendritic cell (DC) subsets possess distinct antigen-presentation abilities. CD8 + DC are specialized in cross-presentation of antigens to CD8 + T cells, whereas CD8 -DC are more efficient in antigen presentation to CD4 + T cells. In this study, we examined the capacity of CD8 + and CD8 -DC subsets to present fungal antigens in MHC class I and II molecules to CD8 + and CD4 + T cells, respectively. We used ovalbuminexpressing Saccharomyces cerevisiae (yeast-OVA) as a fungal model system. Both CD8 + and CD8 -DC subsets phagocytosed yeast in equal amounts and uptake was mediated via dectin-1. In addition, both DC subsets induced similar OVA-specific CD4 + T cell proliferation after incubation with yeast-OVA. However, the induction of OVA-specific CD8 + T cell activation was largely restricted to the CD8 -DC subset. Furthermore, only CD8 -DC produced cytokines such as IL-10 and TNF-a and increased IL-23p19 and IL-23p40 mRNA levels in response to yeast. Our results strongly suggest that DC subsets have different functions in the elicitation of adaptive immune responses in vivo. IntroductionFungal infections with pathogenic yeasts such as Candida albicans, Aspergillus fumigatus, Histoplasma capsulatum and Cryptococcus neoformans are a major problem in immunocompromised persons. These opportunistic pathogens usually do not pose problems in healthy individuals, but frequently become invasive in patients suffering from HIV, patients with malignancies or transplant recipients, resulting in life-threatening diseases [1][2][3].Both innate and adaptive immune responses are essential to induce protection against fungi. Dendritic cells (DC) play a central role in the adaptive immune response by capturing fungi and presenting their antigens in major histocompatibility complex (MHC) class I and MHC class II molecules to T cells [4, 5]. DC express a panel of microbial recognition receptors such as Toll-like receptors (TLR) and C-type lectin receptors that are essential for the elicitation of adaptive immune responses [6]. Of these receptors, TLR2 and the DCassociated C-type lectin (dectin-1) are specifically involved in recognition of fungal components [7][8][9]. Zymosan and fungal pathogens like C. albicans and A. fumigatus are sensed by TLR2 that signals via myeloid differentiation factor 88 (MyD88), resulting in NF-jB activation and the production of cytokines [10][11][12][13]. The importance of this signaling cascade can be inferred from the fact that MyD88-knockout mice show an increased susceptibility to fungal infections [14,15].Dectin-1 is expressed on myeloid cells like macrophages, neutrophils, monocytes, and even a subset of T cells [16]. Dectin-1 mediates fungal recognition and Revised 2/11/07 Accepted 11/12/07 [DOI 10.1002/eji.200737647] Key words: Antigen presentation Á Dendritic cell Á Fungal Á T cell Abbreviations: b2m: b2-microglobulin Á Dectin-1: DC-associated C-type lectin-1 Á CR3: complement receptor 3 Á MR: mannose receptor Á SIGNR1: ICAM-3-grabbing nonintegrin (DC-SIGN) homolog, SIGN-related...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Other compounds, such as miltefosine, widely used in the treatment of visceral leishmaniasis and exhibiting in vitro fungicidal activity against several molds, may need evaluation (29,33). Adjuvant therapies with cytokines, such as gamma interferon, and growth factors, such as granulocyte colony-stimulating factor (G-CSF), have been used to treat IFIs, including Scopulariopsis infections (14,25,27,30).…”

Section: Case Reportmentioning

confidence: 99%

Fatal Invasive Infection with Fungemia Due to Microascus cirrosus after Heart and Lung Transplantation in a Patient with Cystic Fibrosis

et al. 2011

View full text Add to dashboard Cite

Scopulariopsis species are rarely but increasingly recognized as opportunistic pathogens in immunocompromised patients. We report on a patient suffering from cystic fibrosis who developed disseminated fungal infection due to a rare Scopulariopsis species, Microascus cirrosus, after heart and lung transplantation. Despite antifungal combination therapy with voriconazole and caspofungin, the patient died 4 weeks after transplantation. Diagnostic difficulties and optimal management of disseminated Scopulariopsis/Microascus infections are discussed. CASE REPORTA 36-year-old man suffering from cystic fibrosis was admitted to our hospital in June 2009 for a heart and bilateral lung transplantation. He had a first lung transplantation in 1997 but had chronic rejection since 2001 in spite of several immunosuppressive regimens. His medical history also included renal failure (hemodialysis since 2007), diabetes mellitus, and airway colonization with a multiresistant Pseudomonas aeruginosa. Short antifungal therapy courses had been prescribed over the past years for various yeasts (Candida spp.) and molds (Aspergillus, Paecilomyces, and Fusarium species) colonizing his respiratory tract, but there was no evidence of previous isolation of a Scopulariopsis species. At the time of admission, sputum cultures grew only Candida albicans, and fluconazole was thus prescribed (200 mg intravenously [i.v.] after each dialysis).Following graft surgery, the immunosuppressive regimen included induction therapy with basiliximab (anti-CD25 antibody [20 mg i.v. on the day of transplantation and on day 4]) and solumedrol (10 mg/kg of body weight on the day of transplantation, followed by three 120-mg doses per day), followed by cyclosporine adjusted according to dialysis parameters to reach therapeutic blood levels (300 to 350 ng/ml) and solumedrol. Antimicrobial therapy consisted of a broad-spectrum antibiotherapy with tobramycin, vancomycin, piperacillin, and tazobactam. Although the patient seemed to do well in the early postoperative period, with apyrexia and extubation on day 3, his white blood cell count (WBC) increased slowly starting on the day after transplantation, reaching 20 ϫ 10 9 cells/liter by day 8 postsurgery. On day 11 after the operation (WBC ϭ 30 ϫ 10 9 cells/liter), a thoracic computed tomodensitometry (TDM) revealed bilateral pulmonary effusions (Fig. 1A), which were drained on day 19 without clinical improvement. Bilateral hemorrhagic pleural fluid specimens revealed several regular, hyaline, and branched septate hyphae on direct examination ( Fig. 2A), leading to the diagnosis of proven invasive fungal infection (IFI) according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria (8). The patient was given an antifungal combination therapy of voriconazole i.v. (6 mg/kg every 12 h as a loading dose followed by two 4-mg/kg doses a day) and caspofungin (70 mg/day ...

show abstract

“…The improved scavenger innate immune cell antifungal responses are due to 1) augmented neutrophil oxidative killing of A. fumigatus hyphae; 2) prevented corticosteroidmediated suppression of neutrophil killing of fungal hyphae; and 3) enhanced killing of A. fumigatus hyphae by human monocytes [31,32,39,40,47]. Data in mouse models using cytokine depletion, gene knockout mice, and administration of exogenous cytokines have been instrumental in establishing the conceptual basis for immunotherapy in invasive mycoses and in paving the way to early clinical trials [48][49][50].…”

Section: Ifn-γmentioning

confidence: 99%

Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation

Safdar

2010

Curr Fungal Infect Rep

View full text Add to dashboard Cite

Understanding fungal pathogenesis and host-pathogen immune interaction at various stages of infection is critical to examine strategies for bolstering antifungal immune defenses. Recombinant myeloid growth factors, especially granulocyte-macrophage colony-stimulating factor and the protagonist T helper (Th) 1 cytokine, interferon-γ, are most frequently used in patients with refractory invasive aspergillosis. These cytokines are given alone or in combination and have also been used together in neutropenic patients receiving donor granulocyte transfusions. Recently, a number of investigators have presented provoking data regarding auxiliary effect of conventional antifungal drugs on hosts' immune response and pathogen's susceptibility for antifungal immune defenses. Antifungal immunotherapy and its ameliorative role in treatment for disease will need clinical trials that 1) consider well-characterized fungal disease; 2) illustrate underlying immune defect(s) (such as Th1 vs Th2, vs Th17 and functional status of natural killer and effector scavenger cells); 3) include a more specific patient population; 4) include standardized antifungal drug therapy; and importantly 5) consider its impact on hosts' immune response and changes in pathogen's susceptibility and virulence. At present, immunotherapy is reserved for patients with life-threatening invasive fungal disease in whom conventional antifungal drug therapy has failed, or for patients with advanced fungal disease and with factors associated with high probability of failure of conventional therapy alone.

show abstract

Interferon‐γ as an Antifungal

Cited by 34 publications

References 91 publications

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

Fatal Invasive Infection with Fungemia Due to Microascus cirrosus after Heart and Lung Transplantation in a Patient with Cystic Fibrosis

Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation

Contact Info

Product

Resources

About

Interferon‐γ as an Antifungal

Cited by 34 publications

References 91 publications

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

Fatal Invasive Infection with Fungemia Due to Microascus cirrosus after Heart and Lung Transplantation in a Patient with Cystic Fibrosis

Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation

Contact Info

Product

Resources

About

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

CD8^– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens