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

Abstract

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

CD4+FoxP3+ regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection

“…Despite the benefit of antifungal drugs, the emergence of drug-resistant fungal strains and serious side-effects of antifungal agents limit their therapeutic use. In conclusion, there is a significant medical need for additional therapies such as adjunct or sole immunotherapies [3,38].…”

“…Despite the benefit of antifungal drugs, the emergence of drug-resistant fungal strains and serious side-effects of antifungal agents limit their therapeutic use. In conclusion, there is a significant medical need for additional therapies such as adjunct or sole immunotherapies [3,38].It was shown that a dominant Th1-related immune response is associated with protective immunity against fungi, whereas Th2-related immunity is detrimental [36,39,40] may restrain exuberant immune reactions limiting collateral immunopathology but therefore also dampen the efficiency of protective immunity which can lead to immunoevasion of the fungus [41,42]. In a model of fungal infection using Pneumocystis cariniiinfected mice it was shown that Treg cells prevent excessive tissue damage during pathogen clearance [43].…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…Use of IFN-γ has been associated with improvements in both monocyte HLA-DR expression and cytokine production capacity and was associated with lower incidence of ventilator-associated infection after severe trauma and improved clearance of invasive infections in fungal sepsis in several small studies. 35,[50][51][52][53][54] In 1 large randomized controlled trial (RCT) of 416 injured adults, IFN-γ or placebo was given for 21 days or until hospital discharge, with those in the IFN-γ group demonstrating a Table 2 Selected human studies evaluating drugs targeting innate and adaptive immune suppression in critical illness Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN-γ, interferon gamma; IL, interleukin; mHLA-DR: monocyte HLA-DR expression, MODS, multiple organ dysfunction syndrome; PD, programed death; RCT, randomized controlled trial; TNF, tumor necrosis factor.…”

Promising immunotherapy against fungal diseases

“…A pilot study showed that IFN-γ, which is normally produced by T cells and NK cells, increased the cytotoxicity of antigen presenting cells in patients with Candida and Aspergillus infections [75]. Moreover, rIFN-γ treatment was responsible for enhanced secretion of pro-inflammatory cytokines (IL-1β and TNFα) and up-regulation of MHC class II receptors on leukocytes, which in turn results in higher induction of T cell responses [75]. Additionally, it has been reported that rIFN-γ treatment enhanced secretion of IL-17 and IL-22 by antigen presenting cells -both cytokines responsible for stimulating TH17 cells.…”

“…Additionally, it has been reported that rIFN-γ treatment enhanced secretion of IL-17 and IL-22 by antigen presenting cells -both cytokines responsible for stimulating TH17 cells. Differentiation of naïve T cells into TH17 cells is associated with protective immune response in patients with candidemia and IA [75,76]. rIFN-γ is a valuable cytokine already used as prophylactic agent but also in combination with antifungal drugs to stimulate cellular immunity and thereby limiting fungal burden [77].…”