<i>Aspergillus fumigatus</i>Conidia Induce a Th1‐Type Cytokine Response

Grazziutti, Monica; Rex, John H.; Cowart, Richard E.; Anaissie, Elias; Ford, Alysson; Savary, Cherylyn A.

doi:10.1086/514157

Cited by 70 publications

(42 citation statements)

References 33 publications

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“…In a murine model described recently, 4,5,16,17 Cenci et al noted that mouse strains mounting a Th1 response were resistant to experimental invasive aspergillosis, while those with a predominantly Th2 response succumbed to the infection. In addition, we reported previously that A. fumigatus conidia induced a Th1 response in vitro using peripheral blood mononuclear cells from normal volunteers, 12 suggesting that a Th1 response can also be induced in humans. We have now evaluated the role of DC in this response.…”

Section: Discussionmentioning

confidence: 84%

“…fumigatus conidia and C. albicans blastoconidia were killed by heating in a water bath at 100°C for 1 h, washed three times in PBS, and stored at 4°C. 12 The efficiency of this treatment was verified by the failure of the heatexposed fungi to grow when cultured for 10 days in Sabouraud dextrose agar. Before use, the fungi were washed again in medium and resuspended at the appropriate concentration.…”

Section: Preparation Of Fungimentioning

confidence: 99%

“…Controls included fluor-conjugated isotype-matched antibodies that were nonreactive to human lymphocytes (Caltag and Becton Dickinson). Surface staining was performed as described previously, 12 and the cells were analyzed using a FACScan flow cytometer and Consort 30 or Lysys II software (Becton Dickinson). DC were characterized by the absence of lineage (lin)-associated surface molecules (CD3, CD11b, CD14, CD16, CD19, CD20 and CD56) and the presence of HLA-DR using a flow cytometric technique described previously.…”

Section: Flow Cytometrymentioning

confidence: 99%

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Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

Grazziutti

Przepiorka

Rex³

et al. 2001

Bone Marrow Transplant

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Summary:Lymphocytes play a major role in host defense against Aspergillus, but little is known about the contribution of dendritic cells (DC) to antifungal immunity in humans. We have observed that DC derived from normal volunteers phagocytose heat-killed A. fumigatus conidia. Following 24 h of exposure to the fungus, DC displayed an increase in the mean fluorescence intensity of HLA-DR, CD80, and CD86, and an increase in the percentage of CD54 + cells. These DC also displayed increased production of IL-12. DC derived from CD34 + progenitors or monocytes stimulated autologous lymphocytes to proliferate and produce high levels of interferon-␥, but not interleukin-10, in response to fungal antigen. DC generated from CD34 + progenitors collected prior to autologous or allogeneic stem cell transplantation also partially restored the in vitro antifungal proliferative response of lymphocytes obtained from patients 1 month after transplantation. These results suggest that DC are important to host-response to A. fumigatus, and that ex vivo-generated DC might be useful in restoring or enhancing the antifungal immunity after hematopoietic stem cell transplantation. Bone Marrow Transplantation (2001) 27, 647-652. Keywords: fungi; dendritic cell; immune reconstitution; Candida; AspergillusThe ubiquitous mould Aspergillus rarely causes disease in healthy individuals but poses a serious threat to hematopoietic stem cell transplant recipients. [1][2][3] It is the most common etiology of non-Candida fungal infections occurring in these patients, and the case-fatality rate for invasive aspergillosis exceeds 80%. Although prolonged neutropenia is a well-established risk factor for Aspergillus infections, the majority of infections in the allogeneic setting become clinically evident well after engraftment, 2 suggesting that cell-mediated immunity plays an important role in protec- tion against this pathogen. Indeed, animal studies demonstrated that a Th1 response was associated with resistance to induction of experimental Aspergillus infection, 4 and methods stimulating a Th1 response were successful in inducing anti-Aspergillus immunity. 5 We 6 and others 7 have reported that a substantial proportion of blood and marrow transplant recipients have a deficiency in the number of circulating dendritic cells (DC) in the early post-transplant period. To overcome the potential effects of DC deficiency on immune reconstitution post transplant, DC-based vaccines have been used to induce T cell-mediated immunity to tumor early after transplantation. 8 However, despite the importance of DC in immunity, there is virtually no information regarding the role of human DC in resistance to aspergillosis. We have therefore evaluated the phagocytic capacity of human DC for A. fumigatus conidia, the cytokine response of human DC after exposure to A. fumigatus conidia, and the immunostimulatory competence of A. fumigatus conidia-pulsed DC for autologous lymphocytes from blood stem cell transplant recipients. The results of our studies suggest that DC ...

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Section: Discussionmentioning

confidence: 84%

Section: Preparation Of Fungimentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

See 1 more Smart Citation

Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

Grazziutti

Przepiorka

Rex³

et al. 2001

Bone Marrow Transplant

View full text Add to dashboard Cite

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“…The evidence that IL-10, produced in increased levels in HIV infection (24), may have a pathogenetic role in invasive aspergillosis (25) indicates that dysregulated production of Th cytokines may contribute to the pathogenesis of IPA. Recent findings seem to support this observation, as human lymphocytes responded to A. fumigatus conidia in vitro with activation, proliferation, and production of Th1 cytokines (26), and pulmonary aspergillosis was observed in the hyper-IgE syndrome (27).…”

Section: T Cell Vaccination In Mice Withmentioning

confidence: 75%

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Cenci

Mencacci

Bacci

et al. 2000

The Journal of Immunology

204

166

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Aspergillus fumigatus, an opportunistic fungal pathogen, is responsible for multiple airway diseases of an allergic and a nonallergic nature. In a murine model of invasive pulmonary aspergillosis, resistance is associated with a decreased lung inflammatory pathology and the occurrence of an IL-12-dependent Th1-type reactivity that are both impaired by IL-4. In the present study we assess the ability of Aspergillus crude culture filtrate Ags and the recombinant allergen Asp f 2 to induce protective antifungal responses in mice with invasive pulmonary aspergillosis. Similar to what occurred upon nasal exposure to viable A. fumigatus conidia, treatment of immunocompetent mice with Aspergillus crude culture filtrate Ags resulted in the development of local and peripheral protective Th1 memory responses, mediated by Ag-specific CD4+ T cells producing IFN-γ and IL-2 capable of conferring protection upon adoptive transfer to naive recipients. Protective Th1 responses could not be observed in mice deficient of IFN-γ or IL-12 and did not occur in response to Asp f 2, which, on the contrary, elicited high level production of inhibitory IL-4. The results show that Ags of Aspergillus exist with the ability to induce both Th1- and Th2-type reactivity during infection, a finding that suggests a possible mechanism through which potentially protective immune responses are inhibited in mice with the infection. However, the occurrence of Th1-mediated resistance upon vaccination with Aspergillus crude culture filtrate Ags, suggests the existence of fungal Ags useful as a candidate vaccine against invasive pulmonary aspergillosis.

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“…In experimental animals, alveolar and peritoneal macrophages bind and engulf Aspergillus fumigatus conidia in vitro (10,(13)(14)(15) and produce IL-1 and TNF when exposed to either conidia or hyphae (16). In vitro studies of human peripheral monocytes (17,18), monocyte-derived macrophages (19), and alveolar macrophages (20,21) have also shown these cells to phagocytose conidia and kill both conidial and hyphal forms of A. fumigatus. One study has suggested a role for splenic macrophages in acquired immunity against i.v.…”

Section: Macrophage Inflammatory Protein-1␣ Is a Critical Mediator Ofmentioning

confidence: 99%

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

Mehrad

Moore

Standiford

2000

The Journal of Immunology

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Invasive pulmonary aspergillosis is a devastating complication of immunosuppression that usually occurs in neutropenic patients. In this setting, augmentation of the antifungal activity of available immune cells may improve the outcome of the infection. Macrophage inflammatory protein-1α (MIP-1α) is a CC chemokine with potent chemotactic activity for various subsets of mononuclear leukocytes. We therefore tested the hypothesis that the influx of mononuclear cells into the lung in invasive pulmonary aspergillosis is in part mediated by MIP-1α, and the manipulation of this ligand alters the outcome of the infection. We found that in both immunocompetent and neutropenic mice, MIP-1α was induced in the lungs in response to intratracheal administration of Aspergillus fumigatus conidia. In neutrophil-depleted mice challenged with intratracheal conidia, there was evidence of invasive fungal pneumonia associated with a predominantly mononuclear leukocyte infiltrate. Ab-mediated depletion of MIP-1α resulted in a 6-fold increase in mortality in neutropenic mice, which was associated with a 12-fold increase in lung fungal burden. Studies of single-cell suspensions of whole lungs revealed a 36% decrease in total lung leukocyte infiltration as a result of MIP-1α neutralization. Flow cytometry on whole lung suspensions showed a 41% reduction in lung monocyte/macrophages as a result of MIP-1α neutralization, but no difference in other lung leukocyte subsets. These studies indicate that MIP-1α is a critical mediator of host defense against A. fumigatus in the setting of neutropenia and may be an important target in devising future therapeutic strategies against invasive aspergillosis.

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Aspergillus fumigatusConidia Induce a Th1‐Type Cytokine Response

Cited by 70 publications

References 33 publications

Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

Dendritic cell-mediated stimulation of the in vitro lymphocyte response to Aspergillus

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

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