Aspergillus fumigatus suppresses the human ceflular immune response via ghotoxin-mediated apoptosis of monocytes

被引:152
作者
Stanzani, M
Orciuolo, E
Lewis, R
Kontoyiannis, DP
Martins, SLR
St John, LS
Komanduri, KV
机构
[1] Univ Texas, MD Anderson Canc Ctr, Transplant Immunol Sect, Dept Blood & Marrow Transplantat, Houston, TX 77030 USA
[2] Univ Bologna, Inst Hematol Seragnoli, Bologna, Italy
[3] Univ Pisa, Dept Oncol Transplant & Advances Med, Pisa, Italy
[4] Univ Texas, MD Anderson Canc Ctr, Dept Infect Dis Infect Control Employee Hlth, Houston, TX 77030 USA
[5] Fleury Diagnost med Ctr, Dept Hematol, Sao Paulo, Brazil
关键词
D O I
10.1182/blood-2004-09-3421
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aspergillus fumigratus (AF) is a ubiquitous mold and is the most common cause of invasive aspergillosis, an important source of morbidity and mortality in immunocompromised hosts. Using cytokine flow cytometry, we assessed the magnitude of functional CD4(+) and CD8(+) T-cell responses following stimulation with Aspergillus antigens. Relative to those seen with cytomegalovirus (CMV) or superantigen stimulation, responses to AspergilIus antigens were near background levels. Subsequently, we confirmed that gliotoxin, the most abundant mycotoxin produced by AF, was able to suppress functional T-cell responses following CMV or staphylococcal enterotoxin B (SEB) stimulation. Additional studies demonstrated that crude AF filtrates and purified gliotoxin inhibited antigen-presenting cell function and induced the preferential death of monocytes, leading to a marked decrease in the monocyte-lymphocyte ratio. Analysis of caspase-3 activation confirmed that gliotoxin preferentially induced apoptosis of monocytes; similar effects were observed in CD83(+) monocyte-derived dendritic cells. Importantly, the physiologic effects of gliotoxin in vitro were observed below concentrations recently observed in the serum of patients with invasive aspergillosis. These studies suggest that the production of gliotoxin by AF may constitute an important immunoevasive mechanism that is mediated by direct effects on antigen-presenting cells and both direct and indirect effects on T cells. (c) 2005 by The American Society of Hematology.
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页码:2258 / 2265
页数:8
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