The Phenotype of the Cryptococcus-Specific CD4+ Memory T-Cell Response Is Associated With Disease Severity and Outcome in HIV-Associated Cryptococcal Meningitis

被引:109
作者
Jarvis, Joseph N. [1 ,2 ,3 ,4 ]
Casazza, Joseph P. [6 ]
Stone, Hunter H. [6 ]
Meintjes, Graeme [4 ,5 ]
Lawn, Stephen D. [2 ]
Levitz, Stuart M. [7 ]
Harrison, Thomas S. [1 ]
Koup, Richard A. [6 ]
机构
[1] St Georges Univ London, Div Clin Sci, Res Ctr Infect & Immun, London, England
[2] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London WC1E 7HT, England
[3] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa
[4] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7700 Rondebosch, South Africa
[5] Univ Cape Town, Dept Med, ZA-7700 Rondebosch, South Africa
[6] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA
[7] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA
基金
美国国家卫生研究院; 英国惠康基金;
关键词
HIV; cryptococcus neoformans; TB; CMV; memory T cells; flow cytometry; PROTECTIVE TH1 RESPONSE; NECROSIS-FACTOR-ALPHA; INTERFERON-GAMMA; NEOFORMANS INFECTION; IFN-GAMMA; PULMONARY CRYPTOCOCCOSIS; VIRULENCE FACTORS; IMMUNE-RESPONSES; AFFERENT PHASE; MICE;
D O I
10.1093/infdis/jit099
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Correlates of immune protection in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis are poorly defined. A clearer understanding of these immune responses is essential to inform rational development of immunotherapies. Methods. Cryptococcal-specific peripheral CD4(+) T-cell responses were measured in 44 patients with HIV-associated cryptococcal meningitis at baseline and during follow-up. Responses were assessed following ex vivo cryptococcal mannoprotein stimulation, using 13-color flow-cytometry. The relationships between cryptococcal-specific CD4(+) T-cell responses, clinical parameters at presentation, and outcome were investigated. Results. Cryptococcal-specific CD4(+) T-cell responses were characterized by the production of macrophage inflammatory protein 1 alpha, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Conversely, minimal interleukin 4 and interleukin 17 production was detected. Patients surviving to 2 weeks had significantly different functional CD4(+) T-cell responses as compared to those who died. Patients with a response predominantly consisting of IFN-gamma or TNF-alpha production had a 2-week mortality of 0% (0/20), compared with 25% (6/24) in those without this response (P = .025). Such patients also had lower fungal burdens (10 400 vs 390 000 colony-forming units/mL; P < .001), higher cerebrospinal fluid lymphocyte counts (122 vs 8 cells/mu L; P < .001), and a trend toward faster rates of clearance of infection. Conclusions. The phenotype of the peripheral CD4(+) T-cell response to Cryptococcus was associated with disease severity and outcome in HIV-associated cryptococcal meningitis. IFN-gamma/TNF-alpha-predominant responses were associated with survival.
引用
收藏
页码:1817 / 1828
页数:12
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