TY - JOUR
T1 - IFN-γ at the site of infection determines rate of clearance of infection in cryptococcal meningitis
AU - Siddiqui, Asna A.
AU - Brouwer, Annemarie E.
AU - Wuthiekanun, Vannaporn
AU - Jaffar, Shabbar
AU - Shattock, Robin
AU - Irving, Diane
AU - Sheldon, Joanna
AU - Chierakul, Wirongrong
AU - Peacock, Sharon
AU - Day, Nicholas
AU - White, Nicholas J.
AU - Harrison, Thomas S.
PY - 2005/2/1
Y1 - 2005/2/1
N2 - In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-γ, TNF-α, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-α, IFN-γ, and IL-6 levels and baseline cryptococcal CFU. Log IFN-γ, G-CSF, TNF-α, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-γ remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-γ secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-γ in the treatment of refractory HIV-associated cryptococcosis.
AB - In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-γ, TNF-α, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-α, IFN-γ, and IL-6 levels and baseline cryptococcal CFU. Log IFN-γ, G-CSF, TNF-α, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-γ remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-γ secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-γ in the treatment of refractory HIV-associated cryptococcosis.
UR - http://www.scopus.com/inward/record.url?scp=19944432138&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.174.3.1746
DO - 10.4049/jimmunol.174.3.1746
M3 - Article
C2 - 15661940
AN - SCOPUS:19944432138
SN - 0022-1767
VL - 174
SP - 1746
EP - 1750
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -