BACKGROUND AND AIMS: Cellular mediated immunity (CMI) is thought to play a key role in resolution of primary hepatitis C virus (HCV) infection. However, CD4+ and CD8+ T cell responses are also generated during acute infection in individuals who become chronic, suggesting that they developed a defective CMI. The aim of this study was to verify if and when such immune dysfunction is established by measuring the breadth, magnitude, function, and duration of CMI in a large cohort of subjects during the natural course of acute HCV infection. METHODS: CMI was comprehensively studied by prospective sampling of 31 HCV acutely infected subjects enrolled at the onset of infection and followed for a median period of one year. RESULTS: Our results indicated that while at the onset of acute HCV infection a measurable CMI with effector function was detected in the majority of subjects, after approximately six months less than 10% of chronically infected individuals displayed significant CMI compared with 70% of subjects who cleared the virus. We showed that progressive disappearance of HCV specific T cells from the peripheral blood of chronic patients was due to an impaired ability to proliferate that could be rescued in vitro by concomitant exposure to interleukin 2 and the antigen. CONCLUSION: Our data provide evidence of strong and multispecific T cell responses with a sustained ability to proliferate in response to antigen stimulation as reliable pharmacodynamic measures of a protective CMI during acute infection, and suggest that early impairment of proliferation may contribute to loss of T cell response and chronic HCV persistence.
BACKGROUND AND AIMS: Cellular mediated immunity (CMI) is thought to play a key role in resolution of primary hepatitis C virus (HCV) infection. However, CD4+ and CD8+ T cell responses are also generated during acute infection in individuals who become chronic, suggesting that they developed a defective CMI. The aim of this study was to verify if and when such immune dysfunction is established by measuring the breadth, magnitude, function, and duration of CMI in a large cohort of subjects during the natural course of acute HCV infection. METHODS: CMI was comprehensively studied by prospective sampling of 31 HCV acutely infected subjects enrolled at the onset of infection and followed for a median period of one year. RESULTS: Our results indicated that while at the onset of acute HCV infection a measurable CMI with effector function was detected in the majority of subjects, after approximately six months less than 10% of chronically infected individuals displayed significant CMI compared with 70% of subjects who cleared the virus. We showed that progressive disappearance of HCV specific T cells from the peripheral blood of chronic patients was due to an impaired ability to proliferate that could be rescued in vitro by concomitant exposure to interleukin 2 and the antigen. CONCLUSION: Our data provide evidence of strong and multispecific T cell responses with a sustained ability to proliferate in response to antigen stimulation as reliable pharmacodynamic measures of a protective CMI during acute infection, and suggest that early impairment of proliferation may contribute to loss of T cell response and chronic HCV persistence.
Authors: G Missale; R Bertoni; V Lamonaca; A Valli; M Massari; C Mori; M G Rumi; M Houghton; F Fiaccadori; C Ferrari Journal: J Clin Invest Date: 1996-08-01 Impact factor: 14.808
Authors: Andrea L Cox; Timothy Mosbruger; Georg M Lauer; Drew Pardoll; David L Thomas; Stuart C Ray Journal: Hepatology Date: 2005-07 Impact factor: 17.425
Authors: N H Grüner; T J Gerlach; M C Jung; H M Diepolder; C A Schirren; W W Schraut; R Hoffmann; R Zachoval; T Santantonio; M Cucchiarini; A Cerny; G R Pape Journal: J Infect Dis Date: 2000-05-05 Impact factor: 5.226
Authors: A Takaki; M Wiese; G Maertens; E Depla; U Seifert; A Liebetrau; J L Miller; M P Manns; B Rehermann Journal: Nat Med Date: 2000-05 Impact factor: 53.440
Authors: J T Gerlach; H M Diepolder; M C Jung; N H Gruener; W W Schraut; R Zachoval; R Hoffmann; C A Schirren; T Santantonio; G R Pape Journal: Gastroenterology Date: 1999-10 Impact factor: 22.682
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Authors: F Lechner; N H Gruener; S Urbani; J Uggeri; T Santantonio; A R Kammer; A Cerny; R Phillips; C Ferrari; G R Pape; P Klenerman Journal: Eur J Immunol Date: 2000-09 Impact factor: 5.532
Authors: K M Chang; R Thimme; J J Melpolder; D Oldach; J Pemberton; J Moorhead-Loudis; J G McHutchison; H J Alter; F V Chisari Journal: Hepatology Date: 2001-01 Impact factor: 17.425
Authors: F Lechner; D K Wong; P R Dunbar; R Chapman; R T Chung; P Dohrenwend; G Robbins; R Phillips; P Klenerman; B D Walker Journal: J Exp Med Date: 2000-05-01 Impact factor: 14.307
Authors: David G Brooks; Sang-Jun Ha; Heidi Elsaesser; Arlene H Sharpe; Gordon J Freeman; Michael B A Oldstone Journal: Proc Natl Acad Sci U S A Date: 2008-12-15 Impact factor: 11.205
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