TY - JOUR
T1 - Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C
AU - Ahlenstiel, Golo
AU - Edlich, Birgit
AU - Hogdal, Leah J.
AU - Rotman, Yaron
AU - Noureddin, Mazen
AU - Feld, Jordan J.
AU - Holz, Lauren E.
AU - Titerence, Rachel H.
AU - Liang, T. Jake
AU - Rehermann, Barbara
PY - 2011
Y1 - 2011
N2 - Background & Aims: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. Methods: Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response. Results: Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P <.01), concomitant with an increase in alanine aminotransferase levels (P <.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P <.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16 +NK cells (P <.05) and a trend toward increased production of tumor necrosis factorrelated apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P <.05) and remained higher in early virological responders than in nonresponders for weeks. Conclusions: IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-αbased treatment and suggests the involvement of the innate immune cells in viral clearance.
AB - Background & Aims: Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. Methods: Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response. Results: Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of activating receptors NKG2D, NKp30, and CD16 and decreased expression of NKG2C and 2B4, along with inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and tumor necrosis factor-related apoptosis-inducing ligand production, peaked after 24 hours (P <.01), concomitant with an increase in alanine aminotransferase levels (P <.05), whereas IFN-γ production decreased within 6 hours and did not recover for more than 4 weeks (P <.05). NK cells from liver biopsies taken 6 hours after treatment initiation had increased numbers of cytotoxic CD16 +NK cells (P <.05) and a trend toward increased production of tumor necrosis factorrelated apoptosis-inducing ligand. Degranulation of peripheral blood NK cells correlated with treatment-induced, first-phase decreases in viral load (P <.05) and remained higher in early virological responders than in nonresponders for weeks. Conclusions: IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to virologic response. Therefore, NK cell activation indicates responsiveness to IFN-αbased treatment and suggests the involvement of the innate immune cells in viral clearance.
KW - cytokines
KW - hepatitis C virus
KW - interferon
KW - killer cells
UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:43220
U2 - 10.1053/j.gastro.2011.06.069
DO - 10.1053/j.gastro.2011.06.069
M3 - Article
SN - 0016-5085
VL - 141
SP - 1231
EP - 1239
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -