Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes.
Using transgenic mice that replicate hepatitis B virus (HBV) at high levels in the liver as recipients of HBV-specific cytotoxic T lymphocytes (CTLs), we showed that the chemokines responsive to gamma-2/IFN-gamma inducible protein ([Crg2]IP-10) and monokine induced by interferon-gamma (Mig) are rapidly and strongly induced in the liver after CTL transfer. The transferred CTLs produce neither chemokine; rather, they activate (via the secretion of IFN-gamma) hepatocytes and nonparenchymal cells of the liver to produce (Crg2)IP-10 and Mig. Importantly, blocking these chemokines in vivo reduces the recruitment of host-derived lymphomononuclear cells into the liver and the severity of the liver disease without affecting the IFN-gamma-dependent antiviral potential of the CTLs. The finding that neutralization of these chemokines is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.
Kakimi
K
K
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Lane
T E
TE
Wieland
S
S
Asensio
V C
VC
Campbell
I L
IL
Chisari
F V
FV
Guidotti
L G
LG
D000818:Animals; D054357:Chemokine CXCL10; D003602:Cytotoxicity, Immunologic; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006515:Hepatitis B virus / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D015846:Monokines / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D015846:Monokines; D007371:Interferon-gamma