| Background: Hepatitis B virus (HBV) infection is a major public healthproblem. Based on WHO survey, an estimated2billion people worldwidehave serological evidence of past or present infection with HBV and350million people are chronically infected. About one million people die everyyear due to HBV-related end-stage liver disease. In China, according to thelatest national sero-epidemiological survey in2006, the prevalence of HBsAgcarrier was7.18%among the general Chinese population within1-59year-old.Thus there are approximately93million people are chronically infected withHBV,20million are chronic hepatitis B (CHB) patients, and15%to40%ofwhom are at risk of dying of liver failure, decompensated cirrhosis andhepatocellular carcinoma. Although the immune mechanism of HBV infectionleading to hepatitis aggravation and immune activation is still not entirelyunderstood, it has been confirmed that cellular immunity is contributing toliver injury and HBV clearance. Thus, the host immune status is capital onaffecting the outcome after HBV infection. Effective regulation of the hostimmune efficacy by strengthening the specific immune recognition andenhancing clearance of HBV infected hepatocytes is an important strategy forachieving ideal therapeutic endpoint for CHB patients.During the past decades, HBV-specific CD8+cytotoxic T lymphocytes(CTL) was considered to be fateful in HBV immune clearance. However,recent studies have showed that other nonspecific immune cells can also berecruited to the liver and strengthen the immune clearance process especiallywhen the efficacy of CTLs were insufficient. NK cells, the largest componentof non-specific lymphocytes infiltrated into the liver, is particularly importantto regulate immune response. In this process: interferon gamma inducibleprotein10kD (IP-10, also named as CXCL-10) might be an important chemokine to participate NK cells redistribution. On the other hand, activationof NK receptors such as NKG2D might play a crucial role in breaking theimmune tolerance and regulating specific and/or non-specific immuneclearance. Therefore, it is important to explore the mechanism and signalingpathway for NK cells recruitment and activation in HBV infection. The resultsmight particularly significant in exploring anti-HBV immune regulationtargets and improving clinical immunoregulation efficacy.Objective: To explore the variances of NK cell mediated immunity andits influence to HBV clearance, inflammatory injury, and antiviral response atdifferent clinical HBV-infected patients: asymptomatic chronic HBV carriers(AsC), chronic hepatitis B (CHB) and HBV-related acute-on-chronic liverfailure (HBV-related ACLF). Moreover, the NK cells activation, IP-10baseline expression, and their dynamic changes during anti-HBV therapy werestudied in a cohort of CHB patients with Peg IFN-α mono-or combinationtherapy with ADV, with the purpose to evaluate the predictive value of NKcell related parameter on anti-HBV responses in Peg IFN-α therapy, and toexplore immunoregulation potential target and ideal antiviral therapy strategyfor the control of CHB.Methods:1Effect of NKG2D-mediated NK cell activation on immune activity anddisease exacerbation of patients with chronic HBV infectionForty-five patients with chronic HBV infection, including15AsC,15CHB and15HBV-related ACLF patients, were recruited according to theGuidelines on Prevention and Treatment for Chronic Hepatitis B in China(2010) and the Diagnostic and Treatment Guidelines for Liver Failure (2006)issued by the Chinese Society of Hepatology and the Chinese Society ofInfectious Disease. Meanwhile,15healthy volunteers and15liver donorsduring liver transplantations were recruited as the healthy controls (HC). Nonereceive immunotherapy, anti-HBV, or hepatitis B vaccine treatment for6months prior to enrollment. All recruited patients match the exclusion criteria:HAV, HCV, HEV, Elzatein-Barn virus, cytomegalovirus or HIV co-infection; evidence of liver co-morbidities of other etiologies (e.g., alcohol, drug,metabolic, autoimmune disease, and malignancy). Serum albumin (Alb),alanine aminotransferase (ALT), and total bilirubin (TBil) were measured by afully automatic biochemical analyzer. Serum IFN-γ, TNF-α, perforin, andgranzyme B concentrations were measured with sandwich enzyme-linkedimmunosorbent assay (ELISA). HBV DNA was quantified by real-timequantitative polymerase chain reaction (PCR) assay. HBsAg and HBeAgquantifications were detected using an electrochemiluminescence (ECL)technique. PBMCs were isolated from fresh heparinized blood. Frequency ofCD3–CD56+NK cells, NKG2D+NK cells, and IFN-γ+NK cells (intracellularstaining) were analyzed using flow cytometer. Liver specimens were collectedby routine liver biopsy (AsC and CHB) or from donor/receptor livers by livertransplantation (NC and ACLF). Liver tissue sections were stained withhematoxylin and eosin (H&E) for score inflammation activity. IntrahepaticCD3–CD57+NK cells, NKG2D+cells, and IFN-γ+cells percentage anddistribution were observed with immunohistochemistry staining. NKG2D andIFN-γ mRNA expression were determined by real time PCR assay.2Role of NKG2D pathway on TNF-α mediated NK cells activation andcytotoxic effect to target hepatocytes with HBV replicationThe new resuscitated HepG2cells were plated and cultured at5%CO2，37℃in6-well culture plates (5×105cells/well) with HD-DMEM mediumcontaining10%fetal bovine serum (FBS) and1%penicillin and streptomycin.When the logarithmic phase cells fused completely to60%-70%confluence,fresh complete medium was replaced and plasmid transfection was performedwith VigoFect transfection kit. Twenty-four hours later since transfection, thesupernatants of HBV-replicative HepG2(HBV-HepG2) were collected fordetermination of HBV DNA to confirming the effect of transfection, and thecell lines with HBV DNA≥5.0×106copies/ml were screened for further study.In the same period, the new resuscitated NK-92cells were cultured in α-MEMcomplete medium containing FBS (12.5%), horse serum (12.5%), IL-2(200IU/ml), IL-15(0.5ng/ml). After cytotoxicity of NK-92cells were confirmed by MTT, the cells were divided into four groups and were stimulated withdifferent intervention: single-cultured group, single-cultured interventiongroup, co-cultured group, and co-cultured intervention group. Then culture/co-culture supernatants were collected after24h for ELISA detection ofTNF-α, IFN-γ, perforin and granzyme B levels, and real-time PCRquantitative detection of HBV DNA loads.3Effect of NK cells liver migration induced by interferon gammainducible protein10kD on antiviral response to CHB patientsCross-sectional study: Cases screening criteria, biochemical parameters,virological markers, NK cells frequency detection were the same as themethods in first part. In addition, serum interferon gamma inducible protein10kD (IP-10) concentrations were measured with ELISA. IHC staining wasperformed for observation of IFN-γ+cells and IP-10protein expression levels.IFN-γ and IP-10mRNA were determined by real-time quantitative PCR assay.Cohort studies: A cohort of60CHB patients receiving48-weeks antiviraltherapy with Peg IFN-α were recruited according to the Guidelines onPrevention and Treatment for Chronic Hepatitis B in China (2010). Allpatients conformed to the following additional criteria: age18~65years, HBVDNA≥104copies/ml; elevated serum ALT levels between2and10times theupper limit of normal (ULN,80~400U/L), and/or inflammation grade≥G2degree. None receive anti-HBV, immunomodulating, or hepatitis B vaccinetreatment for6months prior to enrollment. Exclusion criteria included thefollowing: pregnancy or nursing; HAV, HCV, HEV, or HIV co-infection;malignancy, autoimmune disease, uncontrolled diabetes mellitus, thyroidismdisorders, psychiatric disorders; other concomitant diseases and/or otherinterferon contraindications. Fasting serum was collected at baseline,on-treatment, and follow-up period. ALT levels, HBV DNA loads, HBsAg/HBeAg quantification, and serum IFN-γ and IP-10concentrations weredetected. Pre-treatment liver specimens were collected by routine liver biopsyin42patients. The necroinflammatory degree of liver tissue was observed byH&E stain, and intrahepatic IFN-γ, IP-10mRNA and pritein expressions were determined by real-time PCR assay and immunohistochemical analyses.4Improved efficacy by individualized combination therapy with PegIFN-α2a and ADV in HBeAg positive CHB patientsThis was a prospective,“real-life” cohort study. One hundred and sixtypatients were recruited (inclusion and exclusion criteria were the same as Part3) and were equally randomized into a standard treatment group (STG) and anindividualized treatment group (ITG) at baseline. The80patients in STGreceived Peg IFNα-2a standard monotherapy. While the80patients in ITGwere further subdivided based on the baseline serum HBV DNA load and/orfibrosis stage:38patients for serum HBV DNA>1.0×107copies/ml and/orfibrosis stage≥S3received Peg IFNα-2a and ADV initial combination therapy.The other42patients received incipient Peg IFNα-2a monotherapy. At weeks24, the patients in ITG were re-assessed and re-grouped according to treatmentresponse. The patients who achieved satisfactory early response (undetectableserum HBV DNA, HBeAg clearance, and ALT normalization) in initialcombination therapy group (ICG) switched to Peg IFN α-2a monotherapysubsequently. The other28patients together with the patients who did notachieve satisfactory early responses in initial monotherapy group (IMG)received combination therapy during the remaining treatment period. Allpatients accepted48weeks antiviral treatment and the sustained antiviralresponse, safety, drug resistance and relapse rates were finally evaluated at endof follow-up period.Results:1Effect of NKG2D-mediated NK cell activation on immune activity anddisease exacerbation of patients with chronic HBV infection1.1Demographic characteristics and baseline serum parameters ofHBV-infected patients and healthy controls:All subjects were well comparable for age and sex. The HBV-relatedACLF patients displayed significantly higher levels of ALT, TBil, but lowerPTA levels than CHB patients, AsC patients, and healthy controls (all P<0.01).Furthermore, the HBV-related ACLF patients also displayed relatively lower levels of HBV DNA loads and HBsAg quantifications than CHB patients(P<0.01or <0.05).1.2Changes of serum IFN-γ, TNF-α, perforin and granzyme B levels:Patients with HBV-related ACLF had a significantly higher levels ofserum IFN-γ (10.78±1.19pg/ml), TNF-α (118.25±25.36pg/ml) than CHBpatients (6.98±1.12pg/ml；69.54±17.35pg/ml), AsC patients (2.24±0.45pg/ml；26.25±6.37pg/ml)(all P<0.01). However, the levels of IFN-γ andTNF-α in healthy controls (1.98±0.58pg/ml；24.58±6.15pg/ml) were thelowest, while difference between AsC group and the healthy control was notsignificant statistically (P>0.05).Similarly, serum perforin and granzyme B levels were the highest inHBV-related ACLF group (5.96±1.89ng/ml;12.56±2.28pg/ml), and thenCHB group (2.75±0.58ng/ml;3.52±0.96pg/ml), AsC group (1.58±0.59ng/ml;2.34±0.65pg/ml) and healthy controls (1.58±0.42ng/ml;2.25±0.48pg/ml)(all P<0.01or <0.05). Except the difference between AsC and thehealthy controls was not significant statistically (P>0.05), there weresignificantly statistical difference for comparisons of each two groups (P<0.01or <0.05).1.3Peripheral CD3–CD56+(NK) cells frequency, and NKG2D+and IFN-γ+NK cells percentage:Compared with the healthy controls (13.58±3.24)%, peripheral CD3–CD56+(NK) cells frequency exhibited a decreasing trend in each chronicHBV-infected group, especially in AsC group (5.42±2.18)%. The frequencywas both increased in CHB group (8.43±2.92)%and ACLF group (7.92±2.85)%as compared to AsC group (all P<0.05), but was still lower than thehealthy controls (all P<0.01). In addition, the frequency was slightly lower inHBV-related ACLF group than CHB group though the difference was notstatistically significant (P>0.05).On the contrary, the percentage of NKG2D+and IFN-γ+NK cells was thehighest in HBV-related ACLF group [(18.92±5.85)%and (42.25±10.17)%],followed by CHB group [(12.85±3.39)%and (27.95±6.12)%], healthy controls [(8.45±2.86)%and (18.69±5.68)%] and AsC group [(3.36±1.05)%and (12.55±3.24)%], and there were significantly statistical difference forcomparisons of each two groups (P<0.01or <0.05).1.4Intrahepatic infiltration of CD3-CD57+NK cells, and the percentage anddistribution of NKG2D+and IFN-γ+cells:NK cells were mainly distributed in the portal and necrotic areas in whichlymphocytes aggregated and inflammation appeared significantly in CHB andHBV-related ACLF group, while scattered in the hepatic sinusoids and portalarea in AsC and healthy controls. Semi-quantitative analysis revealed thatintrahepatic infiltration of CD3-CD57+NK cells in HBV-related ACLF patients(19.6±3.5/hpf) was significantly higher than CHB patients (8.4±3.5/hpf),AsC patients (2.5±1.3/hpf) and healthy controls (1.2±0.6/hpf). There wasstatistical difference for comparisons of each two groups (all P<0.05),excepting for the similarity of AsC with the healthy controls (P>0.05).NKG2D+cell was distributed mainly in the inflammatory areas oflymphocytes infiltration and portal areas. IFN-γ expressed mainly in theindividual hepatocytes in healthy controls and ASC group while in theinfiltrated lymphocytes of inflammatory and portal areas in CHB andHBV-related ACLF group. Semi-quantitative analysis revealed the strongestexpression in the HBV-related ACLF patients and the weakest in AsC patients,and the comparison differences between each two groups were statisticallysignificant (all P<0.01).1.5Expression changes of intrahepatic NKG2D and IFN-γ mRNA:The relative quantitative expressions of NKG2D and IFN-γ mRNA inhealthy controls were set to1.00. The relative levels of NKG2D (6.58±1.86)and IFN-γ (3.56±0.63) mRNA was the highest in HBV-related ACLF patients,followed by CHB (3.25±0.95;1.54±0.33) and AsC (0.69±0.20;0.52±0.09)patients. The differences between each two groups were statisticallysignificant (all P<0.01). In addition, the mRNA expression in AsC patientswas also lower than healthy controls, with statistical difference between thetwo groups (P<0.05). 2Role of NKG2D signaling pathway on TNF-α mediated NK cellsactivation and cytotoxic effect to target hepatocytes with HBV replication2.1Preparation of cell line with HBV replication by plasmid transfection:High HBV-replicative HepG2cell clone (HBV-HepG2) was establishedby wild-type HBV plasmid transfection. Cell culture supernatant was collectedfor HBV DNA detection by real time PCR, ranging from105to107copies/ml.ELISA assays were performed for HBsAg positivity. As compared with theoriginal non-transfected HepG2cells, the level of IFN-γ and TNF-α in cellsupernatant of HBV-HepG2cells increased slightly, but the difference was notstatistically significant (P>0.05).2.2Changes of NK cells cytotoxic activity:NK-92cells stimulated by IL-2and IL-15exhibited a low level ofcytotoxic activity, which was enhanced by stimulation with recombinantIFN-α. The cytotoxicity reduced after blocking with specific recombinanthNKG2D mAb. In particular, a significant reduction of NK cell cytotoxicity toIFN-α induced activation.2.3Effect of NK cells on HBV DNA replication in HBV-HepG2cells:The decline of HBV DNA in supernatant was weak in single-culturedHBV-HepG2cells after intervention by IFN-α. Co-cultured with NK cells(without IFN-α intervention), HBV DNA in supernatant only slightlydecreased too. However, HBV DNA significantly decreased when co-culturedwith NK cells and simultaneously intervened by hIFN-α2a (P<0.05).Anti-NKG2D mAb can partially blocked the inhibitory effect of NK cells onHBV replication in HBV-HepG2cells, especially blocking the effect of IFN-αactivated NK cells on HBV replication (P<0.05).2.4Changes of TNF-α, IFN-γ, perforin, granzyme B contents in cell culturesupernatant:Trace expression of TNF-α, IFN-γ, perforin, granzyme B was detected inculture supernatant of NK-92cells activated by IL-2and IL-15. Theexpression of these cytokines increased in different degrees in supernatant ofsingle-culture NK-92cells by IFN-α stimulation (P<0.05or <0.01), with IFN-γ levels increased more significantly. The expressions of TNF-α, IFN-γ,perforin, granzyme B were higher in co-cultured group than single-culturedgroup (all P<0.01). Meanwhile, stimulation by IFN-α also significantly raisedthe expressions of these cytokines to a higher levels (all P<0.01), especially inco-cultured system. Similarly, the application of Anti NKG2D mAb cansignificantly inhibit the activated effect of NK-92cells induced by IFN-α, withthe difference was statistically significant (all P<0.01). However, AntiNKG2D mAb blocking can not recovered these indexes to the levels ofpre-intervention.3Effect of NK cells liver migration induced by interferon gammainducible protein10kD on antiviral response to CHB patients3.1Demographic and baseline serum parameter characteristics:The baseline demographic, clinical, biochemical and virologicalcharacteristics in AsC, HBV-related ACLF, and healthy controls were shownin the first part (1.1). All of the60CHB patients, with an average age of37±12(16-65) years, were also comparable for age and sex with the otherchronic HBV-infected patients. Furthermore, the two subgroups of38HBeAg-positive and22HBeAg-negative CHB patients were also comparable for ageand sex (P>0.05).3.2Biochemical, virological, and immunological response after antiviraltreatment:All patients were followed-up for another48weeks after Peg IFN-αtherapy for at least48weeks. At the end of follow-up, the rates of ALTnormalization, undetectable HBV DNA were76.67%(46/60) and65.00%(39/60), respectively.58.33%(35/60) patients (23HBeAg-positive and12HBeAg negative) achieved HBsAg decline>1log10IU/ml, but only8.33%(5/60) patients achieved HBsAg clearance. In addition, among38patientswith HBeAg-positive,60.53%(23/38) achieved HBeAg clearance, of which20patients further achieved HBeAg seroconversion.3.3Baseline levels of serum IP-10and IFN-γ concentration:The serum levels of IP-10and IFN-γ in the CHB and HBV-related ACLF group were both significantly higher than those in the AsC and the healthycontrols (all P<0.01). Moreover, HBV-related ACLF group were the highest,and the difference with CHB group was statistically significant (P<0.01), butthere was no statistical difference between the AsC and healthy controls(P>0.05). The levels of serum IP-10in the HBeAg-positive CHB patientswere also significantly higher than that in the HBeAg-negative ones (P<0.01).Retrospective analysis of the38HBeAg-positive CHB patients showed thatbaseline serum IP-10levels were obviously higher in patients who achievedHBeAg clearance than those with HBeAg persistent positive (P<0.01). Inaddition, baseline IP-10levels were also significantly higher in CHB patientswith HBsAg decline>1log10IU/ml than in those with HBsAg decline <1log10IU/ml (P<0.01).3.4Dynamic changes of serum IP-10during antiviral treatment and follow-upperiods:Serum IP-10decreased gradually during antiviral therapy period,particularly in patients who achieved HBeAg clearance and HBsAg decline>1log10IU/ml. The decline was more obvious in patients achieved HBeAgclearance and HBsAg decline>1log10IU/ml than those with HBeAgpersistent positive and HBsAg decline <1log10IU/ml (P<0.01). Moreover,serum IP-10dynamic decline curve was highly consistent with HBsAg declinecurve in patients with HBsAg decline>1log10IU/ml, especially duringon-treatment period.3.5The expression of intrahepatic IP-10mRNA and protein:As the quantitative expressions of IP-10mRNA for healthy controls wereset to1.00, the IP-10mRNA expression levels in HBV-related ACLF group(8.51±0.64) were significantly higher than those in CHB (4.01±0.74) and AsC(1.04±0.03) groups (P<0.01). Except the difference between AsC group andhealthy controls was not significant statistically (P>0.05), there weresignificantly statistical difference for comparisons of each two groups (P<0.01or <0.05). Similarly, Intrahepatic IP-10protein, which was mainly expressedin hepatocytes around portal areas and necro-inflammatory regions, as well as in interstitial cells in perisinusoidal spaces and parts of infiltrated lymphocytes,showed the similarly difference as IP-10mRNA. Moreover, the level ofintrahepatic IP-10mRNA and protein expressions in HBeAg-positive CHBgroup were much higher than that in HBeAg-negative group (P<0.01).3.6Correlation analysis of serum IP-10levels with ALT levels, HBV DNAloads, HBsAg quantifications, peripheral IFN-γ+NK cells percentage, liverinflammation activity and intrahepatic IFN-γ+cells expression:Serum IP-10was shown to be correlated well with intrahepatic IP-10mRNA, protein expression. Moreover, serum IP-10levels was positivelycorrelated with ALT levels, peripheral IFN-γ+NK cells percentage, liverinflammatory activity and intrahepatic IFN-γ+cells expression (r=0.65,0.60,0.77,0.64, P<0.01), but negatively correlated with serum HBV DNA loadsand HBsAg quantifications (r=-0.69,-0.59, P<0.01).3.7Baseline high level of IP-10(>350pg/ml) was predictor of HBeAgclearance and HBsAg decline during Peg IFN-α antiviral treatment:In multivariate logistic regression analysis, factors predictive of HBeAgclearance were higher baseline IP-10level (OR,6.068;95%CI,1.274-28.902)and higher ALT level (OR,3.745;95%CI,0.826-16.983). While thepredictors of HBsAg decline was higher baseline IP-10level (OR,4.677;95%CI,1.102-19.841), higher ALT level (OR,3.186;95%CI,0.842-12.048) andlower HBV DNA load (OR,0.364;95%CI,0.131-1.013). Moreover, IP-10had a stronger predictive value than other parameters.4Improved efficacy by individualized combination therapy with PegIFN-α2a and ADV in HBeAg positive CHB patients4.1Virological response:During the first24weeks,8.75%(7/80) patients in individualizedtreatment group presented no decrease in HBV DNA levels (one in initialcombination therapy group and six in initial Peg IFNα-2a monotherapy group)as compared to16.25%(13/80) patients in the standard treatment group(P>0.05). At week48, serum HBV DNA was undetectable in72.50%(58/80)patients in the individualized treatment group and53.75%(43/80) patients in the standard treatment group (P<0.05). Between48and96weeks, rates toHBV DNA rebound were18.97%(11/58) and11.63%(5/43) respectively inthe individualized and standard treatment group. And therefore, at the end offollow-up period the sustained undetectable HBV DNA rates were declined to58.75%(47/80) and47.50%(38/80) respectively in the two treatment groups(P>0.05).4.2Biochemical response:After24weeks of treatment, ALT normalization was seen in57.50%(46/80) individualized treatment recipients, including65.79%(25/38) in initialcombination therapy group and50.00%(21/42) in initial monotherapy group,which were all higher than40.00%(32/80) in the standard treatment group(P<0.05). At week48, ALT normalization was obtained in86.25%(69/80)patients in the individualized treatment group and76.25%(61/80) in thestandard treatment group (P>0.05). At the end of follow-up, sustained ALTnormalization had been maintained in78.75%(63/80) patients inindividualized treatment group and71.25%(57/80) in standard treatmentgroup (P>0.05).4.3HBeAg seroconversion and HBsAg loss:After48weeks of treatment, HBeAg clearance, HBeAg seroconversionand HBsAg loss were achieved in63.75%,56.25%and15.00%patientsrespectively in individualized treatment group, and45.00%,37.50%,8.75%patients respectively in the standard treatment group (P<0.05,<0.05, and>0.05, respectively). At the end of follow-up, HBeAg seroconversion andHBsAg loss were recorded in53.75%and17.50%patients in individualizedtreatment group and32.50%and10.00%in standard treatment group (P<0.05and>0.05, respectively). By retrospective analysis at the end of follow-up,38.75%(62/160) patients achieved HBV DNA undetectable, HBeAg clearanceor seroconversion, and/or HBsAg loss, with38patients in individualizedtreatment group and24in standard treatment group.4.4Safety:During treatment and follow-up period, none of the patients in either group withdrew because of adverse events. Only one patient in combinationtherapy group who was detected mutation in rt A181V switched to telbivudinetherapy. Two patients showed raised tri-iodothyronine, thyroxine, anddecreased thyrotropic stimulating hormone. The Peg IFNα-2a dose wasreduced in15patients because of granulocytopenia, but no dose modificationswere needed for ADV. There were no deaths or instances of hepaticdecompensation during treatment or follow-up period, though3patients whounderwent paired follow-up liver biopsy showed increased fibrosis.Conclusions:1The frequency, activity, and distribution of NK cells are significantlydifferent in patients with different clinical stages of chronic HBV infection,which confirmed that NK cells as an important component of the innateimmune cells, are involved in immune regulation to HBV infection, and mightaffect disease progression and clinical outcomes.2NK cells were recruited and activated in the liver, and involved in immuneinflammation and liver injury, which partially attribute to the activation ofNKG2D receptor and secretion of IFN-γ cytokine.3HBV replicative HepG2cell line was established successfully in vitro byplasmid transference. Non-specific cytotoxic activity to target cells wasconfirmed by co-culture with NK cells. IFN-α might strengthen NK cellanti-HBV effects by up-regulating NKG2D activation and IFN-γ secretion.4Blocking the NKG2D pathway in vitro could inhibit the IFN-α inducedcytotoxicity of NK-92cells by down-regulating synthesis and secretion ofIFN-γ, perforin, and granzyme B, which indicated NKG2D activation was animportant signal pathway in mediating anti-HBV cytotoxic activity of NKcells.5IP-10was an important chemokine for NK cells. It was related to NK cellsmigration and aggregation, and correlated with inflammation activity, whichsuggested that effective regulation on IP-10might partly reduce the NKcell-mediated immunological liver injury.6Baseline IP-10expression and its dynamic changes during therapy were correlated with Peg IFN-α antiviral response. As a predictor of HBeAgclearance and HBsAg decline, IP-10provide a strong evidence for predictingclinical antiviral response, and might be an important immunoregulatorytherapeutic target.7Individualized combination therapy with Peg IFN-α2a and ADV exhibiteda more rapid on-treatment ALT normalization, HBV DNA suppression, andHBeAg clearance than monotherapy. Moreover, decline of HBV DNA loads,HBeAg quantification might be important basis on guiding individualizedcombination therapy. |
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