A novel composition of endogenous metabolic modulators improves red blood cell properties in sickle cell disease.

The most common forms of sickle cell disease (SCD) are sickle cell anemia (SCA; HbSS) and HbSC disease. In both, especially the more dense, dehydrated and adherent red blood cells (RBCs) with reduced deformability are prone to hemolysis and sickling, and thereby vaso-occlusion. Based on plasma amino acid profiling in SCD, a composition of 10 amino acids and derivatives (RCitNacQCarLKHVS; Axcella Therapeutics, USA), referred to as endogenous metabolic modulators (EMMs), was designed to target RBC metabolism. The effects of ex vivo treatment with the EMM composition on different RBC properties were studied in SCD (n = 9 SCA, n = 5 HbSC disease). Dose-dependent improvements were observed in RBC hydration assessed by hemocytometry (MCV, MCHC, dense RBCs) and osmotic gradient ektacytometry (Ohyper). Median (interquartile range [IQR]) increase in Ohyper compared to vehicle was 4.9% (4.0%-5.5%), 7.5% (6.9%-9.4%), and 12.8% (11.5%-14.0%) with increasing 20×, 40×, and 80X concentrations, respectively (all p < 0.0001). RBC deformability (EImax using oxygen gradient ektacytometry) increased by 8.1% (2.2%-12.1%; p = 0.0012), 9.6% (2.9%-15.1%; p = 0.0013), and 13.3% (5.7%-25.5%; p = 0.0007), respectively. Besides, RBC adhesion to subendothelial laminin decreased by 43% (6%-68%; p = 0.4324), 58% (48%-72%; p = 0.0185), and 71% (49%-82%; p = 0.0016), respectively. Together, these results provide a rationale for further studies with the EMM composition targeting multiple RBC properties in SCD.

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

Education and training of clinical and translational study investigators and research coordinators: A competency-based approach.

INTRODUCTION: Training for the clinical research workforce does not sufficiently prepare workers for today's scientific complexity; deficiencies may be ameliorated with training. The Enhancing Clinical Research Professionals' Training and Qualifications developed competency standards for principal investigators and clinical research coordinators. METHODS: Clinical and Translational Science Awards representatives refined competency statements. Working groups developed assessments, identified training, and highlighted gaps. RESULTS: Forty-eight competency statements in 8 domains were developed. CONCLUSIONS: Training is primarily investigator focused with few programs for clinical research coordinators. Lack of training is felt in new technologies and data management. There are no standardized assessments of competence.

Enhancing Clinical Research Professionals' Training and Qualifications (ECRPTQ): Recommendations for Good Clinical Practice (GCP) training for investigators and study coordinators.

INTRODUCTION: The translation of discoveries to drugs, devices, and behavioral interventions requires well-prepared study teams. Execution of clinical trials remains suboptimal due to varied quality in design, execution, analysis, and reporting. A critical impediment is inconsistent, or even absent, competency-based training for clinical trial personnel. METHODS: In 2014, the National Center for Advancing Translational Science (NCATS) funded the project, Enhancing Clinical Research Professionals' Training and Qualifications (ECRPTQ), aimed at addressing this deficit. The goal was to ensure all personnel are competent to execute clinical trials. A phased structure was utilized. RESULTS: This paper focuses on training recommendations in Good Clinical Practice (GCP). Leveraging input from all Clinical and Translational Science Award hubs, the following was recommended to NCATS: all investigators and study coordinators executing a clinical trial should understand GCP principles and undergo training every 3 years, with the training method meeting the minimum criteria identified by the International Conference on Harmonisation GCP. CONCLUSIONS: We anticipate that industry sponsors will acknowledge such training, eliminating redundant training requests. We proposed metrics to be tracked that required further study. A separate task force was composed to define recommendations for metrics to be reported to NCATS.

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection.

OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400 mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400 mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400 mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis.

UNLABELLED: Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFß, produced by HCV-specific CD8(+) T cells, is a key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGFß as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross-sectional study of two well-defined groups of HCV-infected subjects with slow (≤ 0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV-specific T-cell responses were studied using interferon-gamma (IFNγ)-ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme-linked immunosorbent assay (ELISA) and multiparameter fluorescence-activated cell sorting (FACS). The effects of IHL stimulated with HCV-core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV-specific IFNγ responses strongly correlated with HCV-specific TGFß, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV-specific IL-10. HCV-specific TGFß was produced by CD8 and CD4 T cells. HCV-specific TGFß, not interleukin (IL)-10, inversely correlated with liver inflammation (R = -0.63, P = 0.008) and, unexpectedly, fibrosis (R = -0.46, P = 0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGFß mAb abrogated such expression. CONCLUSION: Although TGFß is considered a major profibrogenic cytokine, local production of TGFß by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell-derived factors, ameliorating HCV liver disease progression.

Incidence and predictors of acute kidney injury in an urban cohort of subjects with HIV and hepatitis C virus coinfection.

Coinfection with hepatitis C (HCV) significantly increases the risk of acute and chronic renal disease in HIV-infected individuals. However, the burden of acute kidney injury (AKI) directly attributable to HIV among HCV-infected individuals and associated risk factors are not well understood. Within a prospective cohort, AKI episodes were identified by a rise in creatinine of 0.5 mg/dL. Incidence of first AKI events was calculated for HIV/HCV coinfected versus HCV monoinfected subjects, and multivariable analyses using Cox proportional hazards were performed to identify predictors of AKI. Throughout the study period, 35% HIV/HCV coinfected and 17% HCV monoinfected subjects developed AKI, with incidence of 8.74/100 person-years and 3.53/100 person-years, respectively (hazard ratio (HR) 2.48; [95% confidence interval (CI) 1.50, 3.74]). In multivariable analysis, HIV coinfection (HR 2.19 [1.33, 3.62]), decompensated cirrhosis (HR 6.64 [3.81, 11.6]), and cocaine use (HR 2.06 [1.15, 3.71]) were independently associated with AKI. HCV genotype, HCV viral load, hazardous drinking, and heroin use were not associated with AKI. Study limitations included potential misclassification bias of HCV-infected individuals as serial HIV antibody testing was not routinely performed after study entry, and inability to adjust for tenofovir use in multivariable analysis. In conclusion, among subjects with HCV infection, decompensated cirrhosis, HIV coinfection, and cocaine use are associated with increased risk of AKI. These findings highlight the importance of preventing and treating cirrhosis, controlling HIV coinfection, and reducing cocaine use in HIV/HCV coinfected persons.

Sustained long-term antiviral maintenance therapy in HCV/HIV-coinfected patients (SLAM-C).

BACKGROUND: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network. METHODS: HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. RESULTS: Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. CONCLUSIONS: Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.

Noninvasive markers of liver fibrosis are highly predictive of liver-related death in a cohort of HCV-infected individuals with and without HIV infection.

OBJECTIVES: Noninvasive markers of liver fibrosis correlate with the stage of liver fibrosis, but have not been widely applied to predict liver-related mortality. METHODS: We assessed the ability of two indices of liver fibrosis, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fib-4, and two markers of extracellular matrix metabolism, hyaluronic acid (HA) and YKL40, to predict liver mortality in a prospective cohort of hepatitis C virus (HCV)-infected individuals with and without HIV coinfection. These were compared with two established prognostic scores, the Child-Pugh-Turcotte (CPT) and model of end-stage liver disease (MELD) scores. RESULTS: A total of 303 subjects, of whom 207 were HIV positive at study entry, were followed up for a mean period of 3.1 years. There were 33 deaths due to liver disease. The ability of each test and score to predict 3-year liver mortality was expressed as the area under the receiver operator curve. The area under the receiver operator curve 95% confidence intervals were: HA 0.92 (0.86-0.96), CPT 0.91 (0.79-0.96), APRI 0.88 (0.80-0.93), Fib-4 0.87 (0.77-0.92), MELD 0.84 (71-0.91). In multivariate analyses HA, APRI, and fib-4 were independent predictors of mortality when included in models with MELD or CPT. CONCLUSION: Noninvasive markers of liver fibrosis are highly predictive of liver outcome in HCV-infected individuals with and without HIV coinfection. These markers seem to have a prognostic value independent of CPT and MELD.

Resolution of chronic hepatitis C following parasitosis.

An inefficient cellular immune response likely leads to chronic hepatitis C virus (HCV) infection. Resolution of chronic HCV infection in the absence of treatment is a rare occurrence. We report the case of a 39-year old white male with a 17-year history of chronic HCV infection, who eradicated HCV following a serious illness due to co-infection with Babesia (babesiosis), Borriela Borgdorferi (Lyme disease) and Ehrlichia (human granulocytic ehrlichiosis). We hypothesize that the cellular immune response mounted by this patient in response to his infection with all three agents but in particular Babesia was sufficient to eradicate HCV.

Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.

BACKGROUND & AIMS: Pegylated interferon therapy has not been adequately evaluated in acute hepatitis C virus (HCV) infection. This randomized trial assessed the efficacy, safety, and timing of pegylated interferon alfa-2b for treatment of acute hepatitis C. METHODS: One hundred seventy-five patients acutely infected with HCV were screened. Patients whose infection did not spontaneously resolve by week 8 were randomized to once weekly peginterferon alfa-2b monotherapy (1.5 microg/kg per week) started at weeks 8, 12, or 20 for a duration of 12 weeks. The primary endpoint was undetectable HCV RNA 24 weeks after the end of treatment (sustained virologic response [SVR]). All patients were followed for 48 weeks after cessation of therapy. RESULTS: One hundred twenty-nine subjects started treatment at week 8 (group A, n = 43), week 12 (group B, n = 43), or week 20 (group C, n = 43). By using an intent-to-treat analysis, the overall SVR rate was 87%. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Overall, SVR rates were better for patients infected with genotypes 2, 3, and 4 than those infected with genotype 1. Earlier initiation of therapy improved SVR rates for patients infected with genotype 1 with high viral load. Peginterferon alfa-2b was well tolerated. Subjects with SVR maintained undetectable HCV RNA 48 weeks after therapy. CONCLUSIONS: Peginterferon alfa-2b monotherapy in acute hepatitis C induces high sustained virologic response rates, prevents chronic evolution, and is well tolerated. Initiation of treatment at week 8 or 12 results in higher sustained virologic rates than initiation at week 20.

Structural proteins of Hepatitis C virus induce interleukin 8 production and apoptosis in human endothelial cells.

Hepatitis C virus (HCV) infection is associated with inflammation of liver endothelium, which contributes to the pathogenesis of chronic hepatitis. The mechanism of this endothelitis is not understood, since the virus does not appear to infect endothelial cells productively. Here, an 'innocent bystander' mechanism related to HCV proteins was hypothesized and it was investigated whether the binding of HCV particles to human endothelium induced functional changes in the cells. Exposure of human umbilical vein endothelial cells (HUVECs) to HCV-like particles (HCV-LPs) resulted in increased interleukin 8 (IL8) production and induction of apoptosis. The IL8 supernatants collected after stimulation of HUVECs with HCV-LPs, BV-GUS (control baculovirus containing beta-glucuronidase) and appropriate controls were used to assay the transendothelial migration of neutrophils. This assay confirmed that HCV-LP-induced IL8 was functionally active. Using specific NF-kappaB inhibitors, it was also shown that HCV-LP-induced NF-kappaB activity mediated IL8 production in HUVECs. Apoptosis appeared to be mediated by the Fas/Fas-L pathway, as neutralizing antibodies for Fas and Fas-L significantly protected HUVECs against HCV-LP-induced apoptosis. Treatment of HUVECs with HCV-LPs also enhanced cellular Fas-L expression and augmented caspase-3 activation. This was confirmed by using a specific caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethyl ketone. As shown by blocking of specific chemokine receptors for IL8 on HUVECs, the induction of IL8 did not appear to contribute to HCV-LP-induced apoptosis. These results suggest that HCV proteins can trigger the release of inflammatory chemokines such as IL8 and cause endothelial apoptosis, thereby facilitating endothelitis.

Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV. METHODS: A total of 66 subjects were randomly assigned to receive 180 microg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement. RESULTS: Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy. CONCLUSIONS: In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.

Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells.

A subset of CD161(+)CD56(+/-) NKT cells can recognize glycolipids presented by CD1d and positively or negatively regulate inflammatory responses, including those implicated in several models of hepatitis. CD1d is expressed at very low levels in the healthy liver, but there is a large fraction of CD161(+)CD56(+) NKT cells. There are high levels of nonclassical proinflammatory hepatic CD1d-reactive T cells in hepatitis C virus (HCV) infection. Hepatic inflammatory cells and biliary cells adjacent to portal tract fibrotic areas of HCV-infected donors specifically up-regulated CD1d. A hepatocyte cell line expressing minimal CD1d was efficiently recognized by hepatic CD1d-reactive T cells, suggesting a role for these cells in disease. Hepatic CD1d-reactive T cells from HCV-positive as well as negative donors produced large amounts of IFN-gamma with some IL-13, but only rarely detectable IL-4. We confirmed large numbers of hepatic CD161(+) T cells, lower levels of CD56(+) T cells, and small numbers of classic invariant NKT cells. However, hepatic CD1d-reactivity was not restricted to any of these populations. We suggest virally infected hepatic cells can process potent CD1d-presented liver Ag(s), for surveillance by resident Th1 hepatic CD1d-reactive T cells. This process may be beneficial in acute viral clearance, but in chronic infection could contribute to liver injury.

Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis.

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.

Cutting edge: Compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver.

Murine intrahepatic lymphocytes (IHL) are dominated by invariant TCR alpha-chain expressing CD1d-reactive NKT cells, which can cause model hepatitis. Invariant NKT (CD56(+/-)CD161(+)) and recently identified noninvariant CD1d-reactive T cells rapidly produce large amounts of IL-4 and/or IFN-gamma and can regulate Th1/Th2 responses. Human liver contains large numbers of CD56(+) NKT cells but few invariant NKT. Compared with matched peripheral blood T cell lines, primary IHL lines from patients with chronic hepatitis C had high levels of CD161 and CD1d reactivity, but the invariant TCR was rare. CD1d-reactive IHL were strikingly Th1 biased. IHL also demonstrated CD1d-specific cytotoxic activity. Hepatocytes and other liver cells express CD1d. These results identify a novel population of human T cells that could contribute to destructive as well as protective immune responses in the liver. CD1d-reactive T cells may have distinct roles in different tissues.