Publications by authors named "Juandy Jo"

14 Publications

  • Page 1 of 1

Fibrinolytic characteristics of G8 isolated from natto.

Biosci Microbiota Food Health 2021 20;40(3):144-149. Epub 2021 Feb 20.

Department of Biology, Faculty of Science & Technology, Universitas Pelita Harapan, Tangerang 15811, Banten, Indonesia.

Due to the high prevalence of vascular obstructive diseases, discovering potent, safe, and affordable fibrinolytic agents is of importance. There is particular interest concerning the use of functional foods that have a fibrinolytic activity, such as natto, a Japanese fermented soy-based product made with (natto) strain BEST195. We recently isolated another bacterial strain from natto commercialized in Indonesia, G8, which has proven to exert fibrinolytic activity. Herein, a further characterization of G8 was assessed through a comparison with commercialized nattokinase, the major fibrinolytic enzyme of , by utilizing various fibrinolytic assays, namely whole blood clot lysis, euglobulin clot lysis, the fibrin plate method, and zymography. Both nattokinase and G8 were able to dissolve both whole blood and euglobulin clots. Furthermore, both nattokinase and G8 were able to lyse blood clots, presumably due to their ability to directly lyse fibrin. Finally, a crude extract of G8 displayed six zymogram bands of approximately 42.0, 35.5, 30.8, 26.7, 20.0, and 13.7 kDa, with the strongest activity observed at 20.0 kDa. This indicates that G8 contained several fibrinolytic enzymes, which might have comprised nattokinase and other fibrinolytic enzymes. In summary, we demonstrated that a crude extract of G8 has potent fibrinolytic activity and that the activity was mediated by various fibrinolytic enzymes.
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http://dx.doi.org/10.12938/bmfh.2020-071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279889PMC
February 2021

Growth Patterns of Indonesian Infants with Cow's Milk Allergy and Fed with Soy-Based Infant Formula.

Pediatr Gastroenterol Hepatol Nutr 2021 May 4;24(3):316-324. Epub 2021 May 4.

Danone Nutricia Research, Singapore.

Purpose: The use of soy-based infant formula has increased widely in infants with cow's milk allergy (CMA). This study aimed to provide evidence on the growth pattern of CMA infants fed with soy-based infant formula in an Indonesian setting.

Methods: A multi-site, intervention study was conducted among full-term and normal birth weight CMA infants. Within six months, the subjects were provided with a soy-based infant formula. Weight, height, and head circumference were measured at baseline, weeks 4, 8, 12, 16, 20, and 24. Adverse events were recorded by scoring atopic dermatitis and symptom-based clinical scores.

Results: Based on the World Health Organization growth chart, we found that most of subjects had normal nutritional status for weight-for-age, length-for-age, weight-for-length, and head-circumference-for-age. There were statistically significant differences between baseline and end-line for weight-for-age, length-for-age, weight-for-length, and head circumference-for-age nutritional status. No allergic symptoms or intolerance toward soy formula were observed at the end of the intervention period.

Conclusion: These results show that infants fed with soy-based infant formula have a normal pattern of growth.
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http://dx.doi.org/10.5223/pghn.2021.24.3.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128776PMC
May 2021

Relationship Between Insulin-Receptor Substrate 1 and Langerhans' Islet in a Rat Model of Type 2 Diabetes Mellitus.

In Vivo 2021 Jan-Feb;35(1):291-297

Department of Immunopathology, Mochtar Riady Institute for Nanotechnology, Tangerang, Indonesia.

Background/aim: In vivo studies on pathogenesis of type 2 diabetes mellitus (T2DM) have been reported, however, the relationship between insulin-receptor substrate 1 (IRS1) and the area of Langerhans' islets was unknown. Therefore, a correlation between both parameters was assessed.

Materials And Methods: Diabetic groups were fed with a high-fat diet (HFD) and injected with three different doses of streptozotocin, namely 25, 35 and 45 mg/kg, and compared to a control group after 9 weeks.

Results: Administration of HFD/streptozotocin increased the level of fasting blood glucose but reduced the level of IRS1 and the area of Langerhans' islets in diabetic groups. The coefficient of correlation between IRS1 and area of Langerhans' islets was 0.259 (p=0.232). In addition, the coefficient of correlation for fasting blood glucose with the area of Langerhans' islets and IRS1 was -0.520 (p=0.011) and -0.603 (p=0.002), respectively.

Conclusion: The reduction of IRS1 was weakly correlated with the destruction of Langerhans' islets, suggesting there is an intermediate step between both parameters.
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http://dx.doi.org/10.21873/invivo.12258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880789PMC
June 2021

Identification of peptides with tolerogenic potential in a hydrolysed whey-based infant formula.

Clin Exp Allergy 2018 10 14;48(10):1345-1353. Epub 2018 Aug 14.

Danone Nutricia Research, Utrecht, The Netherlands.

Background: Failure to induce oral tolerance may result in food allergy. Hydrolysed cow's milk-based infant formulas are recommended in subjects with a high risk of developing allergic disease. Presentation of T cell epitopes is a prerequisite to generate regulatory T cells that could contribute to oral tolerance.

Objective: To investigate whether a specific hydrolysed whey-based infant formula contains peptides that function as T cell epitopes to support the development of oral tolerance to whey.

Methods: First, a novel liquid chromatography-mass spectrometry (LC-MS) method was developed to characterize β-lactoglobulin-derived peptides present in a specific infant formula with a focus on region AA#13-48 of β-lactoglobulin, which has previously been described to contain T cell epitopes with tolerogenic potential. Second, the formula was subjected to the ProImmune ProPresent antigen presentation assay and MHC class II binding algorithm to identify relevant HLA-DRB1-restricted peptides. Third, identified peptides were tested on human cow's milk protein-specific T cell lines to determine T cell recognition.

Results: Thirteen peptides of minimal 9AAs long that overlap with AA#13-48 of β-lactoglobulin were identified. Six of them were found across all batches analysed. It was further confirmed that these peptides were processed and presented by human dendritic cells. The identified HLA-DRB1-restricted peptides were correlated to AA#11-30 and AA#23-39 of β-lactoglobulin. Importantly, the proliferation assay showed that the synthetic peptides were recognized by cow's milk protein-specific T cell lines and induced T cell proliferation.

Conclusion And Clinical Relevance: This study demonstrates that the tested hydrolysed infant formula contains functional HLA-DRB1-restricted T cell epitopes, which can potentially support the development of oral tolerance to whey.
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http://dx.doi.org/10.1111/cea.13223DOI Listing
October 2018

Intrahepatic CD206 macrophages contribute to inflammation in advanced viral-related liver disease.

J Hepatol 2017 09 5;67(3):490-500. Epub 2017 May 5.

Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos Building, Level 4, Singapore 138648, Singapore. Electronic address:

Background & Aims: Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation.

Methods: Intrahepatic CD14 myeloid cells from healthy donors (n=19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n=15) were subjected to detailed phenotypic, molecular and functional characterisation.

Results: Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14HLA-DRCD206 cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14HLA-DRCD206 cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury.

Conclusions: Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14HLA-DRCD206 myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206 myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients.
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http://dx.doi.org/10.1016/j.jhep.2017.04.023DOI Listing
September 2017

Role of cellular immunity in cow's milk allergy: pathogenesis, tolerance induction, and beyond.

Mediators Inflamm 2014 9;2014:249784. Epub 2014 Jun 9.

Program of Immunology, Danone Nutricia Early Life Nutrition, Singapore 138671 ; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht 3584, The Netherlands.

Food allergy is an aberrant immune-mediated reaction against harmless food substances, such as cow's milk proteins. Due to its very early introduction, cow's milk allergy is one of the earliest and most common food allergies. For this reason cow's milk allergy can be recognized as one of the first indications of an aberrant inflammatory response in early life. Classically, cow's milk allergy, as is true for most other allergies as well, is primarily associated with abnormal humoral immune responses, that is, elevation of specific immunoglobulin E levels. There is growing evidence indicating that cellular components of both innate and adaptive immunity play significant roles during the pathogenesis of cow's milk allergy. This is true for the initiation of the allergic phenotype (stimulation and skewing towards sensitization), development and outgrowth of the allergic disease. This review discusses findings pertaining to roles of cellular immunity in allergic inflammation, and tolerance induction against cow's milk proteins. In addition, a possible interaction between immune mechanisms underlying cow's milk allergy and other types of inflammation (infections and noncommunicable diseases) is discussed.
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http://dx.doi.org/10.1155/2014/249784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070503PMC
February 2015

Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

PLoS Pathog 2014 Jun 26;10(6):e1004210. Epub 2014 Jun 26.

Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore; Program Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore; School of Immunity and Infection, College of Medical and Dental Science, University of Birmingham, Edgbaston Birmingham, United Kingdom.

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.
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http://dx.doi.org/10.1371/journal.ppat.1004210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072808PMC
June 2014

Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner.

Hepatology 2014 Apr 25;59(4):1320-30. Epub 2014 Feb 25.

Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK.

Unlabelled: Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor α (TNF-α) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-α increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-α induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-α, providing a direct mechanism for the virus to promote infection.

Conclusion: This study shows a new role for TNF-α to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events.
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http://dx.doi.org/10.1002/hep.26911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255687PMC
April 2014

IL-1β production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease.

PLoS Pathog 2013 25;9(4):e1003330. Epub 2013 Apr 25.

Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington, USA.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease.
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http://dx.doi.org/10.1371/journal.ppat.1003330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635973PMC
January 2014

IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells.

J Immunol 2013 Apr 27;190(7):3142-52. Epub 2013 Feb 27.

Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research, Singapore 117609.

Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A(+) T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.
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http://dx.doi.org/10.4049/jimmunol.1203218DOI Listing
April 2013

Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B.

Gastroenterology 2012 Sep 15;143(3):637-645. Epub 2012 Jun 15.

Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore; Program Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background & Aims: Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance.

Methods: We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.

Results: Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB.

Conclusions: HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.
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http://dx.doi.org/10.1053/j.gastro.2012.06.009DOI Listing
September 2012

Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential.

J Hepatol 2012 Jul 14;57(1):9-16. Epub 2012 Mar 14.

Department of Medicine II, University Medical Center Freiburg, Germany.

Background & Aims: Perforin plays a central role in the immunopathogenesis of different viral infections. However, its role in hepatitis C virus (HCV) infection has not been fully understood. Here, we analyzed two closely related questions: first, is CD8+ T cell-mediated killing of HCV-replicating human hepatoma cells mediated by perforin? Second, if so, do HCV-specific CD8+ T cells obtained from chronically HCV infected patients express and upregulate perforin?

Methods: Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested in vitro by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers ex vivo from 12 chronically infected patients and 12 patients with resolved HCV infection.

Results: HCV-replicating human hepatoma cells were susceptible to cytotoxic killing in vitro and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained ex vivo from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation ex vivo since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression.

Conclusions: Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells.
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http://dx.doi.org/10.1016/j.jhep.2012.02.030DOI Listing
July 2012

Experimental models to study the immunobiology of hepatitis C virus.

J Gen Virol 2011 Mar 9;92(Pt 3):477-93. Epub 2010 Dec 9.

Department of Medicine II, University Medical Center Freiburg, Germany.

Effective host immune responses are essential for the control of hepatitis C virus (HCV) infection and persistence of HCV has indeed been attributed to their failure. In recent years, several in vitro and in vivo experimental models have allowed studies of host immune responses against HCV. Numerous observations derived from these models have improved our understanding of the mechanisms responsible for the host's ability to clear the virus as well as of the mechanisms responsible for the host's failure to control HCV replication. Importantly, several findings obtained with these model systems have been confirmed in studies of acutely or chronically HCV-infected individuals. Collectively, several mechanisms are used by HCV to escape host immune responses, such as poor induction of the innate immune response and escaping/impairing adaptive immunity. In this review, we summarize current findings from experimental models available for studies of the immune response targeting HCV and discuss the relevance of these findings for the in vivo situation in HCV-infected humans.
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http://dx.doi.org/10.1099/vir.0.027987-0DOI Listing
March 2011

Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model.

Gastroenterology 2009 Apr 13;136(4):1391-401. Epub 2008 Dec 13.

Department of Medicine II, University Hospital Freiburg, and Faculty of Biology, Spemann Graduate School of Biology and Medicine, Albert Ludwigs University, Freiburg, Germany.

Background & Aims: Virus-specific CD8+ T cells are required for the control of hepatitis C virus (HCV) infection. We investigated the extent to which different effector functions of CD8+ T cells contribute to the inhibition of viral replication.

Methods: We developed a novel immunologic model by stably transducing the HLA-A2 gene into the replicon system, matching the epitope sequence of the replicon to the sequence targeted by an HCV-specific CD8+ T-cell clone. Luciferase activity was then measured to quantitate HCV RNA replication.

Results: HCV-specific CD8+ T cells strongly inhibited viral replication, through cytolytic and noncytolytic mechanisms, in a dose-dependent manner. HCV replication was almost completely inhibited at an effector-to-target ratio of 1:1 with significant cytotoxicity; however, >95% viral inhibition occurred at ratios as low as 1:100. Importantly, no cytotoxicity was observed at low effector-to-target ratios, indicating a dominant effect of noncytolytic effector functions that was confirmed by Transwell experiments. Neutralization experiments revealed that interferon gamma mediates the noncytolytic inhibition.

Conclusions: Only a very few HCV-specific CD8+ T cells are required to inhibit HCV replication; inhibition occurs primarily by noncytolytic effector functions.
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http://dx.doi.org/10.1053/j.gastro.2008.12.034DOI Listing
April 2009
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