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Immune Response and Immunomodulation in Chronic Hepatitis B Virus Infection

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Immune Response and Immunomodulation in Chronic Hepatitis B Virus Infection IMMUNERESPONSEANDIMMUNOMODULATIONIN CHRONICHEPATITISBVIRUSINFECTION D.SPRENGERS Immune response and immunomodulation in chronic hepatitis B virus infection Immuunresponsenimmunomodulatieinchronische HepatitisBvirusinfectie PROEFSCHRIFT terverkrijgingvandegraadvandoctor aandeErasmusUniversiteitRotterdam opgezagvandeRectorMagnificus Prof.dr.S.W.J.Lamberts envolgensbesluitvanhetCollegevoorPromoties. Deopenbareverdedigingzalplaatsvindenop woensdag1november2006om13.45uur door Dave Sprengers geborenteGoirle Promotiecommissie Promotor: Prof.dr.H.L.A.Janssen Copromotor: Dr.R.G.vanderMolen Overigeleden: Prof.dr.J.H.P.Wilson Prof.dr.A.D.M.E.Osterhaus Prof.dr.S.W.Schalm ThisstudywassupportedbyagrantfromTheNetherlandsOrganisationfor HealthResearchandDevelopment(ZonMw ,Agikostipendium dossiernum mer92003244). Publicationofthisthesiswasfi nanciallysupportedby:ZonMw ,ZambonNederlandBV , NovartisPharmaBV, Aanmijnouders TU REMANEBIS AMICUS MAXIMUS PERPETUO Contents Page Chapter1: introduction 1 Chapter2: Functionalimpairmentofmyeloidandplasmacytoid 17 dendriticcellsofchronichepatitisBpatients Chapter3: Flowcytometryoffi neneedleaspirationbiopsies:anew 33 methodtomonitorintrahepaticimmunologicalenvironmentin chronicviralhepatitis Chapter4: Differentcompositionofintrahepaticlymphocytesinthe 45 immunetoleranceandimmuneclearancephaseofchronic hepatitisB Chapter5: Analysisofintrahepatic HBVspecifi ccytotoxicTcellsduring 59 andafteracuteHBVinfectioninhumans Chapter6: In vivo immunizationfollowingvirussuppression:anovel 73 approachforinducingimmunecontrolinchronichepatitisB Chapter7: In vivo immunization incombinationwithpeginterferonfor 79 chronichepatitisBvirusinfection Chapter8: InductionofC D4+CD25+regulatoryTcellsassociatedwith 93 nonresponsetopegylated Interferonαtherapyforchronic hepatitisBvirusinfection Chapter9: Discussion 109 Summary 123 Samenvatting Dankwoord CurriculumVitae Abbreviations ALT alanineominotransferase antiHBc antibodiesagainsthepatitisBcoreantigen antiHBe antibodiesagainsthepatitisBeantigen antiHBs antibodiesagainsthepatitisBsurfaceantigen CHB chronichepatitisBvirus CTL cytotoxicTcells DC dendriticcells DNA deoxyribonucleicacid FNAB fin eneedleaspirationbiopsy GMCSF granulocyte/macrophagecolonystimulatingfactor HBcAg hepatitisBcoreantigen HBeAg hepatitisBeantigen HBsAg hepatitisBsurfaceantigen HBV hepatitisBvirus HCV hepatitisCvirus HDV hepatitisDvirus HIV humanimmunodefi ciencyvirus HLA humanleukocyteantigen IFN interferon IL interleukin IVI invivoimmunization LIL liverinfi ltratinglymphocytes mDC myeloiddendriticcells NKcell NaturalKillercell PB peripheralblood PBMC peripheralbloodmononuclearcells PCR polymerasechainreaction pDC plasmacytoiddendriticcells PegIFN pegylatedinterferon poly(I:C) polyriboinosinicpolyribocytidylicacid PreS1Ag hepatitisBpreS1antigen PreS2Ag hepatitisBpreS2antigen SAC Staphylococcus aureusCowenstrainI Th1/Th2 type1/type2Thelpercell Thcell Thelpercell TNF tumornecrosisfactor Treg regulatoryTcells CHAPTER 1 Introduction Modifi edfrom: ImmunomodulatorytherapyforchronichepatitisBvirusinfection D.Sprengers,H.L.A.Janssen,FundamClinPharmacol2005;19:1726 INTRODUCTION Chronic hepatitis B virus infection HepatitisBvirus(HBV)is oneofthemostprevalent viralpathogensofman with almost athirdoftheworldpopulation havingevidenceofinfectionandaround350 million chronicallyinfected patients 1.ChronichepatitisBischaracterized byinfl ammatory liver disease of variable severity and is associated with a signifi cantly increased risk of developing cirrhosis, liver failure and hepatocellular carcinoma 1, 2. HBV is a noncytopathic virus and liver injury is mainly mediated by the host immune response against virus infected liver cells and by the production of infl ammatory cytokines. A vigorous, polyclonal and multispecifi c cytotoxic (CTL) and helperT (Th) cell response to HBV is readily detectable in the peripheral blood of patients with acute selflimited hepatitis B, but is weak, antigenically restricted or undetectable in patients with chronic HBV infection 3.ThisT cell response is believed to be responsible for the elimination of the hepatitis B virus. Two major classes of antiviral therapeutics have been adopted to treat the infection: drugs that directly interfere with virus replication and drugs that modulate antiviral immune response.In most countries lamivudine, adefovir dipivoxil and entecavir are the only approved inhibitors of viral replication (HBV-DNA polymerase inhibitors). Although lamivudine leads to rapid and almost absolute discontinuation of HBV replication 4, breakthrough of resistant HBV variants limits longterm use 5, 6.These limitations underline the need for specifi c and nonspecifi c immunotherapeutic strategies in order to enhance or broaden the defectiveT cell response in chronically infected patients. In this chapter we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines andThymic derivates) and vaccine therapies using currently available recombinant antiHBV vaccines, lipopeptidebasedT cell vaccine and newly developed genetic vaccines. The hepatitis B virus HBV is a partly doublestrandedDNA virus belonging to the group of hepadna viridae 7(fi g 1).The replication of HBV is believed to occur preferentially in the hepatocyte. Analysis of the nucleotide sequence revealed 4 open reading frames, regions of the genome witch may code for viral antigens 7. Although the HBV genome contains only 3200 nucleotides, its compactness and circular composition, employing overlapping genes for production of several viral antigens, make the virus highly effi cient for replication. After entry into the hepatocyte’s nucleus the virus is uncoated and the genomicDNA is converted to a supercoiled form of covalently closed fully double strandedDNA, which is transcribed to pregenomic messengerRNA (mRNA).This viral mRNA is transported to the cytoplasm where it codes for the production of viral proteins. mRNA is reverse transcribed into a minus strand ofDNA which is utilized as a template for completion of the plus strand of the newly synthesized viralDNA. The HBV-DNApolymerase exerts both aDNA polymerase activity and a reverse transcriptase activity.Out of these viral proteins and viralDNA in the cytoplasm of the 3 hepatocytenewHBVparticlesareassembled,thatsubsequently leavethe cell into thecirculation. HBsAg HBcAg HBV polymerase HBV DNA (double stranded) Figure1.Schematic overview ofanHBVparticle,also knownastheDaneparticle. TheHBVgenomeencodesforseveralproteinsthatareusedtoassembletheDane particle.Theoutersurface ofthe virus consistsofthreetypesofhepatitisBsurface antigen(HBsAg).Hepatitis Bcoreantigen(HBcAg)formsthe innercore oftheDane particle.TheviralDNA andthe HBVpolymerase resideinsidethe innercoreofthe virus. The immune response to the hepatitis B virus in humans Patients infected with HBV may develop one of two types of antiHBV immune responses.Thefi rst isan effective antiviralresponsethat suppresses viralgrowthas theresultofboth nonspecifi c(innate)aswell asspecifi c(adaptive)immunity.After earlyactionsof naturalkiller(NK)cells,NKT cellsandantiviralcytokines,individuals withacuteselflimitedHBVinfectionmountavigorous polyclonalandmultispecifi c ThandCTL responsetoepitopeswithinthe HBVenvelope(HBe),nucleocapsidand polymeraseproteins.The peptides are presentedtotheT cellsbyprofessionalantigen presentingcells(APC)andon thesurfaceofinfectedhepatocytes in thecontextof a MHCclassI molecule(fi g2).The responseisreadilydetectablein peripheralblood 811.It often coincides with an elevation of serum alanineaminotransferase levels andprecedesclearanceofHBeandHBs(surface) antigens andthe developmentof neutralizingantibodies.Uponrecognitionofviral peptidesCTL acquirethe capacity toeithercureHBVinfectedcellsvia a noncytopathic,cytokinemediated inhibition ofHBVreplication,orto killthemvia perforinFasligand andTNFαmediateddeath pathways1215.Botheffectorfunctions havebeenobservedduringresolutionofacute hepatitisBandthistype1T cell(Th1)response persistsevenafterclinicalrecovery16. Incontrast,thesecondtypeofantiHBVimmuneresponseisan ineffective one.The HBVspecifi cimmuneresponseisweak,antigenicallyrestrictedorundetectable inthe bloodofchronically infected patients,althoughindividualHBVspecifi cT cellclones havebeenisolatedandexpandedfromliverbiopsies 17, 18.SinceHBV isconsidereda noncytopathicvirus andthe degreeofintrahepaticinfl ammatoryleukocyticinfi ltrate is regardedasthehistologicalhallmark oftheseverity ofchronic hepatitis B,ithas been 4 INTRODUCTION postulatedthatthe HBVspecifi c immune response is too weak to eliminate HBV from all infected hepatocytes, but suffi ciently strong to continuously destroy HBVinfected hepatocytes and to induce chronic infl ammatory liver disease in persistently infected individuals.The reason for this ineffi cient, yet harmful nature of the cellular immune response in chronic hepatitis B is currently not known (table 1), but it emphasizes the need for immunomodulatory drugs capable of inducing an effectiveT cell response that enables eradication of chronic HBV infection. Infected hepatocytes IFN-α prevents infection of Cytotoxic neighboring cells T cell Killing infected cell (specific) HBV-particles T cell Cell killing ADCC (nonspecific) Antigen T helper NK cell Presenting Cell cell Soluble factors regulate immune response (cytokines) Antibody B cell producing cell Figure 2. Schematic overview of cellular immune response to the hepatitis B virus. Viral antigens are processed and presented toT cells (on the infected cell surface)
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