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Published papers on project 3-01-169


Quoted papers: 12
Other papers: 24
Total: 36


  1. Type of paper: Paper in book

    Title:

    Authors:
    Koszinowski, Ulrich
    Lučin, Pero (142314)
    Reddehase, Matthias J.
    Editors
    Landini, M.P.
    Publisher: Elsevier Science Publishers B.V.
    ISBN: 0-444-81699-2
    Year: 1991
    Pages: from 277 to 293
    Number of references: 39
    Language: engleski
    Summary: CMV infection in the immunocompetent host is under efficientimmunological control. In absense of adoptive and natural immunedefence mechanisms, as in the final stages of AIDS, CMV infectsmany tissues and the progressive and irreversible devastatingeffects are manifested as intestitial pneumonia, gastrointestinalsymptoms, retinitis, encephalopathy and endocrinopathies, Inorgan and bone marrow transplant patients the infection canremain asymptomatic in some patients despite of theimmunodepressed state, whereas protean manifestaations of CMVdisease are seen in others. Clearly, more severe organ infectionis seen after severe immunosuppression, whereas alograftrejection reguires a certain level o immunocompetence.Immunomodulatory effects by the virus due to direct infection ofcells that produce cytokines or that are involved in antigenpresentation, such as monocytes and endothelial cells, are likelyto set the stage for qualitative and quantitative differences inT-lymphocyte activation includin the response to allo-ntigen. IfT lymphocytees acivated by CMV antigen are present, they willinvariably conribute to inflammation by cytokine production.Under which condition the IFN gamma produced by these cells cangain importance for the initiation or enhancement ofallo-reactivity is unknown to date. Since nonspecific andadoptive immune effector mechanisms show subtle organ-specificdifferences and because the overall capacity of the host todeploy these affector mechanisms is under genetic, a widespectrum of individual reactivity is to be expected. Futureresearch in various tissuespecific CMV disease manifestations.This knowledge will allow targeted immune manipulations and aspecific type of immune intervention.
    Keywords: Cytomegalovirus, transpantation reaction, MHC expression,

  2. Type of paper: Paper in book

    Title:

    Authors:
    Koszinowski, Ulrich
    Reddehase, Matthias J.
    Jonjić, Stipan (95583)
    Editors
    Thomas, Brian
    Publisher: Marcel Dekker, Inc.
    ISBN: 0-8247-9053-7
    Year: 1993
    Pages: from 429 to 445
    Number of references: 47
    Language: engleski
    Summary: CMV infection in the immunocompetent host is under efficientimmunological control. In the absence of specific immunity, as inthe final stages of AIDS CMV infects many tissues, and theprogressive and irreversible devastating effects are manifestedas interstitial pneumonia, gastrointestinal symptoms, retinitis,encephalopathy, and ednocrinopathies. A comparable situation isrefleced by the moedl of the SCID mouse, which, despite of thepresence of natural immune defense mechanisms such as NK cells,succums to MCMV infection (5). In organ and bone marrowtransplant patients, the infection can remain asymptomatic insome patients despite the immunodepressed state, whereas variedmanifestations of CMV disease are seen in others. Due to directinfection of cells that produce cytokines or that are involved inantigen presentation such as monocytes and ednothelial cells, thevirus may cause qualitative and quantitaive changes inT-lymphocyte subset function during MCMV infection has led tothree important findings. One is that CD8 T lymphocytes, withotuany contribution from CD4 T lymphocytes and antibodies, cancontrol infection and clear virus from several tissues.Therefore,if the sam conditions apply to human infection, mechanisms thatallow generation and mainternance of CMV-specific CD8 efffectorcell functions by either active immunization or passive celltransfer may suffice to prevent lethal disease. Secondly, andthis was an unexpected finding that to our knowledge has not beendescibed for any other virus infection, the CD8 T-cell controldid not clear virus from all organs, but failed to terminate thechronic infection of the salivary glands. We hypothesize that asimila mechanism operates in humans. The third and even moeunexpected finding was the plasticity of immune control. Whereasin fully immunocompetent mice the protective effctor cellresponse was associated with the CD8 t-lymphocyte subset, absenceof this subset led to a funcitional replacement by the CD4 subset.Which mechanism cause the preferential activation of CD8functions in immunocompetent mice is as yet unknown. It isremarkable, however, tthat the CD4 subset can fully replace CD8 Tlymhocyites. Two open questions are associated with the role ofCD4 T-lymphocytes in protection against CMV. One is whether themagnitude of the contribution of either subeset differsbetweenmouse starains. Therefoere, the role of both subsets undrphysiological conditions requires further attention. The otherquestion concerns the type oeffector functions by which CD4 cellscontrol CMV spread. Although it is undisputed that CD4 Tlymphocytes do provide help to CD8 T and B cells, theexperimental evidence gathered so far suggests that this is notthe main function required for MCMV control.Therefore, theeffector activity is either associated with direct cytolyticactivity of CD4 T lymphocytes, with the releace of antiviralcytokines, or with a combination of cytolytic activity andcytokine-induced enhancement of MHC class II expression. Antivarl CD4 T cells with cytolytic potential have in fact beenobserved in several virus infections (reviewed in 47). Yet,someof these findings are likely to be related to the in vitrorestimulation conditions employed, and the physiologicalcontribution ofthe CD4 subset has been studied only in very fewcases. It is clear, however, that the biological role of the CD4subset as an effector cell population with cytolytic functionprobably requires the contribution of cytokines, because few celltypes constitutively express the MHC classs II moleculesrequiered for antigen presentation to the CD4 subset. Aninterestin field of further studes concerns the cytokinesreleassed locally by the CD4 subset, and it is an open questionwhether indivudal cytokine or combined effects of more than onecytokine may directly interfere with CMV replication.
    Keywords: T-Lymphocyte Subsets, Cytomegalovirus, antigen presentation

  3. Type of paper: Paper in journal

    Title:

    Authors:
    Koszinowski, Ulrich
    Journal: Current Opinion in Immunology
    ISSN: 0952-7915
    Volume: 3
    Year: 1991
    Pages: from 471 to 475
    Number of references: 40
    Language: engleski
    Summary: Presentation of viral antigen to T cells does not reguire uptakeby "professional" antigen-presenting cells. Viruses havespecialized to enter the cells in which they replicate. Virusentry , uncoating and new viral protein synthesis can load boththe cytosolic and the endosomal pathway of antigen processin,resulting in viral peptide presentation to CD8 and CD4 T cells inthe control of viral infection has been well documented, currentresearch interest centers on the contribution of the differentCD4 T-cell subsets.
    Keywords: viral infection, T lymphocytes, cytokines.

  4. Type of paper: Paper in journal

    Title:

    Authors:
    Lučin, Pero (142314)
    Pavić, Ivica (163242)
    Polić, Bojan (173636)
    Jonjić, Stipan (95583)
    Koszinowski, Ulrich
    Journal: Journal of Virology
    Number: 4
    ISSN: 0022-538
    Volume: 66
    Year: 1992
    Pages: from 1977 to 1984
    Number of references: 33
    Language: engleski
    Summary: Cytomegalovirus (CMV), similar to other members of theHerpesviridae family, can establish both persistent and latentinfections. Each of the CMV s that are found in many animalspecies replicates in the salivary gland, and oral secretionrepresnts a sourrce of horizontal transmission. Locallyrestricted replication characterizes the immunocompetentindividual, whereas in the immunocompromised host, proteandisease manifestations occur due to virus dissemination. Thevirus is cleared by immune surveillance, and CD8 T lymphocytesplay a major role. Remarkably, certain cell types of salivarygland tissues are exempt from CD8 T lymphocyte control of murineCMV infection and require the activity of CD4 T lymphocytes. Theresults presented here suggest that this activity os a functionof Th1 cells. Neutralization of endogenous gamma interferonabrogated the antiviral activity od Th1 cells but not that of CD8T lymphocytes in other tissues. Neutralization of endogenousgamma interferon did not interfere with the induction og thecellular and humoral immune response but acted durin the effectorphase. Recombinant gamma interferon could not replace thefunction of Th1 cells in vivo and had limited direct antiviralactivity in vitro. The results therefore suggest that gammainterferon represents one, but not the only, esssential factorinvolved in salivary gland clearence, establishment of CMVlatency, and, eventually, the control of horizontal transmission.
    Keywords: Gamma interferon, Cytomegalovirus, Salivary Glands

  5. Type of paper: Paper in journal

    Title:

    Authors:
    Pavić, Ivica (163242)
    Polić, Bojan (173636)
    Crnković, Irena (194586)
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Koszinowski, Ulrich
    Journal: Journal of General Virology
    ISSN: 0001-1744
    Volume: 74
    Year: 1993
    Pages: from 2215 to 2223
    Number of references: 48
    Language: engleski
    Summary: Interferon gamma (INF gamma) represents an esential cytokineinvolved in mirine cytomegalovirus (MCMC) clearance from thesalivary gland and the control of horizontal transmission.Because IFN gamma cannot be responsible for all cytokine effestsdurin recovery from MCMV infection we have now tested thepotential participation of tumour necrosis factor alpha (TNFalpha) in the antiviral defence. Neutralization of endogenous TNFalpha abolished the antiviral activity of CD4 cells inimmunocompetent as well in CD8 subset-deficient mice. These datasuggest that the antiviral efeect of the CD4 subset requires thepresence of at least two cytokines, namely IFN gamma and TNFalpha. Depletion of endogenous TNF alpha in adoptive celltransfer recipients diminished the antiviral function of CD8 Tlymphocytes suggesting that TNF alpha also participates in CD8 Tcell effector functions. Futhermore, endogenous cytokines werwfound to be required for survival after infection with lethaldoses of MCMV, whereas immunotherapy with recombinant TNF alphaand IFN gamma could not limit virus replication in vivo. Theresults suggest tha, similar to IFN gamma TNF alpha is anintegral part of the protective mechanisms involved incytomegalovirus cleareance.
    Keywords: tumor necrosis factor alpha, cytomegalovirus.

  6. Type of paper: Paper in journal

    Title:

    Authors:
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Messerle, Martin
    Polić, Bojan (173636)
    Hengel, Hartmut
    Koszinowski, Ulrich
    Journal: Journal of General Virology
    Number: 1
    ISSN: 0001-1744
    Volume: 75
    Year: 1994
    Pages: from 0 to 0
    Number of references: 32
    Language: engleski
    Summary: We have shown previously that the antiviral function of CD4 Tlymphocytes against mouse cytomegalovirus (MCMV) is associatedwith the release of interferon gamma (IFN-gamma). We nowdemonstrate that IFNgamma and tumor necrosis factor alpha(TNFaplha) synergize in theri antiviral activity. As little as 2ng/ml of IFNgamma and TBFalpha reduced the virus yield by aboutthree orders of magnitude. There was no effect on immediate earlyand early gene expression as far as the candidate genes ie1, andthe genes encoding the major DNA binding protein (MDBP) and theDNA polymerase (pol) are concerned. Late gene transcription,assaayed by the candidate genes encoding the glycoprotein B (gB)and the CMV homolog of ICP 18,5, was blocked, whereas MCMV DNAreplication was found reduced but not abrogated. The mostprominent finding of the cytokine effect seein in electronmicroscopy was an alteration of nucleocapsid formation.Alttogether, the synergism is multifaceted and acts at more thanone step durin viral morphogenesis. Because the cytokines clearlydo not act at an early stage of infection we conclude that themode of cytokine activity differs between alpha andbetaherpesviruses.
    Keywords: Cytomegalovirus, inteferon gamma, tumor necrosis factor alpha, virus replication.

  7. Type of paper: Paper in journal

    Title:

    Authors:
    Polić, Bojan (173636)
    Pavić, Ivica (163242)
    Crnković, Irena (194586)
    Lučin, Pero (142314)
    Trobonjača, Zlatko
    Jonjić, Stipan (95583)
    Journal: Croatian Medical Journal
    Number: 4
    ISSN: 0353-9504
    Volume: 34
    Year: 1993
    Pages: from 294 to 300
    Number of references: 59
    Language: engleski
    Summary: The review prosents the current understanding ot the involvementof T-cell subsets in the control of viral infections. Theantiviral response of normal immunocompetent hosts and thosedepleted of CD4+ or CD8+ T lymphocytes indicates a considerableplasticity of the immune system. For example, although the majorhistocompatibility complex (MHC) class I-restriced CD8+ T cellsplay the pivotal role in the protection of immunocompetent hostagainst several viral infections, other compensatory mecanismsexist in the absence of the dominant T cell subset. Thiscompensatory effector function was first detected in micedepleted od CD8 subset by in vivo tretment with anti CD8antibodies. More recently, similar results were observed intransgenic mice lacking functional class I molecules and were, asa result, devoid of CD8+ T lymphocyts. Essential contribution ofTh1 and Th2 subsets of CD4+ T lymphocytes to the in vivo controlof viral infection is also discussed. The mechanismsthe virusesuse to evade the effector mechanisms mediated by T lymphocytesare mentioned.
    Keywords: CD4+ T lymphocytes, CD8+ T lymphocytes, cytokines, viruses.

  8. Type of paper: Paper in journal

    Title:

    Authors:
    Hengel, Hartmut
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Ruppert, Thomas
    Koszinowski, Ulrich
    Crnković, Irena (194586)
    Journal: Journal of Virology
    Number: 1
    ISSN: 0022-538
    Volume: 68
    Year: 1993
    Pages: from 289 to 297
    Number of references: 44
    Language: engleski
    Summary: An imediate-early protein of murine cytomegalovirus (MCMV), pp89,elicits an immunodominant and protective major histocompatibilitycompex (MHC) clas I Ld-restrictd CD8+ T1lymphocyte response.Remarkably, presentation of the naturally processed peptide ofpp89, the nonapeptide YPHFMPTNL, is abolished during permissiveMCMV infection in vitro. This defect in pp 89 presentation is dueto the expression of MCMV early gene functions that specificallyblock the transport of peptide-charged MHC class I complexes tothe cell surface (M. Del Val, H. Hengel,H. Hacker, U. Hartlaub,T. Ruppert, P. Lučin, and U.H. Koszinowski, J. Exp. Med.176:729-738),1992). Here, we demonstrate that MCMV-specific CD8+T lymphocytes can reconstitute pp 89 presentation in a parakrinefashion. The lymphocytes mediate the rstoration of antigenpresentation by MCMV-infected cells by releasing gamma interferon(IFN-gamma). IFN-gamma has no effect on synthesis and stabilityof the viral antigen pp89 nor does it interfere with theexpression of viral early genes and their inhibitory effect onMHC class I molecule maturation. IFN -gamma results in a25-fold increase in the synthesis of MHC class I molecules and asimilar increase in the abundance of pp89 -derived peptide. Manyof the MHC molecules remain, retained by the viral effect, but asurplus of MHC molecules escapes the effect and provides theefective surgace presentation of the peptide. Adoptive celltransfer studies demonstrate the IFN-gamma dependence of CD(+ Tlymphocyte function in vivo. Altogether, these data reconcile theparadoxical findings of an impaired pp89 presentation iv vitro inparallel with pp89 specific CD8+ T-cell protection in vivo. Theresults also imply a role of IFN-gamma in the T lymphocytemediated controlg of cytomegalovirus infection. The knownpropensity of cytomegalovirus to cause serious disease in theimmunocompromised host is discussed in the light of thesefindings.
    Keywords: Cytomegalovirus, Antigen Presentation, Inteeferon gamma.

  9. Type of paper: Paper in journal

    Title:

    Authors:
    Reddehase, Matthias J.
    Balthesen, Monika
    Rapp, Maria
    Jonjić, Stipan (95583)
    Pavić, Ivica (163242)
    Koszinowski, Ulrich
    Journal: Journal of Experimental Medicine
    Number: 1
    ISSN: 0022-1007
    Volume: 179
    Year: 1994
    Pages: from 185 to 193
    Number of references: 29
    Language: engleski
    Summary: Recurrence of cytomegalovirus (CMV) from latency is a frequentcause of disease in immunocompromised patients. To date, there isno explantation for the diversity in the clinical manifestations.Primary infection can occur perinatally or later in life, andinevitably results in latent infection.Seropositivity forantibodies against CMV is indicative of latent infeciton, but isinsufficient as a predictor for the risk of recurrence. As amodel for this important medical problem, we compared the risksof murine CMV recurrence from latency established after neonatalprimary infection and after infection at adult age.The risk ofCMV recurrence was high only after neonatalinfection. The copynumber of latent viral genome in tissues was identified as thekey parameter that determines the coverall and organ-specificrisks of recurrence. Latent CMV burden and riskof recurrence wererelated to the extent of virus multiplication during primaryinfection. The presence of latent CMV in multiple organs providesthe molecular basis for stochastic events of recurrence in singleorgans or in anx combination thereof. These findings arediscussed as a concept of multifocal CMV latency and recurrence.It provides a rationale for the diversity in the clinical outcomeof CMV disease.
    Keywords: Cytomegalovirus, Latent infection, Reactivation.

  10. Type of paper: Paper in journal

    Title:

    Authors:
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Journal: Periodicum Biologorum
    Number: 1
    ISSN: 0031-5362
    Volume: 97
    Year: 1995
    Pages: from 13 to 22
    Number of references: 58
    Language: engleski
    Summary: Cytomegaloviruses (CMV) are members of the herpesvirus family. They share many simularities at the molecular level with herpes simplex virus, the prototype of the herpes group, but also many differences. The molecular differences are reflected in different biological manifestations of infection. This communication presents a brief overview of the replication cycle of human and murine CMV, with emphasis on the structural changes of the host cell induced by infection and events associated with essembly of the viirions.
    Keywords: cytomegalovirus, human cytomegalovirus, murine cytomegalovirus, CMV nucleocapsids, CMV morphogenesis, CMV replication

  11. Type of paper: Paper in proceedings

    Title:

    Authors:
    Jonjić, Stipan (95583)
    Editors
    Frohlich, K.U.
    Sauerbeck, M.
    Schlauer, J.
    Proceedings title: Proceedings of MoBbel
    Language: engleski
    Place: Tuebingen, Njemačka
    Year: 1994
    ISBN/ISSN: 3-926323-77-9
    Pages: from 115 to 124
    Meeting: 9th International Automn Meeting
    Held: from 10/06/94 to 10/09/95
    Summary: The MHC class I restricted CD8+ T cells represent the major mediator of virus control during primary as well as during chronic CMV infection in immunocompetent host and only T cells that can provide protection after adoptive transfer into immunodeficient dyngeneic host. However, mice lacking MHC class I restricted CD8 cells can still clear the infectious virus and establich CMV latency. Although the effector mechanisms operative in mice eith intact CD4 subset, in absence of class I restricted response, have not yet been sufficiently characterised, recent experiments support the role of cytokines, among which IFN-g and TNF-a play a central role. However, the participation of early-induced response mechanisms in the plasticity of immune response can not be excluded. The potential impact of T cells bearing gd TCR has been suggested in some other studies and still has to be determined in MCMV infection. In conclusion, our knowledge on the capacity of various components of immune system to express their cryptic effector function is still fragmentary. The use of mutant mouse strains bearing deletion of essential and nonessential immune response mechanisms will soon improve our knowledge on the plasticity of immune system.
    Keywords: cytomegalovirus, innate immunity, plasticity of immune response, T lymphocytes

  12. Type of paper: Summary in proceedings

    Title:

    Authors:
    Jonjić, Stipan (95583)
    Lučin, Pero (142314)
    Pavić, Ivica (163242)
    Polić, Bojan (173636)
    Crnković, Irena (194586)
    Koszinowski, Ulrich
    Proceedings title: 8th International Congress of Immunology, Abstracts
    Language: engleski
    Place: Budapest, Hungary
    Year: 1992
    ISBN/ISSN: 963-7922-58-X
    Pages: from 401 to 401
    Meeting: 8 th International Congress of Immunology Budapest, Hungary, August 23-28, 1992.
    Held: from 08/23/92 to 08/28/92
    Summary: As the other members of Herpesviridaee family, thecytomegalovirus (CMV),can establish both persistent and latentinfections. Each of the CMV that are found in many animal speciesreplicates in the salivary gland, and oral secretion represents asource of horizontal transmission. Locally restricted replicationcharacterizes the immunocompetent individual, whereas in theimmunocompromised host protean disease manifestations occur dueto virus dissemination. The virus is cleared by immunesurveilance and CD8 T lymphocytes play major role. However,certain cell types of salivary gland tissues are exempt from CD8T lymphocyte control of murine CMV (MCMV) infection and requirethe activity of CD4 T lymphocytes. Our results suggest that thisactivity is a function of Th1 cells of CD4+ T lymphocytes.Neutralization of endogenous IFN-gamma abrogated this function ofTh1 cells but not the antiviral activity of CD8+ T lymphocytes isother tissues. Neutralization of endogenous IFN-gamma did notinterfere with the induction of the cellular and humoral immuneresponse but acted during the effector. Phase. riFN-gamma couldnot replace the function of Th1 cells in vivo and had littledirect antiviral activity in vitro. The results, therefore,suggest that IFN-gamma represents one, but not the only essentialfactor involved in salivary gland clearance, establishment of CMVlatency, and eventually, the control of horizontal tramsission.
    Keywords: Interferon gamma, Cytomegalovirus, T lymphocytes,

  13. Type of paper: Summary in proceedings

    Title:

    Authors:
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Messerle, Martin
    Polić, Bojan (173636)
    Koszinowski, Ulrich
    Proceedings title: Multidisciplinary Aporoach to Understanding Cytomegalovirus Disease
    Language: engleski
    Place: Paris, France
    Year: 1993
    Pages: from 141 to 141
    Meeting: 4th International Cytomegalovirus Conference
    Held: from 04/18/93 to 04/21/93
    Summary: We have previously shown that endogenous interferon-gamma(IFN-gamma) represents one essential factor for murinecytomegalovirus (MCMV) clearance in vivo. Here we describesynergistic antiviral effect of IFN-gamma and tumor necrosisfactor (TNF) against MCMV in vitro. The antiviral state wasachived by pretreatment of cells with nontoxic concentrations ofboth cytokines and resulted in a redction of virus productivityby more than three oreders of magnitude. Analysis of MCMV geneexpression showed and translation of late genes ( glycoprotein B,glycoprotein H, ICP 18,5 dUTPase) was strongly inhibited. ViralDNA replication was decreuse, althought at least two of the sevenealry genes involved in control of herpessviralDNA synthesis(major DNA binding protein and DNA polymerase) werw not affected.DNA synthesis (major DNA binding protein and DNA polymerase) werwnot affected. Electron microscopy analysis showed acharacteristic delayed and altered morphogenesis od MCMV.Cytokinetreatment resulted in the release of a reduced numbers of mainlynoninfeective virons as nocluded by determination of the relationbetwewn infectivity and DNA content from virions released insupernatant. Thus, in order to explain the strong antiviraleffect of CD8 and CD4 T lymphocytes against MCMV in vivo, notonly the cytolytic activity of effector cells but also thecytokines released by these cells have to be considered.
    Keywords: Interferon gamma, Tumor necrosis factor alpha, cytomegalovirus

  14. Type of paper: Summary in proceedings

    Title:

    Authors:
    Koszinowski, Ulrich
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Ruppert, Thomas
    Hengel, Hartmut
    Proceedings title: IXth International Congress of Virology, Abstracts
    Language: engleski
    Place: Glasgow, Scotland, UK
    Year: 1993
    Pages: from 27 to 27
    Meeting: IXth International Congress of Virology
    Held: from 08/08/93 to 08/13/93
    Summary: MHC class I-restricted CD8+ T lymphocytes play a crucial role inthe host defence against CMV. This is counteracted by an E gonelunction of murine cytomegalovirus (MCMV) that blocks thetransport of correctly assemled MHC class I complexes throughtthe Golgi compartment (Del Val et al., J.Exp. Med. 172:729, 19929and prevents MHC class I L-restricted presentation of theimmediate early (IE) protein po89 derived nonapeptide YPHFMPTNLan immunodominat and proective CD8+ T cell responsc in vivo. Herewe demonstrate that MCMV-specific CD8+ T lymphocytes reconstitutepp89 of viral E genes but results in a strong increase in theabundance of pp89 antigen presentation by releasing IFN-gamma.This does not affecet the expression of viral E genes but resultsin a strong increase in the abundance of pp89 peptides, inparallel with a similar increase in the synthesis and assembly ofMHC classI complexes. While most of the MHC class I compexes areretained in the ER/cis-Golgi by the viral effect a surplusescapes and presents the peptide on the cell surface. Adoptivecell transfer studies suggest that the IFN-gamma effect uponclass I antigen presentation regulates the CD8+ T effector colfunction in vivo. Similarly, the antiviral function of DC4+ T lymhpocytes isassociated with IFN-gamma (Lucin et al. J.Virol 66:1977, 1992).The cytokine not only boosts antigen presentation, but also hasdirect antiviral effect. Synergizing with antother CD$+ cellproduct, TNF, IFN-gamma reduces the virus yield in vitro by threeorders of magnitude. While the cytokines have no effect on IEand E gene ehpession, DNA replication and late gene transcriptionis inhibited.
    Keywords: Interferon gamma, CD4+ T lymphocites, CD8+ T lymphocites, Cytomegalovirus

  15. Type of paper: Summary in proceedings

    Title:

    Authors:
    Polić, Bojan (173636)
    Pavić, Ivica (163242)
    Crnković, Irena (194586)
    Jonjić, Stipan (95583)
    Koszinowski, Ulrich
    Proceedings title: IXth International Congress of Virology, Abstracts
    Language: engleski
    Place: Glasgow, Scotland, UK
    Year: 1993
    Pages: from 143 to 143
    Meeting: IXth International Congress of Virology
    Held: from 08/08/93 to 08/13/93
    Summary: It is commonly accepted that the control of primary and chroniccytomegalovirus (CMV) infection as well establishment andmaintenace of latency. is function of T lymphocytes. On the otherhand, the physiological function of specific antibodies whichlimit virus spread but are unable to cleare the infection and toprevent superinfection is less known. Studdies in mice depletedof the CD4 subset have invariably shown that clearance of murineCMV (MCMV) can take place in absence of CD4* T lymphocites andvirus spedifiic antibodies by generation protective CD8+ T cells.However, CD4 depleated mice fail to eliminate virus from acinarglandular epithelial cells of the salivary glands, leading toestablishment of chronic persistent infection in this organ. Thisfinding opens the question whether the antibodiesmight beessential for prevention of persistency and establishment oflatency. Although several later frindings argue against thisassumption (jonjić et al.J.Virol. 64:5457, 1990), such possiblityis not entirely excluded. In this study we used B cell-deficientmice (Kitamura er al. Nature, 350:423, 1991) as model to assesswhether antibodies could be essential for virus clearance andestablishment of latency. The evidence provided indicates thatmice having normal T-cell response, but lacking anyimmunoglobulins, cal still control MCMV infection with clearancekinetics similar to that of normal mice. In addition, the resultsalso suggest that virus-specific antibodies are not essential forestablishment and maintenance of latency.
    Keywords: cytomegalovirus, antibodies, viral latency

  16. Type of paper: Summary in proceedings

    Title:

    Authors:
    Pavić, Ivica (163242)
    Polić, Bojan (173636)
    Crnković, Irena (194586)
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Koszinowski, Ulrich
    Proceedings title: IXth Interational Congress of Virology, Abstracts
    Language: engleski
    Place: Glasgow, Scotland, UK
    Year: 1993
    Pages: from 142 to 142
    Meeting: IXth International Congress of Virology
    Held: from 08/08/93 to 08/13/93
    Summary: It is Well established that CD8+ T lymphocytes represent themajor protective principle involved in response ofimmunocompetent host to cytomegalovirus (CMV) infection. However,in abssence of CD8 subset, CD4+ T lymphocytes fully compensateits function. We have recently shown that the function of CD4+ Tlymphocytes is control of CMV infection is associated withrelease of gamma interferon (IFN-gamma), because neutralizationof endogenous (IFN-gamma abrogates their function in vivo (Lučinet al. J. Virol. 66:1977, 1992). The findings that IFN-gamma hasonly moderate direct anti CMV effect in vitro and the therapywith recombinant IFN-gamma fails to repleace antiviral functionof CD4 subset, ssugest that the function of IFN-gamma isassociated with some other cytokines. The aim of the presentstudy was to determine wheter endogenously formed TNF-alpha andIL4 are required for control of murine CMV(MCMV) infection. Theinvolvement of these cytokines was examined by means ofexperiments in which MCMV infected mice werw treated withneutralizing antibodies to TNF-alpha and IL4. The results suggesttha endogenous TNF-alpha is involved in antiviral functionsimilar to protective capacity of MCMV primed adoptivelytransferred lymphocytes and abolishes the clearance of virus formsalivary glands of acutely infected immunocompetent mice. Inaddition, when virus clearance depends entirely on CD4 subset,such as in CD8 deficiency, ant TNF-alpha compromises virusclearance not only in salivary glands but also in lungs,suggesting that TNF-alpha is prodominantly involved in CD4aubset-dependent control of CMV infection. Neutralization of IL 4had no effect on MCMV replication in vivo.
    Keywords: Tumor necrosis factor alpha, cytomegalovirus,

  17. Type of paper: Summary in proceedings

    Title:

    Authors:
    Koszinowski, Ulrich
    Hengel, Hartmut
    Del Val, Margarita
    Ruppert, Thomas
    Lučin, Pero (142314)
    Jonjić, Stipan (95583)
    Eggers, Maren
    Geginat, Gernot
    Rapp, Maria
    Proceedings title: Journal of Cellular Biochemistry
    Language: engleski
    Place: New York, USA
    Year: 1993
    ISBN/ISSN: 0730-2312
    Pages: from 38 to 38
    Meeting: 8 th International Congress of Immunology Budapest, Hungary, August 23-28, 1992.
    Held: from 03/17/93 to 03/24/93
    Summary: Cytomegalovirus (CMV) causes lethal disease in theimmunocompromised host whereas infecion of the immunocompetent isusually asymptomatic. Yet, even in presence of normal immunecontrol, episodes of productive infection do occur and cause thehorizontal transmission of the virus. Thus, the physiologicalantiviral immune response protect vital tissues but executes aless stringent control over others. By studying the infection ofthe mouse with the murine CMV (MCMV) we wish to unravel therelative contributon of the specific imune effector mechanismsinvolved. Cell transfer experiments showed that only CD8+ Tlymphocytes dominate in the protection against lethal infection.The productive infection in the salivary gland, however, remainedcompletly refractory to the activity of the CD8+ T lymphocytesubset. Despite of high titers in this organ the CD8+ Tlymphocytes prevent the spread to other tissues. Cell transferstudies and experiments with CD4+ deficient mice showed that inthe salivary gland CD4+ T lymphocytes are essential effectorcells, and that they can operate in the absence of the CD8+subset. Thus, in the normal host clearance of the vital tissuesand control of horizontal spread is under control of different Tlyphocyte subset. CD4+ subset control of salivary gland infectionrequires the activity of TH1 cells. This became evident from theblockade of effector function after administration of antibodiesagainst IFNgamma. IFNgamma, in concert with TNF, represents apowerful inhibitor, active in the late phase of the viralreplication cycle. The molecular identification of the majortargets for the CD4+ subsets are under study. Analyisis of the specificity of the CD8+ subsets led to thedefinition of the naturally processed peptide derived from thedominant antigen, an immediate early protein. This nonamericpeptide, when flanked by appropriate sequences in a carrierprotein can serve as a vaccine. Remarkably, viral functions ofthe early phase prevent presentation of this peptide. Thisinhibition is due to the retention of the nascent peptide loadedMHC complex at the ER/cis Golgi level. The progress of theimmune response counteracts this evasion mechanism becauseantigen presentation by cells pretreated with IFNgamma arecapable to export the peptide/MHC complex.
    Keywords: Cytomegalovirus, antigen presentation, cytokines, T lymphocytes

  18. Type of paper: Summary in proceedings

    Title:

    Authors:
    Polić, Bojan (173636)
    Jonjić, Stipan (95583)
    Pavić, Ivica (163242)
    Crnković, Irena (194586)
    Zorica, Irena
    Lučin, Pero (142314)
    Hengel, Hartmut
    Koszinowski, Ulrich
    Proceedings title: ENII Conference 1995
    Language: engleski
    Place: Les Embiez, Francuska
    Year: 1995
    Pages: from 227 to 227
    Meeting: ENII Conference 1995, Physiology and Pathology of the Immune System
    Held: from 05/17/95 to 05/21/95

  19. Type of paper: Ph.D.

    Title: Regulatory role of T lymphocytes and cytokines on the autoantibody response during cytomegalovirus infection
    Date of defense: 09/09/91
    Language: engleski
    Number of pages: 127
    Summary: The objective of this study was to analyse the regulatory role ofT-cell subsets and cytokines in the induction of autoantibodyresponse during the primary and secondary immune response to theinfection with MCMV. During the primary and secondary antibodyresponses to MCMV, a wide array of autoreactive antibodies wasproduced. Autoreactivity is directed to different cellularantigens, mainly to nuclear and cell surface structures. We haveshown that in vivo production of antiviral antibodies andautoantibodies is almost completely dependent on the presence ofCD4+ cells.
    Keywords: Cytomegalovirus, T lymphocytes, cytokines, autoantibodies,


  20. Type of paper: Ph.D.

    Title: The Role of Cytokines in Control of Cytomegalovirus Infection
    Faculty: Medicinski fakultet Sveučilište u Rijeci
    Language: hrvatski
    Number of pages: 108


  21. Type of paper: M.A.

    Title:
    Faculty: Medicinski fakultet Sveučilište u Rijeci
    Date of defense: 12/30/92
    Language: hrvatski
    Number of pages: 120
    Summary: Destruction of virally infectied cells by CD8+ CTL (CitoxicT-cell Lymphocytes) requires the recognition of proteolyticfragment of antigenic viral proteins presented by class I MHCantigens on the surface of infected cells. Thus, the expressionof classs I antigens in tissue can be a limitin factor for theefficacious virus elimination by CTL. There is growing evidencethat viral infections and virus-induced transformation canaaffect class I antigen expression and this might be one of thestrategies used by virus to avoid immunosurveillance. Manyalternative mechanisms by which viruses affect the expression ofMHC molecules may exist. Among observations that appear relevantare the findings oftrans-acting factors, cis-elements, flankingMHC genes, alterations in methylation of genomic DNA, viralintegrations, and effect on both posttranscriptional processingof mRMA and posttranscriptional modification and/or transport ofprotein. Cytomegalovirus (CMV) is an important pathogen forimmunodefficient host and even the immunocompetent host fails toeradicate virus and establish latent infection, especially insalivary glands. So, in this study, we tested the effect ofmurine CMV (MCMV) infection on the surface expression of MHCclass I molecules as a possible immunosubversive mechanism andreported some findings: first, MCMV infection of permissive MEF-s(murine embrional fibroblasts) leads to abolishemnt of class Imolecules from cell surface at five and six hours afterinfection; second, downregulation of class I molecules isdependent of protein synthesis of early phase (E) ofMCMV geneexpression; third, blocking of protein transport preventsdownregulation of class I MHC molecules; fourth, blocking ofglycozilation of proteins in ER also abrogates the effect of MCMVinfection on MHC class I molecules; fifth, downregulation ofalready memabrane-anchored MHC class I molecules is a membraneevent caused by MCMV infection products; sixts, preincubation ofMEF-s with IFNgamma can prevent downregulatory effect of MCMVinfection; and seventh, MCMV infection cannot abrogate IFNgammainduced expression of MHC classe II antigens on MEF-s.
    Keywords: Major Histocompatibily Complex, Cytomegalovirus, Cytokines


  22. Type of paper: M.A.

    Title: Selective role of T lymphocytes in the control of viral infection
    Faculty: Medicinski fakultet Sveučilište u Rijeci
    Date of defense: 11/12/91
    Language: hrvatski
    Number of pages: 83
    Summary: Human cytomegalovirus (HCMV), a member of the herpesvirus family,is endemic in all human populations. The status of immune systemdictates whether infection is asymptomatic or leads to clinicalor even fatal disease. To study the immune mechanisms in theinfected host, infection of mice with murine cytomegalovirus(MCMV) has been used as a suitable animal model. The aim of thestudy was to analyse the contribution of CD4+ and the CD8+ Tlymphocyte subsets to MCMV clearance. The experimental approachhas been depletion of lymphocyte subsets in vivo before andduring infection, and adoptive cell transfer to immunocompromisedsingeneic hosts. In this study we show, among other results, thatmice can control acute MCMV infection in the absence of the CD4+subsets. CD4- mice clear most infected organs but develop achronic infection confined to the salivary glands. Although therelative contribution of different immune effector functions toclearing tissues of cytomegalovirus is controversial, thecontribution of the CD8+ T lymphocytes has generally beenaccepted as essential. We have confirmed that primed CD8+ Tlymphocytes can protect against subsequent lethal MCMV disease.This protective function of antecedent CD8+ T lymphocytesactivity was documented by cell transfer experiments. Ourexperiments invariably showed the whenever CD8+ T lymphocyteswere activated, they played a dominant role in protection.However, we also show that under certain conditions the CD8+ Tlymphocytes can be dispensable for clearance of cytomegalovirus.Mice depleted of the CD8+ T lymphocyte subset eliminatedinfectious virus with a clearance kinetics similar to that ofnormal mice. Adoptive transfer studies revealed that thelimitation of virus spread required the cooperation between theCD4+ subset and other cells. Comparison between protectivefunctions generated in fully immunocompetent and in CD8- micedemonstrated that elimination of the CD8+ subset before infectionaltered the quality of the antiviral immune response. Thecompensatory protective activity gained by CD4+ cells in CD8-mice was absent in normal mice recovering from virus infection.
    Keywords: Cytomegalovirus, CD4+ T lymphocytes, CD8+ T lymphocytes


  23. Type of paper: M.A.

    Title: Downregulation of MHC class I molecules as a mechanism by which cytomegaloviruses escape immunological control
    Faculty: Medicinski fakultet Sveučilište u Rijeci
    Author: CRNKOVIĆ IRENA
    Date of defense: 04/21/94
    Language: hrvatski
    Number of pages: 81


  24. Type of paper: Invited lecture

    Title:
    Institution: Faculty of Helth Science, Ben-Gurion University,
    Year: 1994


  25. Type of paper: Invited lecture

    Title:
    Institution: Hadassah Medical Organization, Liver unit, University of Jerusalem
    Year: 1994


  26. Type of paper: Invited lecture

    Title:
    Institution: Kongres - Europian Association for Study of the Liver (EASL)
    Year: 1994


  27. Type of paper: Invited lecture

    Title:
    Institution: Mechanisms in Local Immunity, 2nd Alps-Adria Immunology and Allergology Meeting
    Year: 1994


  28. Type of paper: Invited lecture

    Title:
    Institution: The molekularbiologische and biotechnologische entwicklungsliga (MoBBEL), 8th Annual Meeting
    Year: 1994


  29. Type of paper: Invited lecture

    Title:
    Institution: Virologisches Seminar, Institut for Medical Virology, University of Heidelberg
    Year: 1995


  30. Type of paper: Invited lecture

    Title:
    Institution: Institut za mikrobiologiju, Medicinski fakultet Sveučilišta u Ljubljani
    Year: 1995



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