- 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,
- 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
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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
- 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,
- 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
- 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
- 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
- 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,
- 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
- 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
- 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,
- 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
- 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
- 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
- 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
- Type of paper
: Invited lecture
Title:
Institution: Faculty of Helth Science, Ben-Gurion University,
Year: 1994
- Type of paper
: Invited lecture
Title:
Institution: Hadassah Medical Organization, Liver unit, University of Jerusalem
Year: 1994
- Type of paper
: Invited lecture
Title:
Institution: Kongres - Europian Association for Study of the Liver (EASL)
Year: 1994
- Type of paper
: Invited lecture
Title:
Institution: Mechanisms in Local Immunity, 2nd Alps-Adria Immunology and Allergology Meeting
Year: 1994
- Type of paper
: Invited lecture
Title:
Institution: The molekularbiologische and biotechnologische entwicklungsliga (MoBBEL), 8th Annual Meeting
Year: 1994
- Type of paper
: Invited lecture
Title:
Institution: Virologisches Seminar, Institut for Medical Virology, University of Heidelberg
Year: 1995
- Type of paper
: Invited lecture
Title:
Institution: Institut za mikrobiologiju, Medicinski fakultet Sveučilišta u Ljubljani
Year: 1995