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*
Virology Unit, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands;
Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands; and
Immunology Unit, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor-deficient (IFN-R-/-) mice
showed an increased susceptibility to coronaviral hepatitis.
Surprisingly, MHV-infected mice lacking IL-12 produced a polarized
Th1-type cytokine response, as evidenced by high IFN- and
nondetectable IL-4 production by CD4+ splenocytes and
normal virus-specific serum IgG2a/IgG1 ratios. The virus-induced type 1
cytokine secretion pattern was not reversed in IL-12-deficient mice by
in vivo neutralization of IFN- nor in IFN-R-/- mice
receiving IL-12-neutralizing Abs. In IL-12-deficient mice, Th1-type
responses were also generated upon immunization with inactivated MHV.
In contrast, following immunization with keyhole limpet hemocyanin,
mice lacking IL-12 mounted strongly reduced specific IgG2a and
increased IgE responses, indicative of a type 2-dominated cytokine
pattern. These findings demonstrate that following a virus infection,
IL-12 is not essential for the generation of polarized T cell type 1
cytokine expression and associated immune responses, which is in marked
contrast to nonviral systems. Our data suggest that viruses may
selectively induce IFN- production and Th1-type immune reactions
even in the absence of IL-12. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production (2), an important lymphokine in antiviral defenses
(for review, see 3 . In a model of acute progressive viral
infection, we have demonstrated recently that mice with a defective
IFN- receptor (IFN-R-/-) gene, generated by
targeted disruption of the IFN-R 
-chain, develop an exacerbated
hepatitis after infection with mouse hepatitis coronavirus
(MHV)2 (4). In comparison
with wild-type 129/Sv/Ev mice that resolved the infection, their livers
had an increased viral load, and most animals succumbed to the
infection within 5 to 10 days. Notably, infected
IFN-R-/- mice produced normal IFN- levels, but less
IL-12 than MHV-infected wild-type mice, as evidenced from marginal
levels of IL-12 gene expression (4, 5). This also has been observed
after Mycobacterium infection (6) and demonstrates that in
vivo IL-12 expression can be facilitated by endogenous IFN-.
Reciprocally, endogenous IL-12 is required for IFN- production and
for the establishment of a Th1-type response after infection with
Listeria, Leishmania, Schistosoma, and
Toxoplasma gondii, and immunization with keyhole limpet
hemocyanin (KLH) or collagen (7, 8, 9, 10, 11, 12).
In a variety of viral infections, IL-12 gene expression has been
observed within 24 to 48 h (5). Recently, Cousens and coworkers
(13) have demonstrated that IFN-/ß produced during viral infection
profoundly inhibits IL-12 and associated IFN- production. However,
Ab-mediated in vivo neutralization of IL-12 before murine
cytomegalovirus (MCMV) infection reduced IFN- synthesis by NK cells,
but not their cytolytic activity (14); late CTL activation and IFN-
production following lymphocytic choriomeningitis virus infection
remained unaffected (14). Interestingly, neutralizing anti-IL-12
Abs increased MCMV burden in NK cell- and in T cell-deficient E26 mice
(15), suggesting an IFN--independent antiviral function for
endogenous IL-12. To examine the in vivo role of IL-12 in viral
hepatitis and especially its significance in the regulation of
antiviral cytokine expression, we studied MHV-infected IL-12-deficient
129/Sv/Ev mice, generated by gene targeting of either the p35 gene
(IL-12p35-/-) or both the p40 and the p35 gene
(IL-12p40/p35-/-). For comparison, wild-type 129/Sv/Ev
mice and IFN-R-/- mice were examined. Our observations
indicate that endogenous IL-12 is dispensable for the control of
coronavirus-induced acute hepatitis. In addition, IL-12 is not required
for the differentiation of naive T cells toward a polarized Th1
phenotype during this infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mutant (129/Sv/Ev) mouse strain deficient in expression of
the intact IFN- receptor -chain (IFN-R-/-),
generated by gene targeting in murine embryonic stem cells (16), was
kindly provided by Dr. M. Aguet (University of Zurich, Switzerland) and
bred at the Central Animal Laboratory Utrecht. The
IL-12p35-/- and IL-12p40/35-/- mice on a
129/Sv/Ev background were generated by Dr. J. Magram and coworkers (9)
and obtained from BRL Fullingsdorf (Fullingsdorf, Switzerland). All
animals were housed in filter top cages. The animal experiments had
been approved by Institutional Animal Welfare Committee.
Virus
Stocks of the virulent hepatotropic MHV strain A-59 had been
generated originally on Sac(-) cells, and the virus
was titrated on L cells. Inactivated MHV was prepared by
ß-propiolactone (ß-PL) treatment in PBS. The inactivated MHV stock
contained an antigenic mass equivalent to 108
plaque-forming units (PFU)/ml and contained no detectable IFN-/ß
activity when examined in a virus inhibition assay against vesicular
stomatitis virus on murine L cells (not shown).
In vivo treatment of mice
Six- to twelve-week-old mice were i.p. infected with
107 PFU of MHV. At designated time points after
infection, the livers and spleens were removed, snap frozen in liquid
nitrogen or embedded in paraffin, and analyzed immunohistochemically
for viral Ag expression using polyclonal rabbit anti-MHV (K134), as
described (4). In survival experiments, groups of MHV-infected mice
were monitored daily for symptoms and mortality. Separate groups of
mice were immunized either with 250 µl of a 1:1 suspension of KLH
(100 µg) in aluminum hydroxide adjuvant, as described (17), or with 1
ml of ß-PL-inactivated MHV (equivalent to 108 PFU/ml).
Both KLH-immunized and virus-infected animals were bled from the
retro-orbital plexus at the indicated time points for determination of
Ag-specific Ab levels in sera. From other groups of mice, either
infected or immunized, spleens were removed at indicated time points,
and splenocyte single cell suspensions were tested for cytokine
production. For in vivo neutralization of IL-12, mice were i.p.
injected with 1 mg of highly purified IgG2a mAb C17.8, kindly provided
by Dr. G. Trinchieri (18), at 5 h before and 24 h after
infection. Endogenous IFN- was neutralized by injection of 5000
neutralizing units DB-1 mAb, provided by Dr. P. Van der Meide
(Biomedical Primate Research Center, Rijswijk, The Netherlands) (19),
at 2 h before and 24 h after infection. Control mice received
isotype-matched monoclonals.
Analysis of lymphokine production
For the analysis of cytokine production, erythrocyte-depleted
splenocytes (3 x 106 cells/ml) were cultured in
24-well plates (Nunc, Breda, The Netherlands) in conditioned medium or
stimulated with ß-PL-inactivated MHV (antigenic mass corresponding to
5 x 106 to 5 x 107 PFU MHV/ml) or
Con A (2.5 µg/ml). In selected experiments, splenocytes were
separated into CD4+ and CD4- fractions, or
into CD8+ and CD8- fractions before cytokine
production analysis. Briefly, splenocytes were incubated with MACS
microbead-conjugated mAbs GK1.5 (anti-CD4) or 53-6.7 (anti-CD8)
and then sorted on MiniMACS biomagnetic columns (Miltenyi Biotec,
Bergisch Gladbach, Germany), exactly as recommended by the
manufacturer. Subsequent FACScan analysis (Becton Dickinson, San Jose,
CA) revealed that the purity of the selected lymphocyte subsets
exceeded 93 to 96%. No CD4+ or CD8+ cells
could be detected in the respective depleted splenocyte fractions.
Supernatants of stimulated cultures were harvested at 48 h and
stored at -20°C until use. IFN- and IL-4 were measured by
two-site ELISA (Holland Biotechnology, Leiden, The Netherlands, and
PharMingen, San Diego, CA) using standard curves established with known
amounts of murine rIFN- (kindly provided by Dr. H. Heremans, Leuven,
Belgium) and rIL-4 (Genzyme, Cambridge, MA). IL-2 levels were
determined by an IL-2-dependent CTLL cell proliferation assay. The
proliferative responses were measured by [3H]thymidine
incorporation for 16 h after 3 days of culture (20).
Proliferative responses
The proliferative splenocyte responses were determined by [3H]thymidine incorporation. Splenocytes were isolated 4 days after infection with MHV or 6 days after immunization with inactivated MHV, and seeded at a concentration of 2 to 5 x 105 cells in 96-well round-bottom plates in 100 µl volumes per well. After 48-h incubation, 0.4 µCi [3H]thymidine was added per well. The cellular DNA was harvested on glass filters and measured by liquid scintillation counting (LKB-Wallac, Gaithersburg, MD).
Assay for serum Abs
Serum levels of KLH-specific Abs were determined by ELISA, as described (17). MHV-specific Ab isotype levels were determined by an ELISA; 96-well flat-bottom plates were incubated overnight at 4°C with MHV (equivalent to 107 PFU/well in NaHCO3 0.05 M, pH 9.6), washed with tap water, and saturated with 1% BSA (Sigma Chemical, St. Louis, MO) in PBS. Twofold serum dilutions were added and incubated for 1 h at 37°C. After washing with tap water, a 1/3200 dilution of isotype-specific peroxidase-coupled goat anti-mouse IgG (Southern Biotechnology Associates, Birmingham, AL) was added. After incubation for 1 h at 37°C and another wash, the substrate was developed with tetramethylbenzidine for 10 min at room temperature. The reaction was stopped with 2 M sulfuric acid and read at an OD of 450 nm in a Titertek Multiskan MC. The titer was defined as the reciprocal of the highest dilution at which the absorbance was equal to two times the background value.
Statistical analysis
Group means of cytokine responses and Ig isotypes of wild-type and mutant mice were compared by using the independent sample Student’s t test. To take into account the greater probability of a type I error due to multiple comparisons of the Ab isotypes, the level of significance was preset according to Bonferroni’s adaptation at p < 0.01 instead of a fixed p < 0.05. Statistical significance of differences between data from wild-type mice vs those from mutant animals is indicated by an asterisk in the figures.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To assess the importance of in vivo IL-12 function for resistance
to acute MHV infection, wild-type, IL-12-/-, and for
comparison IFN-R-/- mice were inoculated with
107 PFU. Since the first MHV-infected
IFN-R-/- mice usually succumb after 5 days (4), livers
were removed after 4 days and examined histologically. At this time
point, the IFN-R-/- animals already exhibited advanced
clinical symptoms. Immunohistologic examination revealed increased
numbers of viral Ag-positive cells and larger histopathologic lesions
in the livers of the IFN-R-/- mice (Fig. 1
, E and F),
as compared with wild-type animals (Fig. 1, A and
B) (4). In contrast, no marked difference was noted
in the number, size, and distribution per section of histopathologic
foci and virus Ag-positive cells in the livers of
IL-12p35-/- mice, when compared with wild-type mice (Fig. 1, C and D). Depending on the experiment,
IFN-R-/- mice suffered 56 to 95% mortality (Fig. 2) (4), while wild-type mice had
mortality rates of 16 to 44%. Virus titers in the liver were not
significantly increased in IL-12p35-/- mice, when
compared with wild-type animals (not shown). Moreover, no difference
was noted in survival rates between IL-12-deficient
(p35-/- and p40/p35-/-) and wild-type mice
after infection with 107 PFU MHV (Fig. 2). These data
establish the contribution of IFN- and the redundancy of IL-12 to
install in vivo defenses against MHV infection.
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and fail to produce increased levels of IL-4
The undiminished antiviral resistance of mice lacking IL-12 is
rather surprising in view of the exacerbated coronaviral hepatitis in
IFN-R-deficient mice, since the monokine is considered critical for
induction of IFN-. Experiments using exogenous IL-12 (21),
IL-12-neutralizing Abs (7), or mice with disrupted genes coding for
IL-12 (9, 10) or STAT4, the IL-12-activated signaling molecule (23),
have demonstrated a critical role for IL-12 in IFN- induction and
Th1 development. Indeed, TCR stimulation of naive spleen cells from
IL-12p35-/- mice with mitogen Con A yielded
significantly reduced (p = 0.018), minimal to
nondetectable amounts of IFN- (about 5.2 ± 1.2 U/ml), and
increased levels of IL-4 (p = 0.001) in 48-h
culture supernatants, when compared with responses from wild-type
splenocytes that produced readily detectable amounts of IFN-
(21 ± 7 U/ml; mean ± SEM) and minimal IL-4 (1.5 U/ml or
less; mean ± SEM; Fig. 3A).
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-producing Th1 cells and concomitantly inhibited
IL-4 production (24). Lack of IL-12 function led to increased IL-4
production. Gene-targeted IL-12-deficient mice, when infected with
Leishmania major or injected with KLH or
collagen, produce a Th2 characteristic cytokine profile (9, 10). To
determine whether IL-12 deficiency leads to reduced IFN- and
increased IL-4 production in virus-infected mice, we isolated spleen
cells from IL-12p35-/- and wild-type mice 4 days after
MHV infection and cultured them in conditioned medium or restimulated
them with either inactivated virus (antigenic mass equivalent to 5
x 106 or 5 x 106 PFU/ml) or Con A
mitogen (2.5 µg/ml) for 48 h before harvesting their
supernatants. Strikingly, IFN- was readily produced by splenocytes
derived from MHV-infected IL-12p35-/--deficient mice when
stimulated with Con A or cultured in conditioned medium. Restimulation
with viral Ag did not further increase IFN- production above levels
observed in cultures maintained in conditioned medium only (not shown).
The minimal, or absence of, increases in cytokine production by
addition of viral Ag or Con A most likely result from saturating
amounts of viral Ag in the spleens of infected mice. IL-4 production
was not detectable in splenocyte cultures derived from MHV-infected
IL-12p35-/--deficient mice when stimulated with Con A or
viral Ag nor when maintained in conditioned medium (less than 1.5
U/ml). Similarly, IL-4 levels were very low in cultures from
virus-infected wild-type mice (<1.5 U/ml). Thus, similar levels of
IFN- and IL-4 were noted in cultures from virus-infected wild-type
and IL-12-deficient mice (Fig. 3
A). Cytokine levels
in supernatants from naive nonstimulated splenocyte cultures were below
detection limit. These observations indicate that endogenous IL-12 is
not involved in inhibition of the expansion and/or differentiation of
Th2 cells during viral hepatitis.
In viral infections, generally a massive Ag nonspecific T cell
proliferation (>90%) occurs, which has been ascribed to
cytokine-mediated (IFN-/ß and IFN-) bystander stimulation (22).
Since IL-12 augments proliferation of preactivated T cells (2), we
looked for alterations in proliferative responses in virus-infected
IL-12-/- mice. As a measure of T cell function, we
determined proliferative responses of IL-12-/- and normal
splenocytes. Coronaviral infection-driven proliferative responses of
splenocytes isolated 4 days after infection were normal in
IL-12-deficient mice (not shown). This may be explained by the normal
levels of IL-2 synthesis observed for splenic cells from both genotypes
(not shown), an observation in line with other antigenic systems
(9).
IL-12-deficient mice primed with replicating or inactivated MHV generate CD4+ Th1 cells
To test whether viral replication is necessary for the induction
of IFN- production, we immunized normal and mutant mice with
ß-PL-inactivated MHV. To our surprise, splenocytes derived from
IL-12-deficient mice injected with noninfectious MHV particles also
gave a type 1 characteristic cytokine secretion pattern, with high
IFN- and low IL-4 secretion (Fig. 3A). This
suggests that IL-12-independent IFN- production with low IL-4
synthesis is based on an intrinsic biochemical property of the virus
particles, independent from their replication.
To investigate whether the virus-induced polarization toward a type 1
cytokine profile in IL-12-deficient mice is only transient and possibly
reversible at later time points, we analyzed the cytokine expression
pattern of IL-12p40/p35-/- splenocytes at 14 days after
infection; again a sustained polarized type 1 pattern, with substantial
IFN- and nonincreased levels of IL-4, was observed in
IL-12-deficient mice, similar to the profile in the wild-type controls
(Fig. 3B).
Depletion of both CD4 and CD8 splenocytes isolated at day 4 after
infection, using microbeads, almost completely abolished IFN-
production (not shown), indicating that only /ß TCR-positive T
cells are responsible for IFN- synthesis. Immunomagnetic selection
of CD4+ and CD8+ cells before seeding in
conditioned medium identified CD4+ cells as the major
source of IFN--producing cells (Fig. 3C).
Together, these data indicate that during coronaviral infection,
CD4+ T cells develop into Th1 type cells, despite the
absence of endogenous IL-12 function.
Virus-infected mice lacking IL-12 produce an IgG isotype profile characteristic for a type 1 cytokine response
In murine systems, the levels of Ag-specific IgG1 and IgG2a are
normally correlated with IL-4 and IFN- production, respectively
(25). MHV-infected IL-12-/- mice produced the same
levels of virus-specific serum IgG2a and IgG1 as wild-type mice (Fig. 4, upper panels). Only
IFN-R-/- mice that survived the infection showed a
reduced serum IgG2a/IgG1 ratio, indicative for defective IFN-
function (16, 19). In contrast, IL-12-deficient mice, immunized with
KLH (absorbed to aluminum hydroxide), showed a reduced KLH-specific
serum IgG2a/IgG1 ratio and increased IgE responses (Fig. 4, lower
panels), indicative of a type 2-dominated cytokine
pattern.
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neutralization in IL-12-deficient mice nor IL-12
neutralization in IFN-R-/- mice prevents the
generation of Th1 cells after MHV infection
Having established that a polarized type 1 cytokine expression
profile, with a high IFN-/IL-4 ratio, after MHV infection prevails
in gene-targeted IL-12-deficient and in IFN-R-deficient mice (4), we
next determined whether the absence of both IL-12 and IFN- would
affect the antiviral cytokine response. We therefore depleted
IFN-R-/- mice of endogenous IL-12 using mAb C17.8
(1 mg/animal injected 5 h before and 24 h after MHV
infection), before assessing splenic IFN- and IL-4 production. In
vivo neutralization of IL-12 in MHV-infected IFN-R-/-
mice had no apparent effect on the virus-induced IFN- production and
failed to promote IL-4 synthesis (Fig. 5). The type 1 pattern of cytokine
responses was also not affected in IL-12p35-/- mice
treated with the IFN--neutralizing mAb DB-1 (Fig. 5). The efficacy
of DB-1 was suggested by increased liver pathology in most Ab-treated
IL-12p35-/- animals.
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are not essential
for developing a Th1 cytokine profile during coronaviral infection. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus, we measured substantial production of IFN-, but no
IL-4 in both normal and IL-12-deficient mice (Schijns et al.,
unpublished observations). Our observation of an IL-12 redundance for
IFN- production supports Orange and coworkers (14), who noted
unimpaired late IFN- production in mice injected with
IL-12-neutralizing Abs after infection with lymphocytic
choriomeningitis virus and MCMV. However, the neutralizing
anti-IL-12 Abs reduced early IFN- production by NK cells after
MCMV infection, resulting in diminished antiviral defense
(14).
Our observations that neither depletion of IFN- in
IL-12-/- mice nor neutralization of IL-12 in
IFN-R-/- mice affects the virus-elicited Th1 cytokine
secretion pattern suggest that other cytokines or host factors
compensate the lack of endogenous IL-12 and IFN-. IFN-, a
characteristic product in most viral infections, has been suggested to
favor the development of Th1 cells (recently reviewed in 26 .
Interestingly, mice deficient for IFN-regulatory factor-1, an activator
for type I IFNs and IFN-inducible genes, exhibit strongly impaired Th1
responses (27). In contrast, IFN-/ß has been shown to inhibit
endogenous IL-12 synthesis and associated IFN- production (13).
Moreover, IFN- is unable to induce Th1 development in a
TCR-transgenic system (28). Alternatively, the recently discovered
IFN--inducing factor is a strong IL-12-independent inducer of
IFN- and Th1 cell development (29). It is induced in IL-12-deficient
mice infected with Mycobacterium tuberculosis (30), but has
not yet been examined during viral infections.
IFN- responses, and most likely Th1-type responses, dominate most
viral infections, also in genetically susceptible BALB/c mice (see
Refs. 31–33), which are predisposed toward developing Th2-type
responses following various parasitic infections (reviewed in 1 .
Even after virus infections at mucosal surfaces, known to favor a type
2 cytokine profile (34), IFN- production prevails (33); additional
low levels of IL-4 may be induced, e.g., following mucosal influenza or
respiratory syncytial virus infections (35, 36). Virus-induced IL-4
production in the absence of IL-12 has not been investigated before.
Our data show that increased IL-4 responses, which are normally
observed in IL-12-/- mice in various antigenic systems,
are suppressed or absent after infection of IL-12-/- mice
with a hepatotropic coronavirus (an RNA virus) or a neurotropic
pseudorabies virus (a DNA virus).
Antiviral Ab responses generally show an isotypic bias toward IgG2a
(37, 38), a major complement-fixing and FcR-binding Ig associated with
IFN- production (16, 19), which is in line with the predominance of
Th1-type responsiveness. In this study, we demonstrated that even in
the absence of physiologic IL-12, antiviral IgG2a (and IgG1) responses
were not altered, conforming to the observation that no shift in
cytokine response had occurred.
IL-12 gene deficiency dramatically increases the susceptibility to
Leishmania major infection (10). In contrast,
this defect did not alter the pathogenesis of MHV hepatitis, an
unexpected finding in view of the increased susceptibility of
IFN-R-/- mice to MHV infection (4).
IFN-R-/- mice resemble IL-12-/- with
respect to antiviral cytokine responses. Similar to IL-12-deficient
mice, they did not produce IL-12p40 serum protein (unpublished data),
and their splenocytes were defective in IL-12p40 mRNA expression (4).
Moreover, their levels of IL-4 were not increased and their levels of
IFN- normal. The latter is nonfunctional due to the genetic lack of
IFN- receptor signaling, which results in increased susceptibility
and reduced IgG2a synthesis (4). The exact antiviral effector mechanism
of physiologic IFN-, however, remains to be established. rIFN-
exerted a pronounced in vitro and in vivo antiviral activity against
MHV, suggesting induction of an antiviral state in the target cells
(4). However, an IFN--induced immunoregulatory activity contributing
to viral resistance cannot be excluded. In transfer studies, a pivotal
role in protection against coronavirus-induced hepatitis has been
demonstrated for CD4+, but not for CD8+ class
I-restricted T cells (39). These antiviral Th cells exerted
virus-specific MHC class II-restricted cytotoxicity and IFN-
secretion, but not IL-4 synthesis (31).
Collectively, our data suggest that the unaltered resistance of
IL-12-deficient mice is due to an unimpaired IFN- response, most
likely derived from activated CD4+ T cells regulating
subsequent antiviral responses. Endogenous IL-12 is not required for
antiviral defense in a coronaviral hepatitis, and most likely for viral
infections in general. In addition, the data establish the development
of antiviral Th1 cells during viral hepatitis in the absence of IL-12
and/or IFN-. Identification of the mechanisms and viral components
directing immunity toward type 1 cytokine responsiveness would be of
interest for prophylactic or therapeutic intervention aiming either at
the induction of cell-mediated immunity or immune deviation away from
type 2-dominated cytokine responses.
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Acknowledgments |
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-neutralizing mAb DB-1 and Dr. K. Teerds (Veterinary
Faculty, Utrecht University, Utrecht, The Netherlands) for assistance
in producing the photomicrographs. |
Footnotes |
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2 Abbreviations used in this paper: MHV, mouse hepatitis coronavirus; ß-PL, ß-propiolactone; KLH, keyhole limpet hemocyanin; MCMV, murine cytomegalovirus; PFU, plaque-forming unit.
Received for publication September 24, 1997. Accepted for publication December 18, 1997.
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M. C. de Wit, M. C. Horzinek, B. L. Haagmans, and V. E. J. C. Schijns Host-dependent type 1 cytokine responses driven by inactivated viruses may fail to default in the absence of IL-12 or IFN-{alpha}/{beta} J. Gen. Virol., April 1, 2004; 85(4): 795 - 803. [Abstract] [Full Text] [PDF]
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S. F. Elsawa and K. L. Bost Murine {gamma}-Herpesvirus-68-Induced IL-12 Contributes to the Control of Latent Viral Burden, but Also Contributes to Viral-Mediated Leukocytosis J. Immunol., January 1, 2004; 172(1): 516 - 524. [Abstract] [Full Text] [PDF]
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O. Weber, A. Siegling, A. Friebe, A. Limmer, T. Schlapp, P. Knolle, A. Mercer, H. Schaller, and H.-D. Volk Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus J. Gen. Virol., July 1, 2003; 84(7): 1843 - 1852. [Abstract] [Full Text] [PDF]
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R. B. Smeltz, J. Chen, R. Ehrhardt, and E. M. Shevach Role of IFN-{gamma} in Th1 Differentiation: IFN-{gamma} Regulates IL-18R{alpha} Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor {beta}2 Expression J. Immunol., June 15, 2002; 168(12): 6165 - 6172. [Abstract] [Full Text] [PDF]
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A. Y. Park, B. Hondowicz, M. Kopf, and P. Scott The Role of IL-12 in Maintaining Resistance to Leishmania major J. Immunol., June 1, 2002; 168(11): 5771 - 5777. [Abstract] [Full Text] [PDF]
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E. C. de Jong, P. L. Vieira, P. Kalinski, J. H. N. Schuitemaker, Y. Tanaka, E. A. Wierenga, M. Yazdanbakhsh, and M. L. Kapsenberg Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals J. Immunol., February 15, 2002; 168(4): 1704 - 1709. [Abstract] [Full Text] [PDF]
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H. H. Smits, E. C. de Jong, J. H. N. Schuitemaker, T. B. H. Geijtenbeek, Y. van Kooyk, M. L. Kapsenberg, and E. A. Wierenga Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development J. Immunol., February 15, 2002; 168(4): 1710 - 1716. [Abstract] [Full Text] [PDF]
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C. P. Simmons, N. S. Goncalves, M. Ghaem-Maghami, M. Bajaj-Elliott, S. Clare, B. Neves, G. Frankel, G. Dougan, and T. T. MacDonald Impaired Resistance and Enhanced Pathology During Infection with a Noninvasive, Attaching-Effacing Enteric Bacterial Pathogen, Citrobacter rodentium, in Mice Lacking IL-12 or IFN-{gamma} J. Immunol., February 15, 2002; 168(4): 1804 - 1812. [Abstract] [Full Text] [PDF]
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 L. D. Hazlett, X. L. Rudner, S. A. McClellan, R. P. Barrett, and S. Ligh |
