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Journal of Virology, February 2001, p. 1205-1210, Vol. 75, No. 3
Pest Animal Control Cooperative Research
Centre, CSIRO Sustainable Ecosystems,1 and
Division of Immunology and Cell Biology, John Curtin School of
Medical Research, Australian National
University,2 Canberra, Australia
Received 25 July 2000/Accepted 13 November 2000
Genetic resistance to clinical mousepox (ectromelia virus) varies
among inbred laboratory mice and is characterized by an effective
natural killer (NK) response and the early onset of a strong
CD8+ cytotoxic T-lymphocyte (CTL) response in resistant
mice. We have investigated the influence of virus-expressed mouse
interleukin-4 (IL-4) on the cell-mediated response during infection. It
was observed that expression of IL-4 by a thymidine kinase-positive ectromelia virus suppressed cytolytic responses of NK and CTL and the
expression of gamma interferon by the latter. Genetically resistant
mice infected with the IL-4-expressing virus developed symptoms of
acute mousepox accompanied by high mortality, similar to the disease
seen when genetically sensitive mice are infected with the virulent
Moscow strain. Strikingly, infection of recently immunized genetically
resistant mice with the virus expressing IL-4 also resulted in
significant mortality due to fulminant mousepox. These data therefore
suggest that virus-encoded IL-4 not only suppresses primary antiviral
cell-mediated immune responses but also can inhibit the expression of
immune memory responses.
Ectromelia virus (ECTV; family
Poxviridae, genus Orthopoxvirus) is a natural
pathogen of laboratory mice that causes a generalized disease
termed mousepox (13). All mice are equally susceptible to
infection by footpad inoculation; however, development of
clinical mousepox among inbred mouse strains differs greatly
(44). In mousepox-sensitive (e.g., BALB/c) mice, the
disease is an acute systemic infection with high viral titers in the
liver and spleen with resultant necrosis and high mortality. In
contrast, infection of mousepox-resistant (e.g., C57BL/6) mice is
usually subclinical, with lower levels of viral replication in the
visceral organs and development of nonfatal lesions. Genetic resistance
has been found to act through the combined activity of innate host
defenses including natural killer (NK) cells, alpha interferon
(IFN- Effector CD4+ T cells can be categorized on the basis of
their cytokine production either as T helper 1 (Th1) cells that produce IL-2 and IFN- Cross-regulation of Th subsets and the generation of an appropriate
type of immune response against a particular pathogen is important
since the dominance of an inappropriate response can exacerbate disease
and lead to the inability to eradicate the infecting organism. The use
of recombinant vaccinia virus (VACV) to study the in vivo effects
of mouse cytokines has demonstrated that the course of infection can be
mediated and biased toward either an antiviral effect by coexpression
of type 1 cytokines or enhanced virus virulence by coexpression of
selected type 2 cytokines (36, 41). Previous studies using
a variety of viral infection models have shown that overexpression or
systemic administration of IL-4 impedes the development of
virus-specific CTL activity, causing a delay in viral clearance,
although infected mice generally survive infection (2, 14, 27,
41). Furthermore, VACV-expressed IL-4 inhibits the expression of
type 1 cytokines (41), biasing the antibody response in
favor of a Th2-mediated immunoglobulin G1 profile (2).
Infection of mice with non-mouse-adapted VACV can be controlled in the
absence of CTL activity in CD8+ T-cell-deficient or
-depleted mice (36, 42). It has been proposed that control
of VACV and other cytopathic virus infections is accomplished by
compensating antiviral soluble mediators such as IFN- In the course of our studies into the development of virally vectored
immunocontraceptive vaccines (16), we have investigated the ability of coexpressed type 2 cytokines to act as adjuvants to
enhance an antibody-mediated response. We have observed that thymidine
kinase (TK)-positive recombinant ECTVs expressing mouse IL-4 are highly
virulent and that infection of mice with these viruses suppresses NK
and CTL cytolytic activity and IFN- Cells and viruses.
L-M(TK Virus titration.
Titration of recombinant ECTVs recovered
from mouse tissues was performed on B-SC-1 cells grown in six-well
culture dishes overlaid with 2 ml of MEM containing 1% (wt/vol)
low-melting-point agarose (SeaPlaque GTG; FMC BioProducts, Rockland,
Maine) and grown at 35°C for 72 h. Plaques produced by viruses
expressing Mice and inoculation.
Animal studies were conducted in
accordance with the Australian Code of Practice for the Care and Use of
Animals for Scientific Purposes. Specific-pathogen-free 6- to
8-week-old female mice were obtained from the Australian National
University Animals Services Division.
(i) Virulence studies.
BALB/c and C57BL/6 mice were
inoculated with various amounts of virus into the right hind footpad,
and disease symptoms were observed for 2 weeks postinfection when
surviving animals were euthanized.
(ii) DTH studies.
BALB/c and C57BL/6 mice were immunized by
inoculation into the right hind footpad with 103 PFU of
highly attenuated ECTV-602. The immune mice were challenged 4 weeks
postimmunization by inoculation into the same footpad with
104 PFU of either ECTV-602(TK+) or ECTV-IL4(TK+).
Delayed-type hypersensitivity (DTH) responses were measured 24 and
48 h postchallenge by measuring the dorsoventral thickness of the
inoculated right foot using calipers and compared to the thickness of
the uninoculated left foot. Mice were monitored for a further 3 weeks
to observed signs of disease and mortality.
(iii) Assessment of antiviral cytolytic responses and IFN- Disease symptoms following infection of mice with recombinant
ECTVs. (i) Control virus.
Footpad inoculation of
mousepox-resistant C57BL/6 mice with 103 PFU ECTV-602(TK+)
caused symptoms similar to the those caused by wild-type Moscow strain
of ECTV. However, unlike infection with the Moscow strain, recovery was
not normally associated with necrosis and sloughing of the infected
limb. In mousepox-sensitive BALB/c mice, ECTV-602(TK+) was clearly less
virulent than the Moscow strain since it did not cause mortality and
behaved similarly to infection of C57BL/6 mice. However, footpad
inoculation of the highly sensitive A/J strain mice with ECTV-602(TK+)
was generally lethal (data not shown). This is consistent with the
known 100-fold-lower 50% lethal dose of the A/J strain relative to
BALB/c mice following infection with the Moscow strain
(13,31).
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.3.1205-1210.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Expression of Mouse Interleukin-4 by a Recombinant
Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and
Overcomes Genetic Resistance to Mousepox
and
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
), IFN-
, IFN-
, activated macrophages, and inducible
nitric oxide production (17, 21, 23, 24, 36).
Mousepox-resistant mice also display the early activation of a strong
virus-specific cytotoxic T-lymphocyte (CTL) response (20,
32) and produce high levels of type 1 cytokines interleukin-2
(IL-2), IL-12, IFN-, and tumor necrosis factor alpha (TNF-) in
response to ECTV infection, whereas these factors are absent or
produced at low levels in susceptible mice (19, 36).
or T helper 2 (Th2) cells that produce predominantly IL-4, IL-5, IL-10, and IL-13 (40). The cross-regulatory
activities of IL-12 and IL-4, factors that play key roles in directing
the development of the Th1 and Th2 subsets, respectively, is well characterized (40). Both in vitro and in vivo, the
presence of IL-4 at the time of stimulation has been shown to inhibit
IL-12 expression by antigen-presenting cells (macrophages and dendritic cells), with Th2 cells dominantly expanded in the acquired response (7, 8, 25). In addition to its effects on development of
Th1 and Th2 subsets, IL-4 has been shown to influence the
differentiation of other lymphocyte types. In vitro stimulation of
naive CD8+ cells in the presence of IL-2, IL-12, or IFN-
generates classical type 1 cytotoxic cells (Tc1) which express IFN-;
however, CD8+ cells stimulated in the presence of IL-4 may
develop a Tc2 phenotype expressing the cytokines IL-4, IL-5, IL-6,
IL-10, sometimes with reduced cytoxicity (11, 38).
Treatment of activated Tc1 cells with IL-4 results in defective
IFN-, TNF-, and IL-2 expression. Although IL-4-treated Tc1 cells
retain short-term in vitro cytotoxic activity, they fail to proliferate
in response to antigen stimulation, compromising their long-term
functional capability to control infection (37). It has
recently been shown that NK cells cultured in the presence of IL-12 or
IL-4 may also differentiate into NK1 or NK2 cells, respectively, with
distinct patterns of cytokine secretion similar to those of Th1 and Th2
cells, although this does not appear to affect their in vitro cytotoxic
activity (33).
, TNF-, and
possibly antibody, and that the lytic activity of CD8+
cells plays only a peripheral role (18, 35). Although the orthopoxviruses VACV and ECTV are both cytopathic viruses and are very
closely related at the genetic level, they differ greatly in
pathogenicity in the mouse. Only in immunocompromised mice does VACV
cause a severe disease following infection with relatively high doses
of virus. In contrast, infection with low doses of ECTV is sufficient
to generate clinical disease in most mouse strains (36,
44). This is because ECTV is naturally mouse adapted and
expresses virulence factors, such as the IFN- binding protein
(28), that have greater affinity for the mouse than the
VACV equivalents. It has been established that macrophages (20,
43), NK cells (17), and CD8+ T cells
(20) are all crucial for controlling infection with ECTV.
IFN-- or IFN- receptor-deficient mice are also highly susceptible
to mousepox even in the presence of normal CTL activity (19, 23,
36). Thus, the neutralization of any one of the major innate or
adaptive cell-mediated antiviral activities has been shown to result in
fulminant mousepox in otherwise genetically resistant mice. The study
of coexpressed mouse cytokines in the context of a pathogenic
host-adapted viral vector provides the opportunity to study
immunological function in a situation where the cell-mediated immune
response is crucial for recovery.
expression by splenic
CD8+ T cells. Suppression of cellular immunity in both
mousepox-resistant mice and ECTV-immune mice resulted in acute mousepox
with a high mortality rate.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) (mouse [Mus
musculus] ATCC CCL-1.3) and B-SC-1 (African green monkey
[Cercopithecus aethiops] ATCC CCL-26) cells were
maintained in minimal essential medium (MEM) supplemented with 5%
fetal bovine serum at 37°C in 5% CO2. ECTVs were grown on the above cells in MEM at 35°C in 5% CO2. Recombinant
ECTVs were constructed by infection of L-M(TK) cells at a
multiplicity of infection of 0.1 PFU/cell with the TK
virus ECTV-602, which contains an insertion of the Escherichia coli lacZ (-galactosidase) gene inactivating the orthopoxvirus TK gene (16). The virus-infected cells were transfected
with plasmid pTK-7.5A (5) or pFB-TK-IL4 (1),
using LipofectAMINE reagent (Gibco-BRL Life Technologies Inc.,
Gaithersburg, Md.). With these vectors, DNA recombination should occur
between the VACV HindIII-F sequences contained in the
vectors and the homologous sequences within ECTV
HindIII-E. Recombinant ECTVs expressing the herpes
simplex virus (HSV) TK gene were selected by growth on L-M(TK) cells
in MEM containing hypoxanthine-aminopterin-thymidine supplement
(Gibco-BRL Life Technologies). Recombinant virus ECTV-602(TK+), which
was constructed using pTK-7.5A, contains a copy of the HSV TK gene
inserted into the natural BamHI site located immediately downstream of the of the VACV F7 open reading frame early promoter. Virus ECTV-IL4(TK+), which was constructed using pFB-TK-IL4, is similar
to ECTV-602(TK+) except that it also contains a copy of the mouse IL-4
cDNA under the transcriptional control of the VACV P7.5 early/late
promoter inserted immediately downstream of the HSV TK gene. IL-4
expression was confirmed in vitro by bioassay of supernatants from
ECTV-IL4(TK+)-infected L-M(TK) cell cultures (15, 41).
-galactosidase were visualized by overlaying the infected
cells with a further 2 ml of MEM-1% agarose containing X-Gal
(5'-bromo-4-chloro-3-indolyl--D-galactopyranoside; 300 µg/ml).
production.
Female C57BL/6 mice were infected by footpad
inoculation with 102, 103, or 104
PFU for CTL assays, or 104 PFU for NK cell assays or
assessment of IFN- production, of either ECTV-602(TK+) or
ECTV-IL4(TK+). For NK cell assays, spleens were removed on days 1, 2, and 3 postinfection (p.i.); for assays of CTL activity or IFN-
expression, spleens were removed on day 7 p.i. NK cell cytolytic
activity was measured on YAC-1 cells (ATCC TIB-160), while CTL activity
was measured on VACV-infected MC57G targets (ATCC CRL-295; a C57BL/6
derived fibroblast line; H-2b) using the
standard 6-h 51Cr release assay (22). IFN-
production was measured using microcultures set up in parallel with
those used in CTL assays. Splenic effector cells were cultured with
VACV-infected or uninfected MC57G targets at a ratio of 20:1.
Supernatants were collected after 6 h, and IFN- levels assayed
by enzyme-linked immunosorbent assay (15).
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
(16) and
virulent wild-type Moscow viruses.
(ii) TK+ IL-4-expressing virus.
To assess the
effects of IL-4 expression by a recombinant ECTV on virulence, we
infected mice with 103 PFU of ECTV-IL4(TK+) and monitored
disease symptoms and mortality. Infection of BALB/c or C57BL/6 mice
with ECTV-IL4(TK+) proved to be uniformly lethal, with mean survival
times (days) being 7.4 ± 0.7 (n = 10/10) and 8.6 ± 1.2 (n = 10/10), respectively. In both strains,
swelling of the inoculated foot was clearly visible by 6 day p.i., and
the foot continued to swell until the mice succumbed to the infection.
Shortly before death, the infected mice became lethargic with ruffled
fur and hunched posture. At autopsy, the mice contained enlarged pallid
spleens and livers, with both organs containing numerous discrete white
spots typical of necrotic lesions. These clinical signs and lesions are
typical of acute mousepox as seen in genetically susceptible mice
infected with the virulent Moscow strain (13). C57BL/6
mice infected with ECTV-IL4(TK+) contained high levels of virus in the
spleen just prior to displaying early symptoms of acute mousepox (Table 1). In contrast, virus titers in the
spleens of mice infected with equivalent doses of ECTV-602(TK+) were
reduced, suggestive of immune mediated clearance. Increasing the
infectious dose of the IL-4-expressing virus exacerbated the onset of
symptoms and decreased survival times (data not shown). All control
mice infected with equivalent doses of ECTV-602(TK+) survived
infection.
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(iii) CTL and NK responses and IFN- production following
infection.
Due to the enhanced virulence of the recombinant ECTV,
we next assessed the effects of IL-4 expression on the development of
antiviral CD8+ CTL, NK activity, and IFN- expression,
responses which are crucial for controlling ECTV infection. Increasing
doses of ECTV-IL4(TK+) were used to infect C57BL/6 mice; spleens were
isolated 7 days p.i. and assayed for CTL activity using the standard
51Cr release assay (Fig. 1A).
Splenocytes isolated from mice infected with the control virus
ECTV-602(TK+) displayed significant specific cytolytic activity toward
orthopoxvirus-infected MC57G cells. In contrast, splenocytes isolated
from C57BL/6 mice infected with ECTV-IL4(TK+) contained no detectable
virus-specific cytolytic activity.
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secretion by
antiviral CD8+ T cells. Mean levels of virus-specific
IFN- produced by splenocytes from mice infected with 104
PFU of ECTV-602(TK+) were sevenfold higher than background levels (733 ± 39 compared to 129 ± 29 U/ml). In contrast,
CD8+ T cells from mice given ECTV-IL4(TK+) failed to
produce IFN- at levels above background (130 ± 47 U/ml).
To assay for induction of innate NK cell activity, spleen cells were
isolated from ECTV-IL4(TK+)-infected mice on days 1, 2, and 3 p.i.
and assayed for lytic activity on YAC-1 cells. Cytolytic activity was
not detected at day 1 after infection with either control or
IL-4-expressing viruses. At day 2 p.i., both groups of mice
expressed approximately equivalent levels of NK activity (20% lysis of
YAC-1 targets at 20:1 effector/target ratio). However, by day 3 p.i., when NK cell activity is usually near maximal during ECTV
infection (29), ECTV-IL4(TK+)-infected C57BL/6 mice
displayed approximately a threefold reduction in splenic NK
cell-mediated lysis of YAC-1 targets compared to similarly infected
controls [(Fig. 1B); compare percent specific lysis of
ECTV-IL4(TK+)-infected mice at 20:1 effector/target ratio and control
virus-infected mice at 6:1 effector/target ratio].
Reinfection of mice immunized against ECTV.
Due to the
observed suppression of NK and CTL activity and IFN- expression
during the primary immune response to ECTV-IL4(TK+) and the reported
inhibitory effect of IL-4 on the Th1-mediated DTH response
(34), we next investigated the effects of ECTV IL-4
expression on the memory response to ECTV in immune mice. Immunization
of both C57BL/6 and BALB/c mice with the attenuated TK
virus ECTV-602 caused a mild swelling at the inoculation site which
resolved within 14 day p.i., with all mice recovering from infection
(16). Twenty-eight days postimmunization, the mice were
challenged with either control ECTV-602(TK+) or ECTV-IL4(TK+). These
immune mice displayed greatly differing DTH responses to infection
(Table 2). Mice challenged with the
control virus displayed a mild DTH response at 24 h, which was
resolving by 48 h postchallenge, and viral titers in the
inoculated footpads were below the detection limits of the viral plaque
assay 7 days p.i., indicating that these mice were immune to infection
with ECTV. Immunized mice were also immune to reinfection with the
virulent Moscow strain (data not shown). In contrast, mice challenged
with ECTV-IL4(TK+) displayed an exacerbated response characterized by
extreme swelling of the inoculated foot 24 and 48 h p.i. (Table
2). The difference in footpad swelling between C57BL/6 and BALB/c mice
24 h after challenge with ECTV-IL4(TK+) is significant by
Student's t test (P < 0.01); however,
there was no significant difference in footpad swelling between these
strains 48 h postchallenge. Twenty-four hours postchallenge,
hematoxylin-and-eosin-stained footpad sections of
ECTV-IL4(TK+)-infected mice showed an enhanced lymphocyte
infiltrate in the inoculated foot relative to the DTH response of the
control mice (data not shown). The inoculated feet continued to swell, and 60% of the mice died between days 6 to 8 p.i. At death, the livers and spleens of these mice were enlarged and contained numerous discrete local lesions, suggestive of death due to acute mousepox. Animals which survived challenge with ECTV-IL4(TK+) were autopsied on
day 21 p.i., at which time they still displayed marked swelling of
the inoculated feet. Viral titration of tissues isolated from surviving
mice indicated they were controlling systemic infection, since virus
was not detected in the spleen. However, virus clearance was
considerably delayed at the site of inoculation. Average titers of
virus in the inoculated feet of the surviving C57BL/6 and BALB/c mice
21 days p.i. were 6.0 × 103 and 1.3 × 105 PFU/g of tissue, respectively.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Footpad inoculation of naive mice with a recombinant
TK+ ECTV expressing mouse IL-4 results in systemic
infection and suppression of splenic NK and CTL cytolytic activity and
IFN- expression. The expression of IL-4 by ECTV renders the virus
lethal to mice that are normally genetically resistant. Importantly,
memory responses in mice previously immunized with ECTV were also
inhibited, leading to uncontrolled viral replication in the visceral
organs and resulting in classic symptoms of acute mousepox.
Previous studies using the closely related orthopoxvirus VACV have
established that IL-4 coexpression is associated with a delay in virus
clearance from the major target organs (2, 41). This is
likely to be the result of the observed combined reduction in antiviral
effectors such as CD8+ CTL precursor (CTLp) development,
IFN- expression, macrophage activation, and inducible nitric oxide
production (4, 41). While no reduction in splenic NK cell
activity was observed in infected CBA mice (41), a
significant reduction was found when SCID mice were infected with VACV
expressing IL-4 (4). It is clear from the VACV model that
IL-4 down-regulates in vivo expression of the key type 1 cytokines
IL-2, IL-12, and IFN- (41), which are pivotal for
stimulation and differentiation of antiviral cell-mediated effectors
such as NK, CD8+ CTL, and CD4+ Th1 cells
(3, 40).
In the classical ECTV pathogenesis study conducted by Fenner
(12), replicating wild-type Moscow strain of ECTV can
first be detected in the liver and spleens of mice by 3 days p.i. At this stage in the present study, virus-encoded IL-4 had a significant effect on the cytolytic activity of NK cells in these organs. The
observed partial down-regulation of NK cell activity seen here is
likely to be the result of the combined IL-4-induced suppression of
IL-12 expression by antigen-presenting cells (7, 8, 25) and type 1 cytokine receptors on NK cells (30, 33, 39, 45) inhibiting activation and proliferation. In the VACV IL-4 infection model, IL-12 expression in the spleen was clearly down-regulated by day
2 p.i. (41). The remaining NK cell cytolytic activity observed during infection with ECTV-IL4(TK+) probably results from the
more usual mode of IFN-/ induction generally seen during viral
infections (3).
Later, at day 7 p.i., when the adaptive anti-ECTV cell-mediated
response in the spleen should be near maximal (29), there was no measurable CD8+ cytolytic activity or IFN-
expression by isolated splenocytes of mice infected with
ECTV-IL4(TK+). Viral replication appeared to be uncontrolled,
with the mice dying shortly thereafter. This is consistent with
the IL-4-induced suppression of IL-12/IFN- expression
inhibiting CTLp development (41). Under some
circumstances, stimulation of naive CD8+ cells in the
presence of IL-4 can generate noncytotoxic Tc2 cells (10,
11). In addition, in vitro IL-4 treatment of activated Tc1 cells
has been shown to cause defective cytokine expression and inhibit
proliferation in response to antigen stimulation (37). Abnormally high IL-4 levels, accompanied by suppressed production of
IL-12 and IFN-, could potentially result in the generation of either
Tc2 cells with reduced cytolytic activity or defective Tc1 cells, which
may also account for the observed reduced CD8+ lytic
activity and IFN- expression following infection with ECTV-IL4(TK+). In marked contrast to the VACV IL-4 model, however, infection with ECTV-IL4(TK+) and suppression of CD8+
effector function appears to be absolute, which could be a consequence of the greater ability of ECTV to replicate in the mouse, with higher
and sustained levels of IL-4 expression compared to VACV.
It is also possible that high levels of ECTV-IL4(TK+) replication in
the spleen may have resulted in enhanced lymphocyte killing, accounting
for the observed reduction in cytotoxic activity and IFN-
expression. However, IL-4 expression by poxviruses is not known to
confer increased replicative ability in vivo. Indeed, peak titers of
VACV-IL4 in the ovary (41) and spleen (2) or
of attenuated ECTV-IL4 at the inoculation site (C. D. Christensen, R. J. Jackson, and A. J. Ramsay, unpublished results) are
equivalent to those seen in infection with control virus.
A similarly constructed TK ECTV expressing IL-4 was
attenuated upon infection of the naive CBA mice, and replication of
this virus was restricted to the inoculated footpad, accompanied by extreme swelling (Christensen et al., unpublished). More importantly, there was no measurable reduction in the generation of splenic cytolytic lymphocyte or IFN- responses compared to control virus infection, although clearance of the virus from the inoculated foot was
again considerably delayed. This suggests that the induced suppression
of the antiviral NK, CTL, and IFN- responses observed in the present
study was localized to the site of viral expressed IL-4 in the lymphoid
tissue. It has previously been shown that the TK+ phenotype
of ECTV is required for replication in macrophages, allowing
dissemination from the site of inoculation and viral replication in the
liver and spleen (26). In the present study, dissemination
of ECTV-IL4(TK+) to the visceral organs, followed by systemic
expression of IL-4, suppressed development of cell-mediated cytotoxic
responses in the lymphoid tissues, culminating in uncontrolled viral
replication, acute organ failure, and death.
It is clear from these studies that IL-4 expression also permits uncontrolled viral replication in the visceral organs of ECTV-immune mice, indicating that this factor can inhibit the generation of effector cells from a pool of memory T cells. In contrast, preexisting immunity to ECTV was sufficient to limit reinfection with either control or virulent Moscow virus. T-cell immunological memory is considered to result from enhanced numbers of antigen-specific CTLp and residual populations of activated CTL effector cells (9). Thus, even in the presence of preexisting immunity, IL-4 can inhibit the expression of immunological memory. These findings demonstrate the effectiveness of IL-4 for the inhibition of powerful cell-mediated immune reactions and suggest strategies potentially useful for the control of deleterious immune responses, such as autoimmune reactions.
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ACKNOWLEDGMENTS |
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We are grateful to Stephen Loof, Kirsty Macpherson, Cristina Musso, Vanda Quinn, Nicole Siddon, and Kyleen Webb-Wagg for technical assistance. We thank Tony Robinson and Michael Holland for critically reading the manuscript.
This research was supported by the Australian Government's Cooperative Research Centres Program.
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FOOTNOTES |
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* Corresponding author. Mailing address: CSIRO Sustainable Ecosystems, GPO Box 284, Canberra ACT 2601, Australia. Phone: 61 (02) 6242 1717. Fax: 61 (02) 6242 1511. E-mail: R.Jackson{at}cse.csiro.au.
Present address: Centre for Biomolecular Vaccine Technology,
Discipline of Immunology and Microbiology, University of Newcastle, Newcastle, New South Wales, Australia.
Present address: CSIRO Plant Industry, Canberra ACT, Australia.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Virology, February 2001, p. 1205-1210, Vol. 75, No. 3
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.3.1205-1210.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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