| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Internal Medicine, University of Texas Medical Branch, and
Shriners Burns Hospital, Galveston, TX 77555
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production in cultures of splenic T cells
from TI mice, IFN- was produced by stimulation with IL-12 when the
producer cells were prepared from TI mice that had been treated
previously with sIL-4R. After stimulation with anti-CD3 mAb,
splenic T cells from TI mice with the established infection of HSV-1
produced IL-4 into their culture fluids. However, IL-4 was not produced
by splenic T cells that were prepared from the same infected mice
treated with IL-12 and sIL-4R in combination. The results obtained
herein indicate that the efficacies of the combination therapy against
the established infection of HSV-1 may result from the IFN-
production stimulated by IL-12 in TI mice that are treated with sIL-4R
for reducing burn-associated type 2 T cell
responses. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, etc.) by type 1 T cells
(Th1 cells and CD8+ type 1 T cells) (9, 10, 11, 12). In contrast,
Th2 cell-associated and/or CD8+ type 2 T cell-associated
cellular responses (type 2 T cell responses) are manifested by the
production of type 2 cytokines (IL-4, IL-10, IL-13, etc.) by type 2 T
cells (Th2 cells and CD8+ type 2 T cells). Type 2 cytokines
secreted from type 2 T cells have been shown to be inhibitors of the
differentiation of type 1 T cells (6, 7, 8, 9, 10, 11). In our previous studies
using a mouse model of thermal injury, thermally injured mice (TI
mice)3 were 100 times more
susceptible to HSV-1 infection compared with normal mice (12). The
susceptibility of TI mice to HSV-1 infection was increased through the
generation of burn-associated CD8+ CD11b+
TCR
+ type 2 T cells (12), because the impaired
resistance of TI mice to HSV-1 infection was completely transferred to
normal unburned mice through the adoptive transfer of burn-associated
type 2 T cells (12). In TI mice and mice inoculated with
burn-associated type 2 T cells, a marked suppression was observed in
the production of IFN- (a typical cytokine involved in type 1 T cell
responses) and in the generation of CTLs (a representative effector
cell in type 1 T cell responses) (13, 14, 15, 16, 17, 18, 19, 20). These findings suggest that
TI mice with sufficient levels of type 1 T cell responses may have a
possibility to resist severe infection with HSV-1.
IL-12 has been shown to be an inducer of type 1 T cell responses (21, 22). Originally, IL-12 had been described as an inducer of IFN- from
resting and activated NK cells and T cells (23, 24). However, recent
papers have described that IL-12 is a pivotal cytokine in promoting the
differentiation of naive T cells into type 1 T cells, and it functions
as a costimulus for maximal IFN- production by already
differentiated type 1 T cells (21, 22). In our previous studies (25),
the resistance of TI mice infected with conditioned doses of HSV-1
could be improved to the levels observed in normal mice by prophylactic
treatment of IL-12. In these experiments, IL-12 was administered to TI
mice 2 days before HSV-1 infection, which occurred 1 day after thermal
injury. However, even though the sufficient amount of IL-12 was
consequently given to the mice beginning 2 days postinfection (3 days
after burn injury), TI mice currently infected with HSV-1 did not
survive. Type 1 T cell responses were not induced by the
administrations of IL-12 in TI mice with an established infection of
HSV-1. A predominance of type 2 T cell responses was detected in these
mice. Therefore, to induce sufficient amounts of IFN- by stimulation
with IL-12, regulation of type 2 T cell responses in TI mice currently
infected with HSV-1 may be required. The soluble form of IL-4R (sIL-4R)
binds IL-4 and inhibits its specific interaction with cell-associated
IL-4R (26). sIL-4R has been described as prolonging the survival of an
allograft in a mouse model of allotransplantation (27). Also, sIL-4R
does induce protective immunity in susceptible mice after infection
with Candida albicans or Leishmania major (28, 29) and prevents allergic airway hyperresponsiveness (30). In our
preliminary study, minimal levels of type 2 T cell responses were
demonstrated in TI mice treated previously with sIL-4R. Therefore, in
the present study, the effect of a combination therapy between IL-12
and sIL-4R on the resistance of TI mice with the established infection
of HSV-1 was investigated. Along with the elimination of type 2
cytokines by sIL-4R, an optimal level of the IFN- production was
induced in these mice by stimulation with IL-12. Also, the mortality
rate of TI mice with the established infection of HSV-1 was greatly
reduced after the combination therapy between IL-12 and sIL-4R. This
combination therapy may have the potential to control current HSV-1
infections in burned patients who routinely carry a predominance of
type 2 T cell responses.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Eight-week-old BALB/c mice (The Jackson Laboratory, Bar Harbor, ME) were used in the experiments. All procedures using animal experiments were approved by the Animal Care and Use Committee (ACUC) of The University of Texas Medical Branch at Galveston (ACUC approval number 95-04-039).
Thermal injury
TI mice were produced according to our previous descriptions
with minor modifications (31). Before being subjected to burn injury,
mice were anesthetized with an i.p. administration of pentobarbital (40
mg/kg). The mice were weighed, and their hair was removed on their back
from groin to axilla with electric clippers. A custom insulated mold
with a 2.5 x 3.5-cm window was pressed firmly against the shaved
back and the area was exposed for 9 s to a gas flame from Bunsen
burner equipped with a flame dispersing cap. This procedure produced a
third-degree burn of 
15% total body surface area on 26-g mice (31).
Immediately after the injury, 4 ml of physiologic saline per mouse was
administered i.p. for fluid reconstitution, and the animals were housed
until used in the experiments. As controls, mice with their back hair
shaved received 4 ml of saline without being exposed to a gas flame.
Reagents, viruses, media, and cells
Murine rIL-12 was kindly provided by Dr. Maurice K. Gately
(Hoffmann-La Roche, Nutley, NJ). Murine sIL-4R, rIL-4, and rIFN-
were obtained from Genzyme (Cambridge, MA). Anti-IFN- and
anti-IL-4 mAbs for ELISA were purchased from PharMingen (San Diego,
CA). Vero cells were serially maintained in minimum essential medium
supplemented with 10% FBS, 2 mM L-glutamine, and
antibiotics. The KOS strain of HSV-1 was propagated in Vero cells and
stored at -70°C until used for infection (12, 25). The titer of the
virus stock solution was 1.8 x 107 PFU/ml as assayed
by the plaque method on Vero cells cultured in maintenance medium
(minimum essential medium supplemented with 2% FBS, 2 mM
L-glutamine, and antibiotics). RPMI 1640 medium
supplemented with 10% FBS, 2 mM L-glutamine, antibiotics,
30 mM HEPES, and 5 x 10-5 M 2-ME (complete media)
was used for the cultivation of murine spleen cells. As described
previously (12, 25), mononuclear cells were prepared from the spleens
of mice by Ficoll-Hypaque sedimentation. Spleens were removed from
normal and TI mice treated with or without IL-12 and/or sIL-4R. T cells
were purified from mononuclear cells using T cell enrichment columns
(R&D Systems, Minneapolis, MN) (32). The purity of the T cells
harvested was >96%, as described previously (32).
Viral isolation from spleen and liver
Spleens and livers were removed from three mice 5 and 7 days after infection with 5 x 102 PFU/mouse of HSV-1. Homogenates of these organs (20% suspension, w/v) were subjected to freezing and thawing three times and subsequently centrifuged at 400 x g for 15 min. The supernatants obtained were assayed for HSV-1 in Vero cells by a standard plaque method (33).
Detection of IFN- and IL-4
Type 1 T cell responses were manifested as the amounts of
IFN- produced by appropriate cells after stimulation with IL-12 (10
U/ml, 48 h) or anti-CD3 mAb (2.5 µg/ml, 48 h). Type 2 T
cell responses were manifested as the amounts of IL-4 produced by
appropriate cells after stimulation with anti-CD3 mAb (2.5 µg/ml,
48 h). Splenic T cells suspended in complete media at a cell
density of 2 x 106 cells/ml were stimulated with
IL-12 for the production of IFN- in vitro. These cell preparations
were also stimulated in vitro with anti-CD3 mAb or UV-inactivated
HSV-1 (HSV-1 Ag) for the production of IFN- or IL-4. Culture fluids
harvested at 48 h poststimulation were assayed for IFN- or IL-4
by ELISA according to the manufacturer’s protocol. In addition, the
sera of mice at various days after thermal injury were assayed for
IFN- and IL-4 by ELISA. Serum specimens were prepared from TI mice
treated with or without rIL-12 and/or sIL-4R. In our assay system, the
detection limit for respective cytokines was 5–50 pg/ml. The assay was
performed three times, and the results were expressed as the mean of
these three tests.
Infection experiments
At 1 day after thermal injury, mice were infected i.p. with HSV-1. An inoculum of 1 x 104 PFU/mouse in normal mice and 1 x 102 PFU/mouse in TI mice has been determined to be equivalent to 1 LD50. A 5 LD50 of HSV-1 (5 x 102 PFU/mouse in TI mice and 5 x 104 PFU/mouse in normal unburned mice) was infected to mice in all experiments. Mice were treated i.p. with IL-12 (31–500 U/mouse) once daily for 5 days beginning 3 days postinfection (4 days after thermal injury). sIL-4R (50 ng/mouse) was administered to mice 3 and 5 days postinfection (4 and 6 days after thermal injury). In experiments for the combination therapy, mice were treated with IL-12 and sIL-4R under the conditions shown in the administration schedule of each agent. The antiviral effects of the combination therapy in TI mice were evaluated using the following criteria: 1) the mean survival time in days (MSD) of tested groups compared with the MSD of controls (mice treated with saline, IL-12 alone, or sIL-4R alone), 2) the survival percentage of tested groups at 3 wk postinfection compared with that of the three control groups shown in 1), and 3) viral growth in organs of treated groups compared with that of control groups. All experiments were performed two times, and the figures and table were displayed by mean values of the results shown by these two experiments.
Statistical analysis
The survival of mice exposed to the pathogen was analyzed by log rank test. Other data expressed as mean ± SD were statistically analyzed by ANOVA followed by Fisher’s protected least significant difference test. If a p value was <0.05, the result obtained was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The effects of IL-12 on HSV-1 infection in TI mice were first
examined. In this experiment, TI mice were treated i.p. with various
doses of IL-12 once daily for 5 days beginning 1 day before the
infection (the same day of burn injury, prophylactic treatment).
Following the same schedule, a control group of TI mice was treated
with saline. As shown in Fig. 1
A, 100% of TI mice treated
with saline died within 17 days after HSV-1 infection (MSD, 9.8 days),
whereas 80% and 30% of TI mice treated with 500 or 125 U/mouse of
IL-12 survived for >21 days, respectively (MSD: 500 U/mouse, >19.3
days; 125 U/mouse, >12.6 days). However, the protective effect of
IL-12 against HSV-1 infection was not demonstrated in TI mice when
IL-12 was administered to mice at the dose of 500 U/mouse once daily
for 5 days beginning 3 days after HSV-1 infection (4 days after burn
injury, therapeutic treatment) (Fig. 1B). TI mice treated
with IL-12 or control mice treated with saline died within 15 days of
the infection in the same fashion. Next, the effect of sIL-4R on the
morbidity and mortality of TI mice exposed to the same amount of HSV-1
was examined. When infected mice were treated with sIL-4R at a dose of
50, 12, or 3 ng/mouse at 3 and 5 days after HSV-1 infection (4 and 6
days after burn injury, therapeutic treatment), 10%, 0%, and 0% of
them survived for >21 days postinfection, respectively (Fig. 1C). According to these results, therapeutic treatment with
IL-12 alone or sIL-4R alone provided no significant protective effect
against HSV-1 infection in TI mice.
|
).
Also, the viral growth in the spleens and livers of TI mice that were
exposed to HSV-1 and treated with IL-12 and/or sIL-4R was examined.
When TI mice were infected with 5 x 102 PFU/mouse of
HSV-1 (5 LD50 in TI mice; 0.05 LD50 in normal
BALB/c mice), 2.2 x 104 PFU/spleen and 7.5 x
104 PFU/liver of HSV-1 were detected in these mice at 5
days postinfection; a total of 8 x 103 PFU/spleen and
2.8 x 104 PFU/liver of HSV-1 were detected in these
mice at 7 days postinfection. When TI mice were exposed to the same
amount of HSV-1 and treated with IL-12 (500 U/mouse) or sIL-4R (50
ng/mouse) alone, amounts of HSV-1 in organs were not significantly
reduced. However, amounts of HSV-1 in organs were reduced in TI mice
treated with IL-12 and sIL-4R in combination (day 5, 7.2 x
102 PFU/spleen and 4.5 x 103 PFU/liver;
day 7, 6.8 x 10 PFU/spleen and 4.8 x 102
PFU/liver) (Fig. 3). These results
suggest that the antiviral resistance of TI mice to HSV-1 infection was
improved after the combination treatment. When the treatment with the
constant amount of IL-12 (500 U/mouse) was combined with various doses
of sIL-4R (3–50 ng/mouse), the maximal protective effect against the
established infection of HSV-1 was produced by IL-12 combined with
sIL-4R at doses of 50 ng/mouse (Table I).
These results, which are shown in Figs. 1
and 2 and Table I, suggest
that TI mice currently infected with HSV-1 may be controlled
therapeutically by the combination treatment between IL-12 and sIL-4R,
whereas therapeutic treatment of TI mice with either IL-12 or sIL-4R
alone did not produce any protective effects against the established
HSV-1 infection.
|
|
|
In the series of our previous studies, the increased
susceptibility of TI mice to HSV-1 infection has been shown to be
produced by type 2 cytokines released from burn-associated type 2 T
cells (12, 25, 32). Therefore, we examined the level of IL-4 in the
sera of TI mice treated with IL-12 once daily for 5 days beginning on
the same day as burn injury or once daily for 3 days beginning 4 days
after burn injury (see Fig. 1B). IL-4 at an amount of 28
ng/ml was detected in the sera of control mice 7 days after thermal
injury. In contrast, IL-4 was not demonstrated in the sera of TI mice 7
days after burn injury when IL-12 was given to TI mice once daily for 5
days beginning on the same day as thermal injury. IL-4 was detected in
the sera of TI mice when the treatment with IL-12 was started 4 days
after burn injury (Fig. 4). These results
indicated that the production of IL-4 in TI mice was inhibited when the
IL-12 treatment was started before burn injury. However, the production
of IL-4 was not inhibited in the sera of TI mice when the IL-12
treatment was started 4 days after burn injury.
|
by splenic T cells from TI mice treated with
sIL-4R
Type 1 T cell responses have been shown to be essential for the
defense of the host against HSV-1 infection. Because TI mice with the
established HSV-1 infection survived after the combination therapy
between IL-12 and sIL-4R, type 1 T cell responses might be developed in
these mice. Therefore, we attempted to induce type 1 T cell responses
by IL-12 in cultures of splenic T cells from TI mice that were
previously treated with sIL-4R. Type 1 T cell responses were manifested
as the amount of IFN- produced by splenic cells. sIL-4R was
administered twice (4 and 6 days postburn) to these mice, and splenic T
cells were prepared from mice 7 days after thermal injury. Culture
fluids harvested 48 h after the stimulation with 10 U/ml of IL-12
were assayed for IFN- by ELISA. As shown in Fig. 5, naive splenic T cells stimulated with
IL-12 produced 520 pg/ml of IFN- into their culture fluids. The
production of IFN- by splenic T cells from mice 7 days after thermal
injury was not elicited after the IL-12 stimulation. However, splenic T
cells from mice treated with sIL-4R (50 ng/mouse) 7 days after burn
injury produced 511 pg/ml of IFN- into their culture fluids when
they were stimulated with 10 U/ml of IL-12. This finding suggests that
IFN- could be induced by IL-12 in cultures of splenic T cells from
TI mice treated with sIL-4R.
|
The IFN--producing capability of splenic T cells from TI mice
with established HSV-1 infection was examined after these mice were
treated with IL-12 and sIL-4R in combination. Mice were exposed to 5
LD50 of HSV-1 at 1 day after thermal injury, and these mice
were treated with IL-12 and sIL-4R in combination at the dose and
schedule shown in Fig. 2. For the induction of IL-4 and IFN-, the
cultures of splenic T cells (2 x 106 cells/ml) from
these infected mice 7 days after thermal injury were stimulated with
anti-CD3 mAb (2.5 µg/ml). Culture fluids harvested at 48 h
poststimulation were assayed for IL-4 or IFN- by ELISA. IL-4
production was stimulated with anti-CD3 mAb in cultures of splenic
T cells from currently HSV-1-infected TI mice that were treated with
IL-12 alone, sIL-4R alone, or saline, whereas IFN- was not produced
by these cells stimulated with anti-CD3 mAb. Alternatively, the
production of IFN- was induced by anti-CD3 mAb in cultures of
splenic T cells from currently HSV-1-infected TI mice that were treated
with IL-12 and sIL-4R in combination. Also, IL-4 was not produced by
these splenic T cells even though they were stimulated with
anti-CD3 mAb (Fig. 6).
|
and IL-4, splenic T cells prepared from
mice exposed to 5 LD50 of HSV-1 were stimulated with HSV-1
Ag. Inactivation procedures of HSV-1 and the amount of HSV-1 Ag used
for the stimulation have been described previously (33). Culture fluids
harvested at 48 h poststimulation were assayed for cytokines by
ELISA. IL-4 (570–880 pg/ml) but not IFN- was detected in the
culture fluids of splenic T cells from HSV-infected TI mice treated
with IL-12, sIL-4R, or saline. However, IFN- (2380 pg/ml) but not
IL-4 was detected in the culture fluids of splenic T cells from
HSV-infected TI mice treated with IL-12 and sIL-4R in combination (Fig. 6). These results suggest that, after the combination therapy between
IL-12 and sIL-4R, HSV-1-specific type 1 T cells may be generated in TI
mice infected with HSV-1. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production in T
cells and NK cells (23, 24). Thus, IL-12 amplifies type 1 T cell
responses through its ability to clonally expand T cells (21, 22),
regulate IFN- expression (21), and down-regulate type 2 T cell
responses (21). These facts show that the immunologic effect of IL-12
might be exerted preferentially on those subsets of T cells capable of
producing IFN-. However, in this study, the protective effect of
IL-12 against HSV-1 infection was not demonstrated in TI mice when it
was administered therapeutically, although the mortality rates of TI
mice infected with HSV-1 were greatly decreased when IL-12 was given to
them prophylactically. A predominance of burn-associated type 2 T cell
responses, manifested by the amount of IL-4, were not changed in TI
mice treated therapeutically with IL-12. Also, type 1 T cell responses,
manifested by the amount of IFN-, were not elicited in these mice or
in cultures of splenic T cells from these mice. In these experiments,
the treatment of IL-12 was given to mice with or without infection 4
days after thermal injury. However, when IL-12 was given to TI mice
prophylactically, splenic T cells from these TI mice produced IFN-
into their culture fluids. These results suggest that, for the
protection of TI mice against the established infection of HSV-1, the
induction of type 1 T cell responses in these mice may be required. In
our previous studies, the susceptibility of TI mice to infection with
HSV-1 was shown to be 100 times greater than that of normal mice (12).
Burn-associated CD8+ CD11b+
TCR+ type 2 T cells were identified as the type 2 T
cells responsible for the increased susceptibility of TI mice to
infection (12). The impaired resistance of TI mice to HSV-1 infection
recovered when burn-associated type 2 T cell responses were reduced by
treatment with 1) mAbs directed against type 2 cytokines (31), 2)
antagonistic cells for type 2 T cells (12), or 3) inducers of
antagonistic cells for type 2 T cells (32). However, the mortality rate
of TI mice with established HSV-1 infection was not effectively reduced
by these three treatments. Also, type 1 T cell responses were not
elicited in these mice or in cultures of their splenic cells stimulated
with anti-CD3 mAb. Because type 2 cytokines (IL-4 and IL-10)
inhibit the generation of type 1 T cells, a predominance of type 1 T
cell responses is not developed in currently HSV-1-infected TI mice
that have a predominance of type 2 T cell responses.
Therefore, we hypothesized that the established HSV-1 infection in TI
mice might be controlled by the induction of type 1 T cell responses
along with the elimination of burn-associated type 2 T cell responses.
sIL-4R has been described as a direct inhibitor for IL-4 (26). It has
been reported that Ia and CD23 cell surface Ag expression and secretion
of IgE and IgG1 from B cells, which were stimulated with IL-4, were
inhibited by sIL-4R (40). Also, the proliferation of T cells stimulated
with IL-4 was suppressed by sIL-4R (40). Therefore, for the regulation
of the established HSV-1 infection in TI mice, we attempted to use
sIL-4R as an inhibitor of type 2 T cell responses, and IL-12 was used
as an inducer of type 1 T cell responses. TI mice currently infected
with HSV-1 were treated with these two agents in combination. Thus,
these mice received the IL-12 therapy starting 3 days postinfection (4
days after thermal injury) and the sIL-4R therapy at 3 and 5 days
postinfection (4 and 6 days after thermal injury). Splenic T cells from
these mice produced IFN- after stimulation with anti-CD3 mAb.
However, IL-4 was not produced by these cells after the same
stimulation. Also, the mortality rates of these mice were greatly
reduced. Alternatively, IL-4 (but not IFN-) was produced by
anti-CD3 mAb-stimulated splenic T cells from currently
HSV-1-infected TI mice that were treated with IL-12 alone, sIL-4R
alone, or saline, whereas similar mortality rates in these three groups
of TI mice were demonstrated.
In our series of studies, neither therapeutic treatment with IL-12 nor sIL-4R showed significant effects on the survival of TI mice infected with HSV-1. The reason for this will be explained through the action of IL-4 secreted from burn-associated type 2 T cells. In our previous studies, type 2 T cells were demonstrated in mice 3–10 days after thermal injury (12). Papers published recently have described that IL-4 dominates the type 1 T cell response-inducing capacity of IL-12 (41, 42, 43). When naive CD4+ T cells are stimulated by comparable concentrations of both IL-12 and IL-4, the effect of IL-12 on type 1 T cell differentiation is not displayed (41, 42, 43). The suppression of type 1 T cell differentiation by IL-4 is expressed based on the extinction of IL-12 signaling in the developing type 2 T cells (43). Type 2 T cells do not respond to IL-12 because of a lack of IL-12-inducing phosphorylation of STAT4, a transcription factor that is typically involved in IL-12 signaling (43). In addition, IL-12 has no inhibitory effect on IL-4-induced type 2 T cell differentiation, but rather enhances the secondary production of IL-4 after restimulation of the T cells (44, 45). Therefore, IL-12 could not induce protective immunity (type 1 T cell responses) in TI mice against HSV-1 infection. Although sIL-4R effectively inhibited IL-4 production in the spleens of TI mice, sIL-4R itself may be insufficient to elicit protective immunity against infection of HSV-1. Scott and Farrell reported (46) that CB6F1 mice (a less susceptible strain) with chronic cutaneous leishmaniasis were protected by combination treatment with IL-12 and anti-IL-4 mAb, whereas treatment by either substance individually had a lesser influence on the subsequent course of the infection. This finding supports our results shown herein that the therapeutic combination treatment between an inhibitor of type 2 T cell responses (sIL-4R) and an inducer of type 1 T cell responses (IL-12) may have the potential to control current HSV-1 infections in thermally injured individuals. The combination treatment between sIL-4R and IL-12 may provide a new therapeutic strategy that could influence the outcome of HSV-1 infections in thermally injured individuals bearing a predominance of type 2 T cell responses.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Fujio Suzuki, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0835. E-mail address:
3 Abbreviations used in this paper: TI mice, thermally injured mice; sIL-4R, soluble IL-4R; MSD, mean survival time in days.
Received for publication November 24, 1998. Accepted for publication April 6, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
responsiveness in mice after thermal injury. J. Immunol. 129:1811.[Abstract]
production by NK cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J. Exp. Med. 173:869.. J. Immunol. 152:1883.[Abstract]
in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J. Exp. Med. 182:1045. and interleukin-10. J. Exp. Med. 183:2559., and IL-4. Chem. Immunol. 68:70.[Medline]
This article has been cited by other articles:
|
|
 |
|
  S. Fujimi, P. H. Lapchak, Y. Zang, M. P. MacConmara, A. A. Maung, A. J. Delisle, J. A. Mannick, and J. A. Lederer Murine dendritic cell antigen-presenting cell function is not altered by burn injury J. Leukoc. Biol., May 1, 2009; 85(5): 862 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Palmer, J. M. Tulley, E. J. Kovacs, R. L. Gamelli, M. Taniguchi, and D. E. Faunce Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells J. Immunol., July 1, 2006; 177(1): 92 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maile, C. M. Barnes, A. I. Nielsen, A. A. Meyer, J. A. Frelinger, and B. A. Cairns Lymphopenia-Induced Homeostatic Proliferation of CD8+ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury. J. Immunol., June 1, 2006; 176(11): 6717 - 6726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takahashi, Y. Tsuda, M. Kobayashi, D. N. Herndon, and F. Suzuki CCL2 as a trigger of manifestations of compensatory anti-inflammatory response syndrome in mice with severe systemic inflammatory response syndrome J. Leukoc. Biol., April 1, 2006; 79(4): 789 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zang, S. M. Dolan, N. N. Choileain, S. J. Kriynovich, T. J. Murphy, P. Sayles, J. A. Mannick, and J. A. Lederer Burn Injury Initiates a Shift in Superantigen-Induced T Cell Responses and Host Survival J. Immunol., April 15, 2004; 172(8): 4883 - 4892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Guo, E. Kavanagh, Y. Zang, S. M. Dolan, S. J. Kriynovich, J. A. Mannick, and J. A. Lederer Burn Injury Promotes Antigen-Driven Th2-Type Responses In Vivo J. Immunol., October 15, 2003; 171(8): 3983 - 3990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kobayashi, H. Takahashi, A. P. Sanford, D. N. Herndon, R. B. Pollard, and F. Suzuki An Increase in the Susceptibility of Burned Patients to Infectious Complications Due to Impaired Production of Macrophage Inflammatory Protein 1{alpha} J. Immunol., October 15, 2002; 169(8): 4460 - 4466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Schwacha, C.-S. Chung, A. Ayala, K. I. Bland, and I. H. Chaudry Cyclooxygenase 2-mediated suppression of macrophage interleukin-12 production after thermal injury Am J Physiol Cell Physiol, February 1, 2002; 282(2): C263 - C270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Furukawa, H. Sasaki, R. B. Pollard, and F. Suzuki Lanoconazole, a new imidazole antimycotic compound, protects MAIDS mice against encephalitis caused by Cryptococcus neoformans J. Antimicrob. Chemother., September 1, 2000; 46(3): 443 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kaji, M. Kobayashi, R. B Pollard, and F. Suzuki Influence of type 2 T cell responses on the severity of encephalitis associated with influenza virus infection J. Leukoc. Biol., August 1, 2000; 68(2): 180 - 186. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, 500
U/mouse; 
, 125 U/mouse; 
, 31 U/mouse) once daily for 5 days
beginning 1 day before (A) or only IL-12 (
, 50 ng/mouse; 
