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Production in the Generalized Shwartzman Reaction
*
Department of Microbiology, Tohoku University School of Dentistry, Sendai, Japan;
Department of Immunology, Faculty of Medicine, University of Tokyo, and
Department of Immunology, Juntendo University School of Medicine, Bunkyou-ku, Tokyo, Japan;
§
Second Department of Oral Surgery, Tohoku University School of Dentistry,
¶
First Department of Surgery and
||
Department of Dermatology, Tohoku University School of Medicine, and
#
Department of Cell Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; and
**
Division of Basic Traumatology, National Defense Medical College Research Institute, Tokorozawa, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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induced by IL-12 is a crucial
cytokine in the priming phase. In vivo depletion of both NK cells and
NK1+ 
ß T cells of mice by anti-NK1.1 Ab
greatly reduced the elevation of serum IFN- induced by IL-12 and
significantly reduced mortality after subsequent injection of LPS,
whereas depletion of NK cells alone by anti-asialo GM1 Ab only
partially decreased serum IFN-, and lethality was not changed. Cell
sorting and culture experiments confirmed that liver NK1+
ß T cells of IL-12-injected mice produced greater amounts of
IFN- than did liver NK cells. MHC class I-deficient mice of C57BL/6
background, which lack a majority of NK1+ ß T cells,
produced low amounts of IFN- by IL-12; no mortality was observed
after the LPS challenge. However, production of TNF- in the second
phase (after LPS challenge) was not inhibited by depletion of NK cells
alone or both subsets. IL-12 and subsequent LPS challenge activated
NK1+ ß T cells in the liver and induced strong
cytotoxicity of these cells not only against tumor cells (including
Fas-negative tumors) but also against a syngeneic hepatocyte cell line.
Our findings show that IFN- produced by NK1+ ß T
cells is essential for the IL-12 priming of the Shwartzman reaction,
and the autoreactivity of NK1+ ß T cells in the liver
is involved in the hepatic disorders that are sometimes caused by
IL-12, LPS, or the generalized Shwartzman reaction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-, and IL-1 are
reportedly involved in the pathogenesis
of the generalized Shwartzman reaction (1, 2, 3), which is known as a
lethal shock syndrome of mice elicited by two consecutive injections of
LPS into mice. IFN- is important for the priming phase, while
TNF- and IL-1 are effector molecules in mice that were already
sensitized by IFN- (2, 3). Recently, it was revealed that IL-12 is a
pivotal factor in the priming phase of the Shwartzman reaction because
of its induction of IFN-. In addition, i.p. injection of either
IL-12 or IFN- can replace the priming effect of an LPS injection
into the footpads of mice (2, 3). IL-12 is a heterodimeric cytokine
with various biologic effects produced mainly by phagocytic and/or
APCs; it plays important roles in the protection against bacterial and
parasitic infections (4). IL-12 also acts against malignant tumors by
activating CD8+ cytotoxic T cells and NK cells (4, 5, 6).
These IL-12 effects are mainly, but not exclusively, mediated through
IFN- production (4).
NK1+ T cells are a recently identified T cell population
that consists of CD4+ as well as
CD4-8- double negative cells. This population
is dependent on MHC class I or related molecules for its development
(7, 8, 9). We recently reported that NK1+ T cells in the liver
(and also presumably in other sites) are one of the responders to
IL-12. IL-12 endows potent antitumor and antimetastatic functions to
these cells (10, 11, 12, 13). LPS also activates NK1+ T cells in
the liver through IL-12 production from Kupffer cells. This LPS-induced
effect is blocked by anti-IL-12 Ab and partly inhibited by
anti-IFN- Ab (12). These findings led us to determine whether or
not NK1+ T cells are involved in a generalized
Shwartzman reaction. In the present study, we demonstrate
that NK1+ T cells are potent producers of IFN- in the
priming phase of an IL-12-induced Shwartzman reaction and are involved
in the mortality of this phenomenon. We also demonstrate that
excessively activated liver NK1+ T cells, as well as NK
cells in the liver, can be cytotoxic even against hepatocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 (B62)+/+ mice, 6 to 8 wk of age, were purchased from CLEA Japan (Tokyo, Japan). Male B6 nu/nu mice were maintained in the Tohoku University School of Medicine (Sendai, Japan). B6 ß2-microglobulin-deficient (ß2m-/-) mice, obtained by backcrossing original ß2m-/- mice eight times with B6 mice (14), were kindly provided by Dr. M. Taniguchi at Chiba University School of Medicine (Chiba, Japan). Mice were fed under specific pathogen-free conditions.
Reagents
Escherichia coli-derived LPS was purchased from Sigma (St. Louis, MO). Recombinant murine IL-12 (15, 16) with an activity of 4.9 x 106 U/mg was kindly provided by Dr. M. Kobayashi of Genetics Institute (Cambridge, MA). The preparations were diluted in sterile PBS(-) briefly before use.
Histologic analysis
Mice were anesthetized and bled from the subclavian artery and vein. The liver, spleen, and kidneys were removed immediately, fixed with 10% formalin for 12 h, and embedded in paraffin. For histologic observation, several tissue sections were deparaffinized and stained with hematoxylin and eosin.
Preparation of mononuclear cells (MNC) from organs
Under ether anesthesia, mice were bled from the subclavian artery and vein. The livers were removed from the mice. Hepatic lymphocytes were prepared essentially as previously described (12). Briefly, the liver was passed through stainless steel mesh and suspended in HBSS. After one washing, cells were resuspended in osmolarity and pH adjusted 30% Percoll containing 100 U/ml heparin and centrifuged at 2000 rpm for 15 min at room temperature. The pellet was resuspended in RBC-lysis solution (0.17 mM NH4Cl, 0.01 mM EDTA, 0.1 M Tris, pH 7.3), and then washed twice in 10% FCS-RPMI 1640 medium.
Induction of Shwartzman reaction in mice by IL-12
As recently reported (2), the priming IL-12 injection was given i.p. and was followed 24 h later by a challenge i.v. LPS injection. The occurrence of the generalized Shwartzman reaction was evaluated by mortality.
Cytotoxicity assay
Target cells used were P815 mastocytoma cells, L5178Y T lymphoma cells of DBA/2 (H-2d) origin, and TLR-2 hepatocyte cells. P815 mastocytoma cells and L5178Y T lymphoma cells were propagated in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, 2 mM L-glutamine, and 25 mM NaHCO3 in humidified 5% CO2 at 37°C. TLR-2 hepatocytes were propagated as previously described (17). This hepatocyte cell line was established from SV40 T-Ag gene transgenic mice of B6 background. It is considered to be very similar to normal hepatocytes because these cells have intracellular p450IA and albumin (17). Target cells were labeled with 100 µCi of Na251CrO4 for 60 min at 37°C in RPMI 1640 medium containing 10% FCS, washed three times with medium, and subjected to cytotoxicity assays as previously described (10). Labeled targets (104/well) were incubated in a total volume of 200 µl with effector cells in 10% FCS-RPMI 1640 in 96-well round-bottom microtiter plates. The plates were incubated for 4 h after they were centrifuged, after which the supernatant was harvested and counted in a gamma counter. The cytotoxicity was calculated as the percentage of releasable counts after subtraction of spontaneous release. The spontaneous release was less than 15% of the maximum release.
In vitro cell depletion
Liver MNC were depleted of specific cell populations by using mAbs and rabbit serum as a source of complement (C) (LOW-TOX-M; Cedarlane, Hornby, Ontario, Canada). As previously described (10), cells (5 x 107) were incubated with the respective Ab at optimal concentrations (45 min, 4°C), washed, and incubated (45 min, 37°C) in 10 ml of a 1:10 dilution of rabbit serum as a source of complement. Optimal concentrations for each Ab were determined by treating isolated MNC with various dilutions of Ab and C, followed by flow cytometric analysis to assay the success of the treatment. The mAbs used, anti-NK 1.1 (PK136) and anti-CD3 (500-A-2), were prepared from hybridomas grown in our laboratory. These Abs were purified from ascites, which were prepared from hybridomas grown in our laboratory, by affinity chromatography on protein G-Sepharose (Pharmacia, Piscataway, NJ). Under these conditions, Ab treatment depleted >95% of the appropriate cell population in MNC.
In vivo cell depletion
Monoclonal mouse anti-NK1.1 Ab (PK136) (200 µg/mouse) or polyclonal rabbit anti-asialo GM1 Ab (50 µg/mouse) was injected into mice twice a week before sacrifice to eliminate NK-type cells. Polyclonal rabbit anti-asialo GM1 (AGM1) Ab was purchased from Wako (Tokyo, Japan). The elimination of NK-type cells was confirmed by flow cytometry and cytotoxicity assays against an NK-sensitive YAC-1 target.
Cell sorting and culture
Liver and/or spleen MNC were obtained from B6 or B6 nu/nu mice that had been injected with IL-12 (0.5 µg/mouse) 6 h before sacrifice. MNC were stained with anti-CD3 Ab and anti-NK1 Ab. NK cells and NK1+ T cells were separated by FACS Vantage (Becton Dickinson, Mountain View, CA). Contaminations by other types of cells in each population were less than 5%. In all, 2 x 106/ml (10% FCS-RPMI 1640) of NK1+ T cells and NK cells were cultured with low amounts of IL-2 (5 U/ml) in 96-well flat-bottom plates for 48 h. Culture supernatants were subjected to ELISA.
Assays for serum IFN- and TNF- levels
Serum levels of IFN- and TNF- were evaluated using the
cytokine-specific ELISA, commercially available from Endogen
(Boston, MA).
Statistical analysis
Differences between groups were analyzed by the Mann-Whitney U test. Differences were considered significant if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Priming of mice by a 0.5 µg IL-12 injection (i.p) followed by a
challenge with an LPS injection (i.v.) could induce the Shwartzman
reaction. Mortality depended on the dose of the second LPS injection
(Table I
). However, neither a 0.25 µg
IL-12 nor a 5 µg LPS injection could prime the reaction. Similarly,
two consecutive injections of 0.5 µg of IL-12 with a 24 h time
interval or a 5 µg LPS injection followed 24 h later by a 0.5
µg injection of IL-12 were ineffective. Similar mortalities were
observed in nude mice by 0.5 µg of IL-12 priming followed by an LPS
challenge.
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by
the stimulation of IL-12
We recently reported that anti-AGM1 Ab injection into mice
could delete NK cells but did not delete NK1+ T cells
(intermediate TCR cells), while anti-NK1 Ab (PK136) depleted both
NK cells and NK1+ T cells in the liver and other organs
(18, 19). Depletion of NK cells and NK1+ T cells by
anti-NK1 Ab diminished serum IFN- levels in the priming phase
(24 h after IL-12 injection) of the Shwartzman reaction (Table II), but anti-AGM1 Ab treatment had
only a moderate effect on serum IFN- levels (Table II). These
findings are further supported by the fact that
ß2m-/- mice, which have NK cells but fewer
NK1+ T cells, are also low producers of IFN- (Table II).
However, since anti-NK1 Ab-treated mice produce low but significant
amounts of IFN-, conventional T cells may be partly responsible for
IFN- production.
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than did NK cells (Table III).
Similar results were obtained from liver MNC from B6 nude mice (Table III). While NK1+ 
T cells of liver T cells of B6 mice
are negligible (10), NK1+ T cells of the liver and spleen
of nude mice contain 40 to 50% T cells (not shown). Therefore,
NK1+ T cells of nude mice may also have participated
in IFN- production. Although we do not deny that anti-CD3 Ab
staining itself may have somewhat stimulated NK1+ T cells
through their CD3/TCR complex, it probably did not have a great effect
because sorted liver NK1+ T cells of B6 mice without IL-12
injection produced only a small amount of IFN- in same culture
condition (data not shown).
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production in the second phase was not affected by
depletion of NK cells and NK1+ T cells
In contrast to IFN- production, elevated serum TNF- levels
in the second phase (1 h after LPS challenge) were not affected by
either Ab pretreatment (Table IV). We
followed the time course of TNF- levels in the second phase and
found that they showed maximal levels at 1 h after the second LPS
challenge.
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The above results suggest that NK1+ T cells are
major IFN--producing cells in the priming phase of the Shwartzman
reaction. To investigate the role of NK1+ T cells in the
pathogenesis of the Shwartzman reaction, either anti-NK1 Ab or
anti-AGM1 Ab was injected into mice twice before IL-12 priming. It
was found that anti-NK1 Ab treatment reduced the mortality
significantly, while anti-AGM1 treatment was ineffective (Table V). Further,
ß2m-/- mice all survived in a Shwartzman
reaction (Table V).
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Subsequently, we evaluated the histologic changes induced in the
liver by IL-12 injection. The result revealed that IL-12 injection
(i.p.) induced lymphocyte infiltration and focal necrosis in the liver
in a dose-dependent manner (Fig. 1).
Although IL-12 and subsequent LPS injection induced more focal necroses
in the liver, serum transaminases were not dramatically elevated (data
not shown).
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Next, we examined whether activated liver MNC cause hepatocytes
damage. Treatment of normal mice with a single injection of IL-12
augmented the cytotoxic activity of hepatic MNC against the P815 target
(Table VI), as we reported previously
(10, 11, 12, 13), while IL-12-activated hepatic MNC possessed lower
cytotoxicities against Fas Ag-negative L5178Y cells (20) and the
hepatocyte cell line, TLR-2 (17) (Table VI). However, among
combinations of two consecutive injections of IL-12 (0.5 µg) or LPS
(5 µg) with a 24 h time interval, IL-12 injection followed 24 h
later by a challenge of LPS induced greatly augmented in vitro
cytotoxicity against L5178Y and TLR-2 48 h after LPS challenge
(Table VI).
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).VII These results
show that although activated NK cells also seem to be responsible for
cytotoxicity against hepatocytes, activated
NK1+CD3+ cells are a main population causing
hepatocyte damage. It was also shown that NK1+ T cells
exert cytotoxicity, at least partly, in a Fas-Fas ligand-independent
fashion. NK1+ T cells of nude mice MNC also may
participate in cytotoxicity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells are potent responders to IL-12 (10, 11, 13) or LPS (via
production of IL-12 from Kupffer cells) (12), the role of these cells
in the Shwartzman reaction has not been explored. In the present study,
we demonstrate that NK1+ T cells are major producers of
IFN-, which is an essential cytokine for priming of the Shwartzman
reaction (2). IL-12 administration and extended doses of subsequent LPS
injection induced a lethal Shwartzman reaction. Depletion of NK cells
and NK1+ T cells before IL-12 priming greatly decreased
IFN- production and thereby reduced the mortality of mice, whereas
depletion of NK cells alone only partially decreased IFN- production
by IL-12 and did not improve mouse mortality. The result of
ß2m-/- mice also supports these findings.
In addition, the fact that the mortality of athymic nude mice was
comparable to that of normal mice and liver high TCR cells did not
produce a substantial amount of IFN- suggests that thymus-derived T
cells are not significantly involved in the pathogenesis of the
Shwartzman reaction. Cytotoxic activities of NK1+ T cells
and NK cells against hepatocytes were also induced by IL-12 and
subsequent LPS injection.
It was recently reported that LPS can activate macrophages to release
IL-12 (2, 4), a cytokine that stimulates T and NK cells to produce
IFN- (4, 6, 21, 22). IFN- induced by IL-12 is important in the
priming phase of the Shwartzman reaction (2, 3). On the other hand, it
has been recently reported that NK1+ T cells also produce
IFN- and IL-4 by the stimulation via their TCR (23, 24). However, NK
cells as well as NK1+ T cells produce IFN- but not IL-4
by the stimulation via their NK1.1 Ag or by IL-12 (25). It also has
been reported recently that liver NK1+ T cells produce IL-4
by stimulation with Con A in vivo (26). The present study confirmed
that NK1+ T cells are potent producers of IFN- by
stimulation of IL-12. Therefore, we propose that this novel population
of T cells can trigger either Th1 or Th2 immune responses by producing
IFN- or IL-4, depending upon Ags or factors.
IFN- produced by NK1+ T cells may further activate
monocytes or macrophages in a positive feedback loop and augment their
functions (27), including phagocytosis and Ag presenting capacity. It
is known that a majority of bacteria and their components, including
LPS and peptidoglycan polysaccharide, accumulates in the liver after
entering the blood stream and is removed there by Kupffer cells (12).
Thus, the liver seems to be an organ that is prepared to protect
against acute bacterial infection by inducing a Th1 response. However,
we do not deny that NK cells may produce larger amounts of IFN- than
NK1+ T cells in response to other cytokines or factors.
Further study of this phenomenon is now in progress.
IL-12 injection and subsequent LPS administration, but not two
consecutive injections of IL-12, killed mice. It is suggested that LPS
might induce a lethal reaction by inducing greater amounts of cytokines
or perhaps even different inflammatory cytokines (e.g., IL-1, TNF-)
than those induced by IL-12. In fact, IL-12 administration to mice does
not induce a significant elevation of serum TNF- (our unpublished
observation). TNF- and IL-1 reportedly are effector molecules in the
second phase of a lethal Shwartzman reaction. LPS also activates
granulocytes to release enzymes and radicals (2). However, it was
recently revealed that IFN- production in the priming phase, or
presensitization of mice by this cytokine, is essential to cause
mortality in the Shwartzman reaction (2) because neither IL-1, TNF-,
nor a combination of the two alone can cause mortality. Our finding is
consistent with this observation. It is notable that TNF- production
in the second phase per se is independent of IFN- production in the
priming phase. IFN- may prime the Shwartzman reaction through
up-regulation of MHC class I or class II expression of tissues and
cause the susceptibility of mice to LPS challenge (28). Consistent with
this speculation, ß2m-/- mice, which
produced more IFN- than NK cell- and NK1+ T
cell-depleted mice, are resistant to the Shwartzman reaction,
supporting the possibility that class I molecules expressed on the
tissues are involved in the mortality evolved in this phenomenon.
Although IL-12 and subsequent LPS administration induced cytotoxicity of NK1+ T cells and NK cells against hepatocytes in vitro and induced focal necroses in the liver in vivo, elevation of transaminase was not so evident. This is probably partly due to the fact that, in contrast to in vitro experiments, hepatocytes in vivo are surrounded by sinusoidal endothelial cells and are largely protected from direct contact with these activated cells. In addition, a new factor that causes more severe hepatocyte damage was recently reported in mice treated with Propionibacterium acnes and subsequent LPS challenge (29), indicating that additional factors are needed to cause more severe liver damage in vivo. Nevertheless, while infiltration by NK1+ T cells and NK cells per se may not be a major direct cause of mouse mortality in the Shwartzman reaction, it is indicated that these cells sometimes attack hepatocytes under certain conditions.
NK1+ ß T cells mainly use an invariant V14 gene
product (coupled with Vß8 or Vß7) for their TCR (19, 30, 31, 32). This
finding indicates that these cells recognize limited sets of Ags. We
recently reported that while human PBL contains several percentages of
ß T cells with a NK cell marker, CD56, human liver contains a
large population of these cells (33). Nevertheless, CD56+
ß T cells or CD56+ T cells selectively expand
and acquire strong MHC-unrestricted cytotoxicity against tumors when
monocyte-depleted PBL are cultured with a combination of IL-12 and IL-2
(33). It can be speculated that these CD56+ ß T cells
in humans are a functional counterpart of mouse NK1+ ß
T cells (19, 33). In fact, CD4+CD56+ ß T
cells selectively expand in vitro from the liver MNC of hepatitis B
patients and recognize hepatitis virus Ag with self-MHC molecules (34),
and NK1+ ß T cells are also reportedly responsible for
the elimination of adenovirus-infected hepatocytes in mice (35). These
findings and the present results raise the possibility that these T
cells with an NK cell marker can recognize virus Ags and self-molecules
of hepatocytes or of liver APC (Kupffer cells or dendritic cells) and
sometimes can be autoreactive effectors.
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Footnotes |
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2 Abbreviations used in this paper: B6, C57BL/6; AGM1, asialo GM1; ß2m-/-, ß2-microglobulin deficient; MNC, mononuclear cells.
Received for publication May 15, 1997. Accepted for publication December 3, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and tumor necrosis factor are the key cytokines of the generalized Shwartzman reaction. J. Exp. Med. 180:907. production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25:672.[Medline]
production. J. Immunol. 153:1697.[Abstract]
/ß+ cells in the liver of mice. J. Exp. Med. 180:699.ß T cells with intermediate TCR induced in the liver of mice by IL-12. J. Immunol. 154:4333.[Abstract]
ß T cells in the lungs of euthymic and athymic
mice. Immunology 88:82.
ß T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells. J. Immunol. 156:2436.[Abstract]
ß T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. J. Immunol. 156:3366.[Abstract]
14+ T cells by non-major histocompatibility complex-encoded class I-like molecules expressed on bone marrow-derived cells. Proc. Natl. Acad. Sci. USA 92:1200./ß+ thymocytes against a CD4+ 8+ thymocytes population associated with intact Fas antigen expression on the target. J. Exp. Med. 180:423.ßint liver lymphocytes: influence of thymus, ß2-microglobulin and NK1 expression. Int. Immunol. 7:1729. production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183:2391. in monocytic cells. J. Exp. Med. 183:147. is necessary for the T cell-mediated elimination of recombinant adenovirus infected hepatocytes in vivo. Proc. Natl. Acad. Sci. USA 92:7275.
production by T cells. Nature 378:88.[Medline]
24 J281 TCR. Int. Rev. Immunol. 11:31.[Medline]
chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-CD8- cells in mice and humans. J. Exp. Med. 180:1097.ß+ T cells. J. Immunol. 153:637.[Abstract]
or ß T cells with a natural killer cell marker, CD56, induced from human peripheral blood lymphocytes by a combination of IL-12 and IL-2. J. Immunol. 157:3886.[Abstract]
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G. Zhang, R. D. Nichols, M. Taniguchi, T. Nakayama, and M. J. Parmely Gamma Interferon Production by Hepatic NK T Cells during Escherichia coli Infection Is Resistant to the Inhibitory Effects of Oxidative Stress Infect. Immun., May 1, 2003; 71(5): 2468 - 2477. [Abstract] [Full Text] [PDF]
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T. Kambayashi, E. Assarsson, A. E. Lukacher, H.-G. Ljunggren, and P. E. Jensen Memory CD8+ T Cells Provide an Early Source of IFN-{gamma} J. Immunol., March 1, 2003; 170(5): 2399 - 2408. [Abstract] [Full Text] [PDF]
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T. Inui, R. Nakagawa, S. Ohkura, Y. Habu, Y. Koike, K. Motoki, N. Kuranaga, M. Fukasawa, N. Shinomiya, and S. Seki Age-Associated Augmentation of the Synthetic Ligand- Mediated Function of Mouse NK1.1 Ag+ T Cells: Their Cytokine Production and Hepatotoxicity In Vivo and In Vitro J. Immunol., December 1, 2002; 169(11): 6127 - 6132. [Abstract] [Full Text] [PDF]
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K. Ami, M. Kinoshita, A. Yamauchi, T. Nishikage, Y. Habu, N. Shinomiya, T. Iwai, H. Hiraide, and S. Seki IFN-{gamma} Production from Liver Mononuclear Cells of Mice in Burn Injury As Well As in Postburn Bacterial Infection Models and the Therapeutic Effect of IL-18 J. Immunol., October 15, 2002; 169(8): 4437 - 4442. [Abstract] [Full Text] [PDF]
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K. Ogasawara, S. K. Yoshinaga, and L. L. Lanier Inducible Costimulator Costimulates Cytotoxic Activity and IFN-{gamma} Production in Activated Murine NK Cells J. Immunol., October 1, 2002; 169(7): 3676 - 3685. [Abstract] [Full Text] [PDF]
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 Y. Hayakawa, K. Takeda, H. Yagita, M. J. Smyth, L. Van Kaer, K. Okumura, and I. Saiki IFN-gamma -mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha -galactosylceramide Blood, August 13, 2002; 100(5): 1728 - 1733. [Abstract] [Full Text] [PDF]
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M. Emoto, M. Miyamoto, I. Yoshizawa, Y. Emoto, U. E. Schaible, E. Kita, and S. H. E. Kaufmann Critical Role of NK Cells Rather Than V{alpha}14+NKT Cells in Lipopolysaccharide-Induced Lethal Shock in Mice J. Immunol., August 1, 2002; 169(3): 1426 - 1432. [Abstract] [Full Text] [PDF]
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 T. K. Varma, C. Y. Lin, T. E. Toliver-Kinsky, and E. R. Sherwood Endotoxin-Induced Gamma Interferon Production: Contributing Cell Types and Key Regulatory Factors Clin. Vaccine Immunol., May 1, 2002; 9(3): 530 - 543. [Abstract] [Full Text] [PDF]
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H. N. Le, N. C. Lee, K. Tsung, and J. A. Norton Pre-Existing Tumor-Sensitized T Cells Are Essential for Eradication of Established Tumors by IL-12 and Cyclophosphamide Plus IL-12 J. Immunol., December 15, 2001; 167(12): 6765 - 6772. [Abstract] [Full Text] [PDF]
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M. J. Skeen, E. P. Rix, M. M. Freeman, and H. K. Ziegler Exaggerated Proinflammatory and Th1 Responses in the Absence of gamma /delta T Cells after Infection with Listeria monocytogenes Infect. Immun., December 1, 2001; 69(12): 7213 - 7223. [Abstract] [Full Text] [PDF]
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R. Nakagawa, I. Nagafune, Y. Tazunoki, H. Ehara, H. Tomura, R. Iijima, K. Motoki, M. Kamishohara, and S. Seki Mechanisms of the Antimetastatic Effect in the Liver and of the Hepatocyte Injury Induced by {{alpha}}-Galactosylceramide in Mice J. Immunol., June 1, 2001; 166(11): 6578 - 6584. [Abstract] [Full Text] [PDF]
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Y. Habu, S. Seki, E. Takayama, T. Ohkawa, Y. Koike, K. Ami, T. Majima, and H. Hiraide The Mechanism of a Defective IFN-{{gamma}} Response to Bacterial Toxins in an Atopic Dermatitis Model, NC/Nga Mice, and the Therapeutic Effect of IFN-{{gamma}}, IL-12, or IL-18 on Dermatitis J. Immunol., May 1, 2001; 166(9): 5439 - 5447. [Abstract] [Full Text] [PDF]
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M. J. Parmely, F. Wang, and D. Wright Gamma Interferon Prevents the Inhibitory Effects of Oxidative Stress on Host Responses to Escherichia coli Infection Infect. Immun., April 1, 2001; 69(4): 2621 - 2629. [Abstract] [Full Text] [PDF]
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 F. Dieli, G. Sireci, D. Russo, M. Taniguchi, J. Ivanyi, C. Fernandez, M. Troye-Blomberg, G. De Leo, and A. Salerno Resistance of Natural Killer T Cell-Deficient Mice to Systemic Shwartzman Reaction J. Exp. Med., December 4, 2000; 192(11): 1645 - 1652. [Abstract] [Full Text] [PDF]
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K. Takeda, Y. Hayakawa, M. Atsuta, S. Hong, L. Van Kaer, K. Kobayashi, M. Ito, H. Yagita, and K. Okumura Relative contribution of NK and NKT cells to the anti-metastatic activities of IL-12 Int. Immunol., June 1, 2000; 12(6): 909 - 914. [Abstract] [Full Text] [PDF]
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E. Takayama, S. Seki, T. Ohkawa, K. Ami, Y. Habu, T. Yamaguchi, T. Tadakuma, and H. Hiraide Mouse CD8+ CD122+ T Cells with Intermediate TCR Increasing with Age Provide a Source of Early IFN-{gamma} Production J. Immunol., June 1, 2000; 164(11): 5652 - 5658. [Abstract] [Full Text] [PDF]
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D. K. Thibodeaux, S. E. Hunter, K. E. Waldburger, J. L. Bliss, W. L. Trepicchio, J. P. Sypek, K. Dunussi-Joannopoulos, S. J. Goldman, and J. P. Leonard Autocrine Regulation of IL-12 Receptor Expression Is Independent of Secondary IFN-{gamma} Secretion and not Restricted to T and NK Cells J. Immunol., November 15, 1999; 163(10): 5257 - 5264. [Abstract] [Full Text] [PDF]
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N. Koide, K. Narita, Y. Kato, T. Sugiyama, D. Chakravortty, A. Morikawa, T. Yoshida, and T. Yokochi Expression of Fas and Fas Ligand on Mouse Renal Tubular Epithelial Cells in the Generalized Shwartzman Reaction and Its Relationship to Apoptosis Infect. Immun., August 1, 1999; 67(8): 4112 - 4118. [Abstract] [Full Text] [PDF]
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K. B. Nguyen and C. A. Biron Synergism for Cytokine-Mediated Disease During Concurrent Endotoxin and Viral Challenges: Roles for NK and T Cell IFN-{gamma} Production J. Immunol., May 1, 1999; 162(9): 5238 - 5246. [Abstract] [Full Text] [PDF]
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G. D. Sempowski, D. M. Lee, R. M. Scearce, D. D. Patel, and B. F. Haynes Resistance of CD7-deficient Mice to Lipopolysaccharide-induced Shock Syndromes J. Exp. Med., March 15, 1999; 189(6): 1011 - 1016. [Abstract] [Full Text] [PDF]
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S. Seki, S.-i. Osada, S. Ono, S. Aosasa, Y. Habu, T. Nishikage, H. Mochizuki, and H. Hiraide Role of Liver NK Cells and Peritoneal Macrophages in Gamma Interferon and Interleukin-10 Production in Experimental Bacterial Peritonitis in Mice Infect. Immun., November 1, 1998; 66(11): 5286 - 5294. [Abstract] [Full Text] [PDF]
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 K. Takeda, Y. Hayakawa, L. Van Kaer, H. Matsuda, H. Yagita, and K. Okumura Critical contribution of liver natural killer T cells to a murine model of hepatitis PNAS, May 9, 2000; 97(10): 5498 - 5503. [Abstract] [Full Text] [PDF]
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S. Kim, K. Iizuka, H. L. Aguila, I. L. Weissman, and W. M. Yokoyama In vivo natural killer cell activities revealed by natural killer cell-deficient mice PNAS, March 14, 2000; 97(6): 2731 - 2736. [Abstract] [Full Text] [PDF]
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