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-Galactosylceramide in Mice
*
Pharmaceutical Research Laboratory, Kirin Brewery Company, Takasaki, 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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-galactosylceramide (-GalCer) has been
unclear. We now show that, whereas -GalCer increased the serum
IFN-
concentration and alanine aminotransferase activity in NK
cell-depleted C57BL/6 (B6) mice and B6-beige/beige mice
similarly to its effects in control B6 mice, its enhancement of the
antitumor cytotoxicity of liver mononuclear cells (MNCs) was abrogated.
Depletion of both NK and NKT cells in B6 mice reduced all these effects
of -GalCer. Injection of Abs to IFN- also inhibited the
-GalCer-induced increase in antitumor cytotoxicity of MNCs.
-GalCer induced the expression of Fas ligand on NKT cells in the
liver of B6 mice. Whereas -GalCer did not increase serum alanine
aminotransferase activity in B6-lpr/lpr mice and
B6-gld/gld mice, it increased the antitumor cytotoxicity of
liver MNCs. The -GalCer-induced increase in survival rate apparent
in B6 mice injected intrasplenically with B16 tumor cells was abrogated
in beige/beige mice, NK cell-depleted B6 mice, and B6 mice
treated with Abs to IFN-. Depletion of CD8+ T cells did
not affect the -GalCer-induced antitumor cytotoxicity of liver MNCs
but reduced the effect of -GalCer on the survival of B6 mice. Thus,
IFN- produced by -GalCer-activated NKT cells increases both the
innate antitumor cytotoxicity of NK cells and the adaptive antitumor
response of CD8+ T cells, with consequent inhibition of
tumor metastasis to the liver. Moreover, NKT cells mediate
-GalCer-induced hepatocyte injury through Fas-Fas ligand
signaling. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(3, 4, 5). The TCR of mouse
NKT cells comprises the V14J281 gene product combined with a
V
8, V2, or V7 chain (6, 7), and the development
of these cells is dependent on the nonclassical MHC class I molecule
CD1d (8). Liver NKT cells produced more IFN- and
exhibited a greater antitumor cytotoxicity in response to stimulation
with IL-12 in vivo than did NK cells (4). In contrast, the
amount of IFN- produced by liver NK cells was greater than that
produced by NKT cells in mice with bacterial peritonitis
(5). Furthermore, injection of mice with LPS induced a
marked increase in the antitumor cytotoxicity of NKT cells as a result
of the IFN- produced by NK cells (3, 4, 9).
The glycolipid Ag -galactosylceramide (-GalCer) induces the
production of IFN- by mouse NKT cells in a CD1d-dependent manner
(10). We previously suggested that liver antitumor
effectors activated by -GalCer might include NK cells
(11), whereas other studies have implicated NKT cells as
important mediators of the antitumor effect of -GalCer both in vitro
and in vivo (10, 12). However, -GalCer-induced
antitumor cytotoxicity was recently shown to be mediated predominantly
by NK cells in response to the IFN- produced by NKT cells (13, 14). Osman et al. (15) also recently showed that
liver NKT cells undergo apoptosis in response to injection of
-GalCer in mice. These researchers suggested that activated NKT
cells may be effectors of the hepatocyte damage induced by -GalCer
injection but that NK cells may also play a role in this process. The
importance of NKT cells in both antitumor immunity and hepatocyte
injury induced by -GalCer was revealed by the observation that these
phenomena do not occur in CD1-deficient or
2-microglobulin-deficient mice
(15), both of which lack NKT cells. However, the effectors
of the antimetastatic action of -GalCer in the liver as well as of
the hepatocyte damage induced by this glycolipid remain to be
definitively identified.
We have now shown that the principal mediators of the direct antitumor
effect and the antimetastatic effect of -GalCer in the liver are NK
cells that have been activated by IFN- produced by NKT cells. We
also show that CD8+ T cells contribute to the
antimetastatic effect of -GalCer, whereas NKT cells mediate
-GalCer-induced hepatocyte damage through the Fas-Fas ligand
signaling pathway. These conclusions are supported by observations with
beige/beige (bg/bg) mice, in which NK cell
function is impaired (16, 17), as well as with
lpr/lpr (lpr) mice (2, 18, 19) and
gld/gld (gld) mice (20), in which
Fas and Fas ligand, respectively, are defective.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 (B6) mice at 6 wk of age were obtained from Nippon SLC (Hamamatsu, Japan), and male B6-bg/bg, B6-lpr, and B6-gld mice of the same age were obtained from The Jackson Laboratory Japan (Tokyo, Japan). Mice were maintained and fed under standard laboratory conditions. Hepatic MNCs were prepared essentially as described (1, 4). In brief, the liver was passed through a stainless steel mesh, and the resulting dissociated cells were suspended in HBSS, washed, resuspended in an isotonic 30% Percoll solution (Sigma) containing heparin (100 U/ml), and centrifuged at 500 x g for 15 min at room temperature. The resulting pellet was resuspended in RBC lysis solution and then washed twice in RPMI 1640 supplemented with 5% FCS.
Reagents
-GalCer, or
(2S,3S,4R)-1-O-(-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1,2,4-octadecanetriol
(KRN7000), was synthesized in our laboratory (21, 22, 23). The
original solution of -GalCer (220 µg/ml) was prepared with 0.5%
polysorbate 20 (Nikko Chemical, Tokyo, Japan) in saline and was
subsequently diluted with this solution (vehicle) or with saline before
i.v. injection at a dose of 100 µg/kg of body mass.
Flow cytometric analysis
The surface phenotypes of liver MNCs were characterized by two-
or three-color flow cytometric analysis. An FITC-conjugated hamster mAb
to mouse TCR (H57-597, IgG) and a PE-conjugated mouse mAb to
NK1.1 (PK136, IgG2a) were obtained from PharMingen (San Diego, CA).
Before staining with Abs, the MNCs were incubated for 10 min with
Fc-blocker (2.4 G2; PharMingen) to prevent nonspecific binding. For
analysis of Fas ligand expression, liver MNCs were isolated 1 h
after the injection of -GalCer or vehicle into B6 mice. The cells
were then stained with the FITC-conjugated mAb to TCR, the
PE-conjugated mAb to NK1.1, and a biotin-conjugated hamster mAb to Fas
ligand (MFL1, IgG; PharMingen); immune complexes formed by the latter
Ab were detected with Cy5-streptavidin. Flow cytometry was performed
with FACSCalibur and FACScan instruments (BD Biosciences, Mountain
View, CA).
In vivo cell depletion
Monoclonal Abs to CD4 (L3T4), to CD8 (Lyt2.2), or to NK1.1 were derived from GK1.5, 2.43, and PK136 hybridoma cells (IBL, Gunma, Japan), respectively. We previously showed that a single i.v. injection of an optimal dose of Abs to asialo-GM1 (AGM1) (Wako, Tokyo, Japan) resulted in depletion of NK cells alone, whereas injection of Abs to NK1.1 depleted both NK and NKT cells for at least 5 days (24). Mice were injected i.p. with 500 µg of anti-CD4 or anti-CD8, 50 µg of anti-AGM1, or 200 µg of anti-NK1.1.
Cytotoxicity assay
NK cell-sensitive YAC-1 lymphoma cells and B16 melanoma cells
(of B6 origin) were used as target cells. Target cells (3 x
106) were labeled for 60 min at 37°C with 100
µCi of
Na251CrO4
in 500 µl of RPMI 1640 supplemented with 10% FCS. Then, they were
washed three times with medium alone and subjected to the cytotoxicity
assay. Labeled targets (2 x 103 cells per
well) were incubated for 4 h at 37°C in 96-well round-bottom
microtiter plates containing RPMI 1640 (total volume of 100 µl) and
liver MNCs obtained from mice injected 24 h previously with
-GalCer (100 µg/kg). The plates were then centrifuged, and the
resulting supernatants were harvested and their content of
radioactivity was determined with a gamma counter. Cytotoxicity was
calculated as the percentage of released radioactivity after correction
for spontaneous release, which was <15% of maximal release.
Measurement of serum IFN- and alanine aminotransferase (ALT)
The serum concentration of IFN- was measured by ELISA
(Endogen, Boston, MA). The activity of ALT in serum was determined with
a DRI-CHEM 3000V instrument (Fuji Medical Systems, Tokyo, Japan).
B16 model of hepatic metastasis
Hepatic metastases of B16 tumor cells were produced as described (25). In brief, the spleen of anesthetized mice was exposed to allow the direct intrasplenic injection of 3 x 106 B16 cells in 0.1 ml of medium. The spleen was then removed after clamping of the artery and vein, and the abdomen and skin were surgically sutured. This approach results in the metastasis of B16 tumor cells almost exclusively to the liver.
In vivo depletion of IFN-
Rat monoclonal IgG1 to mouse IFN- was derived from R4-6A2
hybridoma cells (IBL). Mice were injected i.p. with 1 mg of
anti-IFN- or an isotype-control Ab (R3-34; PharMingen) at the
same time that they received an i.v. injection of -GalCer (100
µg/kg).
Statistical analysis
Data are expressed as means ± SD, and differences among groups were analyzed by the Mann-Whitney U test with StatView software. Mouse survival rates were analyzed by the log-rank test. A p value of <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GalCer
Injection of B6 mice with -GalCer (100 µg/kg, i.v.) resulted
in a decrease in the number of NKT cells in the liver that was first
apparent after 
3 h, with most such cells having disappeared by
12 h after injection (Fig. 1
). In
contrast, the proportion of NK cells gradually increased for up to 5
days after -GalCer injection; NKT cells also began to reappear from
2 days after injection. Injection of -GalCer also induced a
transient disappearance of NKT cells in bg/bg mice (data not
shown).
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-GalCer
The total number of liver MNCs showed a 4-fold increase 3 days
after injection of -GalCer in B6 mice (Fig. 2A). This effect was
accompanied by an increase in antitumor cytotoxicity of liver MNCs that
was apparent with either YAC-1 lymphoma or B16 melanoma cells and
persisted for >5 days (Fig. 2B). Such a long-lasting and
marked antitumor cytotoxicity was not observed after injection of
either IFN- or IL-12 (data not shown).
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-GalCer-induced antitumor cytotoxicity of liver
MNCs by injection of mice with Abs to AGM1, to NK1.1, or to IFN-
Depletion of NK cells by pretreatment of mice with anti-AGM1
or depletion of both NK and NKT cells by pretreatment with
anti-NK1.1 (Fig. 3A)
almost completely abolished the effect of -GalCer on antitumor
cytotoxicity of liver MNCs apparent with either YAC-1 or B16 cells
(Fig. 3B, a and b). However, depletion
of either CD8+ or CD4+ T
cells by pretreatment of mice with anti-CD8 or anti-CD4 did not
affect the -GalCer-induced increase in antitumor cytotoxicity of
liver MNCs (Fig. 3B, c and d).
Anti-IFN- also markedly inhibited the -GalCer-induced increase in
antitumor cytotoxicity of liver MNCs (Fig. 3B, e
and f). Depletion of liver NKT cells by injection of mice
with anti-NK1.1 was also confirmed by the disappearance of
CD4+ V8 T cells with intermediate TCR
expression (data not shown). Although injection of anti-CD8 almost
completely depleted CD8+ T cells, and injection
of anti-CD4 depleted CD4+ T cells with high
TCR expression, the number of CD4+ NKT cells with
intermediate TCR expression was not substantially affected by injection
of anti-CD4 (data not shown). CD4+ NKT cells
have been shown to express CD4 only at a low level (26, 27).
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-GalCer on antitumor cytotoxicity of liver
MNCs in bg/bg mice
Given that the function of NK cells is impaired in
bg/bg mice (16, 17), we next examined the
effect of -GalCer on the antitumor cytotoxicity of liver MNCs in
these animals. Consistent with the results obtained by injection of B6
mice with anti-AGM1, -GalCer did not increase the antitumor
cytotoxicity of liver MNCs of bg/bg mice with either YAC-1
or B16 cells as targets (Fig. 4).
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-GalCer and Ab pretreatment on serum IFN- and ALT
levels in B6 and bg/bg mice
Injection of B6 mice with -GalCer resulted in an increase in
the serum concentration of IFN- that was apparent at 6 h and
maximal at 12 h (Table I); the
IFN- concentration had decreased markedly at 24 h and had
returned to basal values by 48 h (data not shown) after -GalCer
injection. Whereas depletion of NK cells alone by pretreatment of B6
mice with anti-AGM1 did not inhibit the production of IFN-,
depletion of both NK and NKT cells by pretreatment with anti-NK1.1
markedly inhibited the -GalCer-induced increase in the serum
concentration of IFN- (Table I). Furthermore, injection of
-GalCer induced an increase in the serum concentration of IFN- in
bg/bg mice that was similar to that observed in B6 mice
(Table I). Thus, these results suggested that most of the IFN-
produced in response to -GalCer is derived from NKT cells rather
than from NK cells.
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-GalCer induced an increase in the
activity of ALT in serum that was apparent at 3 h and maximal at
12 h; the ALT activity had decreased by 48 h (Table II) and had returned to basal values by
72 h (data not shown) after -GalCer injection. Similar to the
results obtained for serum IFN-, the effect of -GalCer on serum
ALT activity was not affected by depletion of NK cells alone but was
significantly inhibited by the depletion of both NK and NKT cells. In
addition, -GalCer also induced a marked increase in serum ALT
activity in bg/bg mice. However, treatment of B6 mice with
anti-IFN- did not inhibit the -GalCer-induced increase in
serum ALT activity (data not shown). Thus these observations suggested
that NKT cells, but not NK cells, contribute to -GalCer-induced
hepatocyte injury in an IFN--independent manner.
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-GalCer to induce liver injury in lpr and
gld mice and -GalCer-induced expression of Fas ligand on
NKT cells of B6 mice
To explore the mechanism by which -GalCer induces hepatocyte
injury, we examined the effects of this compound in lpr and gld mice,
which are defective in the function of Fas and Fas ligand,
respectively. Injection of both lpr and gld mice
with -GalCer increased the cytotoxicity of liver MNCs toward YAC-1
cells (Table III). NKT cells in these
mice also disappeared within 12 h of -GalCer injection (data
not shown). However, -GalCer had no significant effect on the serum
ALT activity in either lpr or gld mice (Table III). Furthermore, flow cytometric analysis of liver MNCs revealed that
-GalCer induced an increase in the expression of Fas ligand on NKT
cells 1 h after injection of B6 mice that was markedly greater
than that apparent for either NK or T cells (Fig. 5). These observations are consistent
with the notion that the liver injury induced by -GalCer is mediated
predominantly by NKT cells through the Fas-Fas ligand signaling
pathway.
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-GalCer and various Abs on the survival of mice after
intrasplenic injection of B16 tumor cells
We next evaluated mouse survival rates after intrasplenic
injection of B16 cells under various conditions. Consistent with the
results of the antitumor cytotoxicity experiments, whereas -GalCer
induced a marked increase in the survival rate of B6 mice injected with
B16 tumor cells, depletion of NK cells alone by pretreatment with
anti-AGM1 prevented this effect of -GalCer (Fig. 6A). Similarly, depletion of
both NK and NKT cells also completely inhibited the prolongation of
mouse survival induced by -GalCer (Fig. 6A). Furthermore,
the survival rate of B16 cell-injected bg/bg mice was not
markedly affected by -GalCer (Fig. 6B). Pretreatment of
mice with anti-CD8 partially inhibited the survival-promoting
effect of -GalCer in B6 mice (Fig. 6C), suggesting that
CD8+ T cells contribute to the antimetastatic
effect of -GalCer in the liver. Although anti-CD4 tended to
reduce the increase in survival rate induced by -GalCer, this effect
was not statistically significant (Fig. 6C). Treatment of B6
mice with anti-IFN- also completely inhibited the
-GalCer-induced increase in survival rate (Fig. 6D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GalCer in the liver. Most NKT cells had
disappeared from the liver within 12 h of -GalCer
administration, probably as a result of apoptosis (15).
However, IFN- produced by -GalCer-activated NKT cells was
required for the antitumor and antimetastatic actions of NK cells. In
addition, CD8+ T cells were also shown to
contribute to the antimetastatic effect in the liver and the
prolongation of mouse survival induced by -GalCer. Our observations
that -GalCer did not induce hepatic injury in lpr and
gld mice also indicate that NKT cells mediate the hepatocyte
damage induced by this compound through the Fas-Fas ligand signaling
pathway.
NKT cells are activated by IL-12 to produce IFN- and thereby exert
an antimetastatic effect in the liver of both normal and
bg/bg mice (28). In contrast, -GalCer did
not induce a marked increase in the antitumor cytotoxicity of liver
MNCs of bg/bg mice and did not exert an effective
antimetastatic action in the liver of these animals injected with B16
tumor cells. Thus, these observations indicate that the function of NK
cells is impaired in bg/bg mice, whereas that of NKT cells
is intact. Indeed, -GalCer injection resulted in the depletion of
NKT cells from the liver and increased the serum concentration of
IFN- in bg/bg mice to extents similar to those apparent
in B6 mice. The role of IFN- produced by NKT cells in the antitumor
action of -GalCer in the liver was demonstrated by the observation
that treatment of mice with anti-IFN- greatly reduced both the
antitumor cytotoxicity of liver MNCs and the antimetastatic effect
induced by this glycolipid. It was also recently shown that -GalCer
induces NK cell proliferation and the acquisition by these cells of
antitumor activity in vitro and in vivo, and that the antitumor
activity of NK cells was, at least in part, dependent on IFN-
produced by NKT cells (13, 14).
The marked increase in the antitumor cytotoxicity of liver MNCs induced
by -GalCer persisted for up to 10 days. Neither IFN- nor IL-12
induced such a long-lasting increase in the antitumor cytotoxicity of
liver MNCs. Indeed, we previously showed that administration of
-GalCer to mice that had received an intrasplenic injection of
colon-26 tumor cells (which metastasize to the liver) increased the
survival rate more effectively than did treatment with IL-12
(11). Furthermore, we have now also shown that
CD8+ T cells participate in the antimetastatic
effect of -GalCer. Although IFN- produced by NKT cells was
essential for theantitumor action of -GalCer, the serum
concentration of this cytokine had returned to basal values within
48 h after -GalCer injection. Therefore, other factors may also
be required for the long-lasting antitumor effect of -GalCer.
-GalCer also inhibited liver metastasis of i.v. injected EL4 cells
(murine T lymphoma) and increased the survival rate of the injected
mice (29). However, in contrast to IL-12
(28), -GalCer did not effectively inhibit lung
metastasis of i.v. injected 3LL Lewis tumor cells (which are highly
resistant to NK cells) or liver metastasis of 3LL cells injected into
the spleen, nor did it significantly increase the survival rate of the
injected mice (R. Nakagawa and K. Motoki, unpublished data).
Thus, the antitumor function of activated NKT cells appears to be
important for inhibiting the metastasis of NK cell-resistant tumors
(28).
Although treatment of mice that had received an intrasplenic injection
of colon-26 tumor cells with -GalCer induced the complete rejection
of the tumor cells in some mice and rendered them resistant to
subsequent s.c. challenge with the same tumor cells, such treatment did
not affect susceptibility to s.c. injection with Meth A or other tumor
cells (11). Given that the inhibitory effect of -GalCer
on s.c. growth of tumors in nonsensitized mice is weak compared with
that on tumor metastasis (11), NK and NKT cells may be
important for innate immunity against tumor metastasis, whereas
cytotoxic CD8+ T cells (possibly with the help of
CD4+ T cells) may be important either for
inhibition of s.c. tumor growth or for adaptive antitumor immunity (as
memory T cells). Thus, a cascade of NKT, NK, and cytotoxic
CD8+ T cells may be responsible for the antitumor
action of -GalCer. Both NK and NKT cells were recently shown to be
important antitumor effectors in response to the i.p. injection of
tumor cells (30). Furthermore, cooperation of NK and
CD56+ T cells (which may be a human functional
counterpart of mouse NKT cells; Refs. 3 and
31) in human liver appears important in inhibition of the
generation of hepatocellular carcinoma (31). These various
observations not only support our previous proposal that the lymphocyte
subsets primarily responsible for antitumorigenesis may differ among
tissues (1) but also suggest that the interaction of
lymphocyte subsets is important in antitumor immunity.
Our results indicate that NKT cells are the effectors of hepatocyte
damage induced by -GalCer, given that prior depletion of NK cells
alone did not inhibit the increase in serum ALT activity in
-GalCer-treated mice whereas depletion of both NK and NKT cells did.
In addition, -GalCer induced a marked increase in the serum activity
of ALT in bg/bg mice. Furthermore, our observations that
-GalCer increased the expression of Fas ligand most markedly on NKT
cells in B6 mice and that this glycolipid did not trigger hepatic
injury in lpr and gld mice indicate that NKT
cells activated by -GalCer induce hepatocyte damage through the
Fas-Fas ligand pathway.
Injection of IL-12 was previously shown to induce a marked increase in
antitumor cytotoxicity of liver NKT cells, and IFN- produced by
activated NKT cells was shown to be responsible for the hepatocyte
damage and lethal shock induced by IL-12 and subsequent injection
(after 24 h) of LPS (4). In contrast, NK cells were
shown to be responsible for hepatic failure induced by injection of LPS
in Propionibacterium acnes-primed mice, and IL-12, IL-18, or
IFN- was essential for this hepatic failure (32).
Bacterial superantigens also activate liver NK and NKT cells through
the IL-12 produced by Kupffer cells (33). These
observations suggest that, although liver Kupffer, NKT, and NK cells
are essential leukocyte subsets for protection against both malignant
tumors and bacterial infection, as a result of their induction of the
Th1 cell-mediated immune response, inadequate activation of this
defense mechanism can lead to hepatic dysfunction and multiple organ
failure (3, 4).
-GalCer was originally isolated from a marine sponge
(21). No disease or condition has been shown to induce
this molecule in mice, suggesting that it is not likely an endogenous
ligand in these animals. The initial rapid disappearance of NKT cells
from the liver of -GalCer-treated mice, probably as a result of
apoptosis, is followed by the reappearance of these cells around 2 days
after -GalCer injection; these presumably newly produced NKT cells
are likely not hepatotoxic. Injection of a second dose of -GalCer
into B6 mice 7 days after the first administration did not result in an
increase in the serum levels of IFN- or ALT or in the disappearance
of NKT cells from the liver (data not shown), suggesting that the mice
had developed tolerance to this glycolipid.
LPS was recently shown to induce a marked increase in the antitumor
cytotoxicity of NKT cells (4, 9), whereas NK cells
produced more IFN- in response to LPS than did NKT cells
(3). Given that the LPS-induced increase in antitumor
cytotoxicity of liver MNCs and the extent of tumor metastasis to the
liver were reduced by pretreatment of mice with either anti-IFN-
or anti-IL-12 (3, 9), IL-12 produced by Kupffer cells
and the subsequent production of IFN- by NK cells appear important
for the LPS-induced antitumor cytotoxicity of NKT cells. This
relationship between NK and NKT cells is opposite to that
revealed by our present results showing that -GalCer induces NKT
cells to produce IFN-, which then increases the antitumor
cytotoxicity of NK cells; IL-12 was also shown not to contribute to the
-GalCer-induced antitumor cytotoxicity of liver MNCs
(14). Cells of the hepatic monocyte lineage, including
Kupffer (or dendritic), NK, NKT, and CD8+ T
cells, thus appear to interact with each other and to modulate
precisely the immune response in various immunopathologic states in the
liver.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: NKT cells, NK1.1 Ag+ T cells; -GalCer, -galactosylceramide; MNC, mononuclear cell; AGM1, asialo-GM1; ALT, alanine aminotransferase; B6, C57BL/6; bg/bg, beige/beige; lpr, lpr/lpr; gld, gld/gld.
Received for publication January 18, 2001. Accepted for publication March 29, 2001.
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 M. N. Ajuebor Role of NKT Cells in the Digestive System. I. Invariant NKT cells and liver diseases: is there strength in numbers? Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G651 - G656. [Abstract] [Full Text] [PDF]
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 R. Safadi, E. Zigmond, O. Pappo, Z. Shalev, and Y. Ilan Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution Int. Immunol., August 13, 2007; (2007) dxm069v1. [Abstract] [Full Text] [PDF]
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 X.-c. Chen, R. Wang, X. Zhao, Y.-q. Wei, M. Hu, Y.-s. Wang, X.-w. Zhang, R. Zhang, L. Zhang, B. Yao, et al. Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs Carcinogenesis, December 1, 2006; 27(12): 2434 - 2441. [Abstract] [Full Text] [PDF]
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M. Kinoshita, N. Shinomiya, S. Ono, H. Tsujimoto, T. Kawabata, A. Matsumoto, H. Hiraide, and S. Seki Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa J. Immunol., October 1, 2006; 177(7): 4627 - 4635. [Abstract] [Full Text] [PDF]
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S Nagaraj, C Ziske, J Strehl, D Messmer, T Sauerbruch, and I. Schmidt-Wolf Dendritic cells pulsed with alpha-galactosylceramide induce anti-tumor immunity against pancreatic cancer in vivo Int. Immunol., August 1, 2006; 18(8): 1279 - 1283. [Abstract] [Full Text] [PDF]
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R. R. Brutkiewicz CD1d Ligands: The Good, the Bad, and the Ugly J. Immunol., July 15, 2006; 177(2): 769 - 775. [Abstract] [Full Text] [PDF]
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 M. J. Ragin, N. Sahu, and A. August Differential Regulation of Cytokine Production by CD1d-Restricted NKT Cells in Response to Superantigen Staphylococcal Enterotoxin B Exposure Infect. Immun., January 1, 2006; 74(1): 282 - 288. [Abstract] [Full Text] [PDF]
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M. Margalit, S. A. Ghazala, R. Alper, E. Elinav, A. Klein, V. Doviner, Y. Sherman, B. Thalenfeld, D. Engelhardt, E. Rabbani, et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G917 - G925. [Abstract] [Full Text] [PDF]
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S. Kojo, K.-i. Seino, M. Harada, H. Watarai, H. Wakao, T. Uchida, T. Nakayama, and M. Taniguchi Induction of Regulatory Properties in Dendritic Cells by V{alpha}14 NKT Cells J. Immunol., September 15, 2005; 175(6): 3648 - 3655. [Abstract] [Full Text] [PDF]
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S.-Y. Ko, H.-J. Ko, W.-S. Chang, S.-H. Park, M.-N. Kweon, and C.-Y. Kang {alpha}-Galactosylceramide Can Act As a Nasal Vaccine Adjuvant Inducing Protective Immune Responses against Viral Infection and Tumor J. Immunol., September 1, 2005; 175(5): 3309 - 3317. [Abstract] [Full Text] [PDF]
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T. Osada, M. A. Morse, H. K. Lyerly, and T. M. Clay Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs Int. Immunol., September 1, 2005; 17(9): 1143 - 1155. [Abstract] [Full Text] [PDF]
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M. Biburger and G. Tiegs {alpha}-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-{alpha} but Independent of Kupffer Cells J. Immunol., August 1, 2005; 175(3): 1540 - 1550. [Abstract] [Full Text] [PDF]
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K. Haraguchi, T. Takahashi, A. Matsumoto, T. Asai, Y. Kanda, M. Kurokawa, S. Ogawa, H. Oda, M. Taniguchi, H. Hirai, et al. Host-Residual Invariant NK T Cells Attenuate Graft-versus-Host Immunity J. Immunol., July 15, 2005; 175(2): 1320 - 1328. [Abstract] [Full Text] [PDF]
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J. S. Bezbradica, A. K. Stanic, N. Matsuki, H. Bour-Jordan, J. A. Bluestone, J. W. Thomas, D. Unutmaz, L. Van Kaer, and S. Joyce Distinct Roles of Dendritic Cells and B Cells in Va14Ja18 Natural T Cell Activation In Vivo J. Immunol., April 15, 2005; 174(8): 4696 - 4705. [Abstract] [Full Text] [PDF]
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T. Crough, M. Nieda, and A. J. Nicol Granulocyte Colony-Stimulating Factor Modulates {alpha}-Galactosylceramide-Responsive Human V{alpha}24+V{beta}11+ NKT Cells J. Immunol., October 15, 2004; 173(8): 4960 - 4966. [Abstract] [Full Text] [PDF]
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A. Ahmad and F. Alvarez Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis J. Leukoc. Biol., October 1, 2004; 76(4): 743 - 759. [Abstract] [Full Text] [PDF]
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Y. Y. Setiady, P. Pramoonjago, and K. S. K. Tung Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex J. Immunol., July 15, 2004; 173(2): 1051 - 1058. [Abstract] [Full Text] [PDF]
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R. Nakagawa, T. Inui, I. Nagafune, Y. Tazunoki, K. Motoki, A. Yamauchi, M. Hirashima, Y. Habu, H. Nakashima, and S. Seki Essential Role of Bystander Cytotoxic CD122+CD8+ T Cells for the Antitumor Immunity Induced in the Liver of Mice by {alpha}-Galactosylceramide J. Immunol., June 1, 2004; 172(11): 6550 - 6557. [Abstract] [Full Text] [PDF]
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 L. Poirot, C. Benoist, and D. Mathis Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity PNAS, May 25, 2004; 101(21): 8102 - 8107. [Abstract] [Full Text] [PDF]
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M. Maeda, A. Shadeo, A. M. MacFadyen, and F. Takei CD1d-Independent NKT Cells in {beta}2-Microglobulin-Deficient Mice Have Hybrid Phenotype and Function of NK and T Cells J. Immunol., May 15, 2004; 172(10): 6115 - 6122. [Abstract] [Full Text] [PDF]
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 M. Nieda, M. Okai, A. Tazbirkova, H. Lin, A. Yamaura, K. Ide, R. Abraham, T. Juji, D. J. Macfarlane, and A. J. Nicol Therapeutic activation of V{alpha}24+V{beta}11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity Blood, January 15, 2004; 103(2): 383 - 389. [Abstract] [Full Text] [PDF]
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 R. A. Campos, M. Szczepanik, A. Itakura, M. Akahira-Azuma, S. Sidobre, M. Kronenberg, and P. W. Askenase Cutaneous Immunization Rapidly Activates Liver Invariant V{alpha}14 NKT Cells Stimulating B-1 B Cells to Initiate T Cell Recruitment for Elicitation of Contact Sensitivity J. Exp. Med., December 15, 2003; 198(12): 1785 - 1796. [Abstract] [Full Text] [PDF]
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I. F. Hermans, J. D. Silk, U. Gileadi, M. Salio, B. Mathew, G. Ritter, R. Schmidt, A. L. Harris, L. Old, and V. Cerundolo NKT Cells Enhance CD4+ and CD8+ T Cell Responses to Soluble Antigen In Vivo through Direct Interaction with Dendritic Cells J. Immunol., November 15, 2003; 171(10): 5140 - 5147. [Abstract] [Full Text] [PDF]
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N. Y. Crowe, A. P. Uldrich, K. Kyparissoudis, K. J. L. Hammond, Y. Hayakawa, S. Sidobre, R. Keating, M. Kronenberg, M. J. Smyth, and D. I. Godfrey Glycolipid Antigen Drives Rapid Expansion and Sustained Cytokine Production by NK T Cells J. Immunol., October 15, 2003; 171(8): 4020 - 4027. [Abstract] [Full Text] [PDF]
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C. N. Baxevanis, A. D. Gritzapis, and M. Papamichail In Vivo Antitumor Activity of NKT Cells Activated by the Combination of IL-12 and IL-18 J. Immunol., September 15, 2003; 171(6): 2953 - 2959. [Abstract] [Full Text] [PDF]
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T. Kenna, L. G. Mason, S. A. Porcelli, Y. Koezuka, J. E. Hegarty, C. O'Farrelly, and D. G. Doherty NKT Cells from Normal and Tumor-Bearing Human Livers Are Phenotypically and Functionally Distinct from Murine NKT Cells J. Immunol., August 15, 2003; 171(4): 1775 - 1779. [Abstract] [Full Text] [PDF]
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Y. Hayakawa, S. Rovero, G. Forni, and M. J. Smyth {alpha}-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis PNAS, August 5, 2003; 100(16): 9464 - 9469. [Abstract] [Full Text] [PDF]
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 K. Kuwata, H. Watanabe, S.-Y. Jiang, T. Yamamoto, C. Tomiyama-Miyaji, T. Abo, T. Miyazaki, and M. Naito AIM Inhibits Apoptosis of T Cells and NKT Cells in Corynebacterium-Induced Granuloma Formation in Mice Am. J. Pathol., March 1, 2003; 162(3): 837 - 847. [Abstract] [Full Text] [PDF]
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 G. Giaccone, C. J. A. Punt, Y. Ando, R. Ruijter, N. Nishi, M. Peters, B. M. E. von Blomberg, R. J. Scheper, H. J. J. van der Vliet, A. J. M. van den Eertwegh, et al. A Phase I Study of the Natural Killer T-Cell Ligand {alpha}-Galactosylceramide (KRN7000) in Patients with Solid Tumors Clin. Cancer Res., December 1, 2002; 8(12): 3702 - 3709. [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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N. Y. Crowe, M. J. Smyth, and D. I. Godfrey A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas J. Exp. Med., July 1, 2002; 196(1): 119 - 127. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, A. Kroger, D. Stober, F. Leithauser, P. Moller, H. Hauser, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. II. IFN-{beta} Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation J. Immunol., April 15, 2002; 168(8): 3763 - 3770. [Abstract] [Full Text] [PDF]
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