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and IFN-
at the Effector Phase of Liver Injury Mediated by Th1 Cells Specific to Hepatitis B Virus Surface Antigen1
*
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, and
Division of Biological Sciences, Graduate School of Science, Hokkaido University, Sapporo, Japan;
Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan;
§
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
¶
Department of Immunology, National Institute of Animal Health, Tsukuba, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mAb prevented liver injury, whereas severe liver
injury was induced in TNF--/- mice.
Moreover, IFN-
receptor-deficient mice were resistant to
Th1-mediated liver injury. Therefore, TNF- and IFN-, which were
produced by HBsAg-specific Th1 cells during the effector phase,
appeared to be indispensable in the pathogenesis of fulminant
hepatitis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-2 in response to viral Ags (4, 5). In
contrast, chronic hepatitis patients showed weak CTL activity and
lacked Th1 responses against viral Ags (6, 7).
Consistent with the observations in human hepatitis, the role of Th1
responses in the pathogenesis of hepatitis was also demonstrated in
several experimental liver injury models. In our prior work, we have
proposed an important role for IFN--producing Ag-specific
CD4+ Th1 cells in the pathogenesis of liver
injury (8). In the absence of CD4+ T
cells or IFN-, liver injury was not invoked by Con A administration
(9, 10) or treatment with Propionibacterium
acnes plus LPS (8, 11). We have also shown a pivotal
role for IL-12, which is critically important for the activation of
Th1-type immunity, in liver injury elicited by P. acnes plus
LPS (8). Recently, we established a novel Ag-specific Th1
cell-dependent liver injury model in the absence of nonspecific immune
activators such as LPS and Con A (12). The model utilized
OVA-specific Th1/Th2 cells induced from TCR-transgenic mice and
OVA-containing liposomes to target the Ag toward the liver. Using this
model, we demonstrated directly that Th1 cells, but not Th2 cells,
could initiate liver injury (12).
The pathogenic mechanism of viral hepatitis has been investigated in
hepatitis B virus transgenic murine models (13, 14, 15).
Chronic liver injury was also demonstrated in hepatitis B virus surface
Ag (HBsAg)3-transgenic
mice, and this model revealed the relevance of prolonged immunological
liver damage to hepatocarcinogenesis (16). Acute liver
injury was also demonstrated in HBV-transgenic mice by the transfer of
HBsAg-specific CTL (14) or Th1 cells (17).
For both CTL and Th1 cells, IFN- was an essential cytokine for
induction of liver injury.
In this report, we document a novel and simple method for eliciting
HBsAg-specific liver injury induced by Th1 cells. First, we showed that
i.v. injection of small HBsAg protein (24 kDa) resulted in specific
accumulation in the liver. Utilizing this unique property of HBsAg, we
examined whether adoptive transfer of HBsAg-specific Th1 cells to
HBsAg-injected mice could induce liver inflammation. This protocol
resulted in acute liver injury, which was transient but more severe
than the disease observed in the liver injury induced with OVA-specific
Th1 cells (12). We applied this liver injury model to
mutant and gene knockout mice, including Fas-deficient
(lpr),
perforin-/-,
TNF--/-, and IFN-
receptor-/-
(IFN-R-/-) mice, to
evaluate the molecular mechanisms underlying Th1 cell-mediated liver
injury. We demonstrate a requirement for TNF- and IFN- produced
by HBsAg-specific Th1 cells during the effector phase of liver
injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J mice and C57BL/6J-lpr mice were obtained
from Japan SLC (Shizuoka, Japan) and used at 6–8 wk of age.
Perforin-/--(C57BL/6
x 129SvEv) mice were obtained from Taconic (Germantown, NY).
TNF--/--C57BL/6
mice were provided by Dr. K. Sekikawa (Department of Immunology,
National Institute of Animal Health, Tsukuba, Japan).
IFN-R-/--C57BL/6 mice
were provided by Dr. Y. Iwakura (Institute of Medical Science,
University of Tokyo, Tokyo, Japan).
Reagents and mAbs
Recombinant yeast-derived small HBsAg (>99% pure) was donated
by the Chemo-Sero-Therapeutic Research Institute (Kumamoto, Japan).
IL-12 was donated by Genetics Institute (Cambridge, MA). Anti-IL-4 mAb
(11B11) was purchased from American Type Culture Collection (Manassas,
VA). Recombinant mouse IFN- and anti-IFN- mAb (R4-6A2) were
purchased from PharMingen (San Diego, CA). Anti-TNF- mAb (MP6-XT22)
was a gift from Dr. H. Yagita (Juntendo University School of Medicine,
Tokyo, Japan). Freeze-dried liposomes (Coatsome EL-A-01) were kindly
donated by NOF (Tokyo, Japan), and OVA-containing liposomes were
prepared as described previously (12).
Preparation of HBsAg-specific Th1 cells
HBsAg (100 µg/mouse) emulsified in CFA (Difco, Detroit, MI)
was injected into female C57BL/6 mice. After 2 wk, mice were further
immunized with HBsAg emulsion in IFA (Difco), and this treatment was
repeated four times at 2-wk intervals. Spleen cells from the immunized
mice were stimulated with 20 µg/ml HBsAg in the presence of 20 U/ml
IL-12, 1 ng/ml IFN-, 50 µg/ml anti-IL-4 mAb, and 20 U/ml IL-2.
After 72 h, CD8+ T cells in this culture
were removed using Dynabeads (Dynal AS, Oslo, Norway), and the
CD8+ T cell-depleted fraction was restimulated
under the conditions described above with mitomycin C-treated C57BL/6
spleen cells. Then, Th1 cells were expanded in the presence of high
concentrations of IL-2 (80 U/ml). Cytokine levels (IFN- and IL-4)
produced by these cells were determined by ELISA (PharMingen).
HBsAg-specific Th1 cells from
perforin-/- mice were
obtained by the same method.
Detection of HBsAg
FITC-conjugated HBsAg (FITC-HBsAg) was prepared as described previously (12). C57BL/6 mice were injected i.v. with 15 µg FITC-HBsAg/0.2 ml PBS. Tissue samples were obtained after 2 h, fixed in 1% glutaraldehyde/4% paraformaldehyde/PBS for 6 h, and frozen in liquid N2 using OCT compound (Sakura Finetechnical, Tokyo, Japan). Tissue blocks were sectioned and examined by fluorescence microscopy.
Induction of liver injury
C57BL/6 mice were treated first with i.v. injection of HBsAg (in
200 µl saline) and 2 h later with cell transfer. Cultured
HBsAg-specific Th1 cells were washed and resuspended in saline, and
2 x 107 cells (in 200 µl saline) were
injected i.v. at a volume of 200 µl. Mice were sacrificed after
24 h unless stated otherwise and sera were collected to determine
aspartate aminotransferase and alanine aminotransferase concentrations
as described previously (8). Sera were also tested for
IFN- levels by ELISA (Phar-Mingen). Tissue samples were fixed in
10% formalin-PBS and embedded in paraffin, and sections were stained
with hematoxylin and eosin. In some experiments, mice were pretreated
i.p. with 500 µg/mouse of anti-IFN- mAb or anti-TNF-
mAb 24, 1 h before the injection of HBsAg.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate disposition of i.v.-injected HBsAg, we administered
15 µg FITC-HBsAg per mouse to C57BL/6 mice through the tail vein and
examined distribution of HBsAg by fluorescence microscopy (Fig. 1
). After 2 h, fluorescence was
detected in the liver (Fig. 1, A and B) and
spleen (Fig. 1C) but was barely found in the kidney (Fig. 1D). As shown in Fig. 1A, FITC-HBsAg was equally
distributed across the liver lobule. Fluorescence was present along the
sinusoid lining cells but was not found in parenchymal cells (Fig. 1B). In the spleen, FITC-HBsAg was located mainly in the
marginal zone and red pulp (Fig. 1C). We could not observe
such a specific distribution by injection of FITC-labeled OVA protein
Ag (data not shown), indicating that this tissue distribution was
specific to HBsAg.
|
We have previously demonstrated liver injury could be induced
against OVA proteins targeted to the liver with liposomes by adoptive
transfer of OVA-specific Th1 cells (12). We therefore
tested whether adoptive transfer of HBsAg-specific Th1 cells to
HBsAg-treated mice could induce hepatitis. HBsAg-specific Th1 cells
were prepared from mice immunized with HBsAg by repeated restimulation
in vitro in the presence of Th1-biasing cytokines. The resulting cell
population included >99% CD4+ T cells and
produced IFN-, but no IL-4, on restimulation with HBsAg (data not
shown). When C57BL/6 mice were injected with these Th1 cells after i.v.
administration of HBsAg, a marked elevation of serum transaminase
levels was noted, whereas HBsAg or Th1 cells alone had no effect (Fig. 2). Furthermore, HBsAg-specific Th1 cells
did not induce liver injury in combination with OVA, targeted to the
liver using liposomes. Therefore, Th1 cells induced liver injury in an
Ag-specific manner. Moreover, no hepatic injury was observed even when
OVA-specific Th1 cells were injected into mice after i.v. injection of
soluble OVA (data not shown). Therefore, HBsAg, combined with
HBsAg-specific Th1 cells, appeared to be unique in its ability to
induce liver injury.
|
A), there were
necroinflammatory foci with degenerating hepatocytes and hemorrhage
(Fig. 3D). Such highly inflammatory areas were prevalent in
the liver and frequent at the edge of the tissue, and we could observe
necrotic white spots macroscopically on the surface of the liver (data
not shown). Treatment with HBsAg and Th1 cells also induced
histopathological changes in the spleen (Fig. 3E). However,
we could not observe any changes in the kidney (Fig. 3F).
Thus, it appeared that HBsAg-specific Th1 cell-mediated tissue injury
occurred at those sites where i.v. injected HBsAg accumulated
(Fig. 1
).
|
A). As for cell number,
adoptive transfer of 1 x 107 Th1 cells to
the mice could induce liver injury as strong as 2 x
107 Th1 cells and 5 x
106 Th1 cells was also pathogenic with diminished
liver damage (data not shown). However, cell numbers lower than 2
x 107 are not always pathogenic to all mice in
the same group, and we used 2 x 107
cells/mouse in the following experiments. To characterize the duration
of this liver injury, we examined kinetics of liver injury in mice
treated with 15 µg HBsAg and 2 x 107 Th1
cells. Increase of serum transaminase levels became prominent at
16 h and reached a peak at 24 h (Fig. 4B). The
extent of liver injury gradually reduced thereafter rather than
persist; after 48 h, serum transaminase levels diminished to 6%
of maximum value although these levels were still significantly higher
than those of controls and recovered to control levels by 72 h. An
elevation of serum IFN- levels always preceded the liver injury
(Fig. 4B). It was maximum 8 h after cell transfer,
began to fall after 16 h, and further declined after 24 h
when serum transaminase levels were maximum. These results suggested
that passively transferred HBsAg-specific Th1 cells triggered a cascade
of liver injury.
|
We next examined the mechanism by which Ag-specific Th1 cells
cause severe liver injury. One explanation may be the direct cytolytic
action of Th1 cells via Fas ligand or perforin. However, when
Fas-deficient lpr mice were used as recipients, the extent
of liver injury was equal to that of wild-type mice (Fig. 5A). This suggested that lack
of Fas-Fas ligand interaction did not inhibit liver injury.
Furthermore, we induced HBsAg-specific Th1 cells from
perforin-/- mice to
investigate the precise role of perforin in Th1-mediated liver injury.
As clearly shown in Fig. 5B, these perforin-deficient
HBsAg-specific Th1 cells induced liver injury that was as severe as the
injury induced by wild-type Th1 cells. Perforin-deficient Th1 cells
could also induce severe liver injury in lpr mice (Fig. 5B). From these results, we concluded that neither Fas
ligand nor perforin were required for the effector function of Th1
cells in this model for liver injury.
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and IFN- in the liver injury
induced by HBsAg-specific Th1 cells
The results described above showing that direct cytolytic action
of Th1 cells was not responsible for the liver injury prompted us to
test the participation of cytokines in liver injury. As shown in Fig. 5, we examined effects of anti-IFN- mAb and anti-TNF- mAb
in wild-type mice and lpr mice given Th1 cells from
wild-type mice or
perforin-/- mice. In all
combinations of recipient mice and Th1 cells, pretreatment with
anti-TNF- mAb suppressed the levels of serum transaminase to
control levels. On the other hand,
TNF--/- mice revealed
severe liver injury on treatment with HBsAg and Th1 cells (Fig. 6). These results suggest that TNF-
produced by Th1 cells is a very important factor in the pathogenesis of
liver injury.
|
has been shown to be a crucial factor in several hepatitis
models (10, 17, 18). We have also observed a protective
effect of anti-IFN- mAb in P. acnes plus LPS-induced
hepatitis (8) and in OVA-specific Th1 cell-dependent liver
injury (12); however, anti-IFN- mAb did not block
liver injury in this model (Fig. 5). Suppression of serum IFN- level
was verified by ELISA, which indicated that the level was under the
limit of detection. Failure of anti-IFN- mAb to block the liver
injury can be interpreted as follows: 1) IFN- is not responsible for
the pathogenesis of liver injury; or 2) the very small amounts of
IFN- that escaped neutralization by anti-IFN- mAb were
sufficient to cause liver injury. To distinguish between these
alternative explanations, we examined
IFN-R-/- mice as
recipients. As shown in Fig. 6, IFN-R-/- mice showed
no symptom of liver injury on treatment with HBsAg and Th1 cells. Thus,
we concluded that IFN- is indispensable for the induction of liver
injury and that small amounts of IFN- are sufficient. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing
CD4+ T cells play a critical role in the
pathogenesis of liver injury induced by P. acnes plus LPS
(8, 11). In addition, pretreatment with anti-IL-12 mAb
completely suppressed P. acnes plus LPS-induced liver injury
(8). Therefore, Th1-type immunity during the priming phase
appeared to be essential to P. acnes-induced injury;
however, it was also reported that IL-4-producing Th2-type
CD4+ T cells contribute to the effector phase
after LPS administration (19). Recently, we have
established an Ag-specific CD4+ T cell-dependent
liver injury model using a combination of OVA-specific Th cells and
OVA-containing liposomes (12). Using this model, we
demonstrated that Ag-specific Th1 cells, but not Th2 cells, are
responsible for the onset of liver injury. Here we established a liver
injury model induced by HBsAg-specific Th1 cells and showed a critical
role of IFN- and TNF- in the pathogenesis of the resulting liver
injury.
In a previous report, we described a liver injury model induced by
OVA-specific Th1 cells and OVA-containing liposomes (12).
Liposomes are useful for carrying compounds into the liver. Here,
however, we found that the small HBsAg protein did not require
liposomal encapsulation for targeting into the liver. Although its
mechanism for uptake is unclear, intact small HBsAg protein distributed
to the liver and spleen but not to the kidney (Fig. 1). HBsAg, the
envelope protein of the virus, has been studied to clarify how the
virus attaches and penetrates to target cells (20). To
date, several cell surface molecules have been identified as
HBsAg-binding proteins. Among them, apolipoprotein H (21, 22) and annexin V (23, 24) are candidates for the
small HBsAg attachment site. It is possible that these molecules
expressed in the liver and spleen may contribute to the interaction
with small HBsAg protein, although other mechanisms such as endocytosis
by phagocytes are also possible. In any case, tissue damage
corresponded with the tissue distribution of injected HBsAg (Figs. 1 and 3). These results suggest that APCs can process HBsAg and present
antigenic peptide on their surface MHC class II molecules, which leads
to activation of immune responses elicited by Th1 cells and eventually
tissue injury.
We have established two Ag-specific Th1 cell-inducible liver injury models using the same strategy, OVA-specific model and HBsAg-specific model, yet the magnitude of liver injury induced was different. Moderate liver damage occurred in the OVA-specific model (12), whereas severe injury was induced in the HBsAg model as shown by 10-fold higher elevation of serum transaminase levels. Although these two models utilize a similar method, there are some differences that may affect the magnitude of liver injury. One possible explanation is that the availability of the antigenic epitopes by HBsAg-specific Th1 cells may be greater than that by OVA-specific Th1 cells. Because OVA-specific Th1 cells were induced from OVA323–339-specific TCR-transgenic mice, these cells can recognize only the OVA323–339 epitope among the antigenic epitopes of OVA presented by MHC class II molecules. On the other hand, we induced HBsAg-specific Th1 cells from mice immunized with HBsAg, and it is expected that this polyclonal population recognizes multiple antigenic epitopes of HBsAg. This difference may result in a larger dose of antigenic HBsAg peptides that can activate Th1 cells and cause more severe tissue damage.
Another possible factor is the genetically controlled difference of
Th1/Th2 balance in mice. The OVA-specific model and HBsAg-specific
model were established on the BALB/c and C57BL/6 backgrounds,
respectively. As we have shown previously, C57BL/6 mice are more
susceptible than BALB/c mice to P. acnes plus LPS-induced
liver injury (8). Similar strain differences were reported
for the Con A-liver injury model (25). Conversely, BALB/c
mice are susceptible to Leishmania major
infection whereas C57BL/6 mice are resistant (26, 27, 28).
Furthermore, when stimulated with anti-CD3 mAb,
CD4+ T cells from C57BL/6 mice produced
significantly lower levels of IL-4 than CD4+ T
cells from BALB/c mice (29). These results imply effective
activation of Th1-type immune responses in C57BL/6 mice so that these
animals can eliminate intracellular pathogens, yet they are susceptible
to severe liver injury. Although BALB/c mouse-derived Th1 cells produce
equal or even higher levels of IFN- than C57BL/6 mouse-derived Th1
cells in our liver injury models, the magnitude of liver injury on the
BALB/c background is much lower than that of C57BL/6 background.
Therefore, it is also possible that the progression of Th1-type immune
responses triggered by IFN- is suppressed in BALB/c mice compared
with C57BL/6 mice.
Recent findings suggest a central role of CD4+ T cells in antitumor responses and CD4+ T cell-mediated activation of effector cells, including CD8+ T cells, eosinophils, and macrophages (30, 31). As for liver injury models, involvement of CD8+ CTLs (14) and NKT cells (32) was also reported. Although direct interaction is uncertain, HBsAg-specific Th1 cells may activate the recipient’s effector cells to increase the liver injury. Consistent with this idea, Yoneyama et al. (19) demonstrated that Th1 responses primed by P. acnes were followed by release of thymus and activation-regulated chemokine on LPS administration, recruitment of IL-4-producing CCR4+ CD4+ T cells, and massive liver damage. Likewise, we cannot exclude the possibility that HBsAg-specific Th1 cells and the recipient’s immune system may act synergistically to develop the severe tissue damage.
We examined the relative contribution of Fas ligand, perforin, IFN-,
and TNF- to the liver injury induced by Ag-specific Th1 cells and
showed the requirement for IFN- and TNF- and no requirement for
Fas ligand and perforin (Figs. 5 and 6). Similarly, Nakamoto et al.
(15) reported that IFN--producing CTL kill hepatocytes
without Fas ligand and perforin in an Ag-specific manner. In several
experimental hepatitis models established to date, IFN- and TNF-
were demonstrated to play an important role in the pathogenesis of
liver injury (8, 10, 12, 17, 18, 33, 34, 35). In our model,
anti-TNF- mAb strongly blocked Th1 cell-inducible liver injury
(Fig. 5), but TNF--/-
mice were susceptible to liver injury (Fig. 6). Thus, our results
suggested the importance of TNF- production by Th1 cells. As for
IFN-, although anti-IFN- mAb was not effective (Fig. 5),
resistance of IFN-R-/-
mice suggested the necessity of IFN- to liver injury (Fig. 6). These
results suggest requirement of both IFN- and TNF- in this liver
injury. It can be postulated that IFN- and TNF- produced by
ligand-stimulated Th1 cells prime APC for activation of cytotoxic
effector cells. In this mechanism, inducible NO synthase (iNOS) induced
by IFN- and TNF- may participate to the cytotoxicity. Induction
of iNOS has been reported in human chronic viral hepatitis
(36) and mouse liver injury model (37). It is
also possible that IFN- sensitizes liver cells to the cytotoxicity
of TNF- (38, 39). To elucidate their mechanism of
action, the possible synergistic effect of IFN- and TNF- in the
induction of liver injury should be further examined.
In conclusion, we established a novel liver injury model induced by
HBsAg-specific Th1 cells. The development of severe liver injury in
this model will be useful for examination of the mechanisms underlying
Ag-specific fulminant hepatitis. Here, we clearly demonstrated that
TNF- and IFN- produced by HBsAg-specific Th1 cells are critically
important in the late effector phase of acute liver injury.
|
Acknowledgments |
|---|
mAb; the Chemo-Sero-Therapeutic Research Institute for
donation of recombinant HBsAg; and NOF for donation of Coatsome
EL. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Takashi Nishimura, Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
3 Abbreviations used in this paper: HBsAg, hepatitis B virus surface Ag; IFN-R, IFN- receptor; iNOS, inducible NO synthase.
Received for publication January 18, 2000. Accepted for publication April 14, 2000.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. Gastroenterology 111:462.[Medline]
-deficient mice by a concomitant reduction of TNF-, IL-12, and IL-18 production. J. Immunol. 162:1049.-dependent hepatic injury in mice. Hepatology 27:513.[Medline]
or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169:59. in the pathogenesis of activated-macrophage-mediated hepatitis in mice. Gastroenterology 99:758.[Medline]
--/- mice, but not in TNF--/- mice: role for IFN- in activating apoptosis of hepatocytes. J. Immunol. 159:1418.[Abstract]
-interferon on human colon carcinoma cell lines. Cancer Res. 47:2809. and tumor necrosis factor-: cytotoxicity to murine islets of Langerhans. J. Immunol. 141:2325.[Abstract]
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