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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4051-4055
Differential Effects of Anti-Fas Ligand and Anti-Tumor Necrosis
Factor  Antibodies on Acute Graft-Versus-Host Disease
Pathologies
By
Koichi Hattori,
Takao Hirano,
Hiroaki Miyajima,
Norifumi Yamakawa,
Masatoshi Tateno,
Kazuo Oshimi,
Nobuhiko Kayagaki,
Hideo Yagita, and
Ko Okumura
From the Division of Hematology, Department of Internal Medicine, and
the Division of Pathobiology, Department of Immunology, Juntendo
University School of Medicine, Tokyo, Japan; and the Department of
Pathology, Sapporo City General Hospital, Sapporo, Japan; and CREST
(Core Research for Evolutional Science and Technology) of Japan Science
and Technology Corporation (JST), Tokyo, Japan.
 |
ABSTRACT |
Both tumor necrosis factor  (TNF) and Fas ligand (FasL) have
been implicated in the pathogenesis of graft-versus-host disease (GVHD). In this study, we examined the ameliorating effects of neutralizing anti-FasL and/or anti-TNF monoclonal antibody
(MoAb) in a lethal acute GVHD model in mice. Whereas the treatment with either anti-FasL or anti-TNF MoAb alone significantly delayed the
mortality and improved the body weight, a complete protection was
achieved by the administration of both MoAbs. Pathological examination
indicated differential effects of anti-FasL or anti-TNF MoAb on
GVHD-associated pathologies. Hepatic lesion was improved by anti-FasL
but not anti-TNF MoAb. In contrast, intestinal lesion was improved
by anti-TNF but not anti-FasL MoAb. Cutaneous and splenic lesions
were improved by either MoAb. The combination of both MoAbs improved
all these lesions. These results indicate that FasL and TNF
differentially contribute to the GVHD pathologies and a complete
protection from mortality can be achieved by neutralization of both
FasL and TNF.
| |
INTRODUCTION |
ALLOGENEIC bone marrow transplantation
(BMT) has been a clinical treatment modality for hematopoietic
disorders and hematologic malignancies.1 The success rate
of BMT has steadily increased in recent years, but graft-versus-host
disease (GVHD) is still a major cause of posttransplant
mortality.2,3 An acute lethal form of GVHD is caused by
activation of the host-reactive donor T cells as represented by a
murine model that is caused by transfusion of C57BL/6 splenic T cells
into (DBA/2 × C57BL/6)F1 or (BALB/c × C57BL/6)F1
mice.4 Acute GVHD affects the skin, liver, gastrointestinal tract, and lymphoid tissues where inflammatory reactions characterized by mononuclear cell infiltration and histopathologic damage take place,
which lead to erythroderma, diarrhea, wasting, and finally death. The
effector mechanisms leading to the GVHD-associated tissue damage have
not been fully clarified.
Tumor necrosis factor (TNF) has been implicated in the
pathogenesis of GVHD. TNF has been identified as a principal
mediator of cachexia in rodents5 and is a potent mediator
of various inflammatory diseases.6 It has been shown that
serum levels of TNF were increased in patients undergoing GVHD after
allogeneic BMT7 and that administration of anti-TNF
antibody markedly reduced the weight loss and mortality in a mouse
model of acute GVHD.8 Some beneficial effects of an
anti-TNF monoclonal antibody (MoAb) for the treatment of refractory
acute GVHD have been obtained in the phase I-II clinical
trials.9 These observations substantiate that TNF is an
important target for the clinical treatment of GVHD. Furthermore, a
recent study showed that TNF receptor p55 (TNFRp55)-deficient
recipients of allogeneic T cells exhibited a reduced mortality as
compared with wild-type recipients, indicating a critical contribution
of host TNFRp55 to the GVHD mortality.10
Recently, the ligand for Fas (FasL) has been also implicated in the
pathogenesis of GVHD. Fas (APO-1, CD95) is a member of the TNF receptor
family and transmits an apoptotic cell death signal upon ligation by
FasL.11 Fas is expressed in various tissues, including the
skin, liver, and intestine, that are target tissues of
GVHD.12 A recent study using allogenic T cells from FasL-defective gld (generalized lymphoproliferative disease)
mice clearly showed that FasL plays a critical role in the pathogenesis of acute GVHD, especially in the development of hepatic and cutaneous lesions.13 In a different murine model of acute GVHD,
others also showed the involvement of FasL in the lymphoid organ
damage.14 However, the contribution of FasL to the
mortality varied among previous studies.13-15
In the present study, we compared the ameliorating effects of
neutralizing anti-FasL and anti-TNF MoAbs in a lethal acute GVHD
model in mice. Whereas the treatment with either MoAb alone was
effective in delaying the mortality, a complete protection was achieved
by the combination of both MoAbs. Histological examination indicated
differential effects of anti-FasL and anti-TNF MoAbs on GVHD
pathologies. Pathogenic and clinical implications are discussed.
| |
MATERIALS AND METHODS |
Mice.
Six-week-old female BALB/c (H-2d), C57BL/6 (B6;
H-2b), and (BALB/c × C57BL/6)F1 (CBF1;
H-2b/d) mice were purchased from SLC (Shizuoka, Japan) and
maintained in our animal facilities.
Reagents.
A neutralizing antimouse FasL MoAb, K10 (mouse IgG2b,  ), was
prepared as described previously.16 A neutralizing
antimouse TNF MoAb (MP-6 XT22) and control mouse or rat IgG were
obtained from PharMingen (San Diego, CA).
Induction of lethal acute GVHD.
CBF1 mice (10 mice in each group) were intravenously (IV) injected with
1 × 108 spleen cells from B6 mice on days 0 and 7. Some mice received intraperitoneally (IP) 2 mg of
anti-FasL MoAb and/or 1 mg of anti-TNF MoAb on days 0, 4, 8, and 12. Some mice received IP 2 mg of control mouse IgG and 1 mg of
control rat IgG on the same schedule. Survival was monitored until day
60. The body weight of the survivors was measured weekly until day 60. On day 19 for the GVHD group or day 21 for the other groups, 3 mice in
each group were killed and their ear skin, livers, small intestines,
spleens, and bone marrow were subjected to histopathological
examination.
Histopathology.
Tissues were fixed in 10% buffered formalin and paraffin-embedded.
Sections were stained with hematoxylin and eosin and examined under
microscopy.
Flow cytometric analysis.
Splenocytes were prepared from normal CBF1, GVHD, or MoAb-treated mice
on day 21 and stained with fluorescein isothiocyanate (FITC)-conjugated anti-H-2Kd (SF1-1.1;
PharMingen), biotin-conjugated anti-H-2Kb (AF6-88.5;
PharMingen), and phycoerythrin (PE)-conjugated anti-CD4 (RM4-5; PharMingen), anti-CD8 (53-6.7; PharMingen), or anti-B220 (RA3-6B2; PharMingen) MoAbs followed by APC-conjugated avidin (PharMingen). Cells (1 × 104) were analyzed on FACS
Vantage and analyzed by Cell Quest program (Becton Dickinson, San Jose,
CA). Recipient and donor lymphocytes were identified as
H-2Kd+Kb+ and
H-2Kd Kb+ cells, respectively. Cell
numbers of CD4+ T, CD8+ T, and
B220+ B cells of recipient or donor origin were calculated
from the total numbers of splenocytes recovered, and the percentages of each subpopulation were determined by the three-color analysis.
Statistical analysis.
Significant differences between experimental groups were determined
using the Mann-Whitney U test for the survival rate or using
the Student s t-test for the body weight. P
values less than .05 were considered statistically significant.
| |
RESULTS |
Effect of anti-FasL and/or anti-TNF MoAb on
GVHD-induced mortality and weight loss.
A lethal acute type of GVHD was induced by IV injection of B6
splenocytes into CBF1 mice. As represented in
Fig 1A, all the recipients administrated
with control IgG died within 21 days. In these mice, clinical symptoms
of acute GVHD, such as hair ruffling, lesser mobility, and weight loss
(Fig 1B), became apparent within 2 weeks. Administration of either
anti-FasL MoAb or anti-TNF MoAb alone significantly delayed but not
completely reduced the mortality, and 1 of 10 or 4 of 10 mice survived
at day 60, respectively (Fig 1A). In these surviving mice, no
significant weight loss was observed as compared with the age-matched
normal mice until day 14, but their growth was retarded after the
discontinuation of the treatment at day 14 (Fig 1B) with
clinical symptoms of GVHD.
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| Fig 1.
Prevention of lethal acute GVHD by anti-FasL
and/or anti-TNF antibodies. Lethal acute GVHD was induced by
IV injection of B6 splenocytes into CBF1 mice on days 0 and 7. Ten mice
in each group received IP 2 mg anti-FasL MoAb ( ), 1 mg anti-TNF
MoAb ( ), 2 mg anti-FasL MoAb and 1 mg anti-TNF MoAbs ( ), or
control IgG ( ) on days 0, 4, 8, and 12. Survival (A) was monitored
every day until day 56. Body weight (B) was measured at the indicated days is indicated as the mean ± standard deviation (SD) of 5 to 10 mice. In (B), the body weight of age-matched normal CBF1 ( ) is also
plotted. In (A), *P < .05 and **P < .01 compared
with the GVHD group. In (B), *P < .05 compared with
the normal CBF1 group.
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In contrast, all the recipient mice treated with both anti-FasL and
anti-TNF MoAbs survived over 60 days (Fig 1A). Even after the
discontinuation of the treatment at day 14, no apparent clinical symptoms of acute GVHD were observed in these mice and their growth was
comparable to that of the age-matched normal mice (Fig 1B).
Effect on GVHD-associated histopathologies.
In the liver from the control mice undergoing GVHD, a massive
infiltration of mononuclear cells and fibrosis were observed mainly in
the periportal areas (Fig 2A). A similar
hepatic pathology was observed in the liver from the
anti-TNF-treated mice (Fig 2B). In contrast, such inflammatory
changes were minimal in the liver from the anti-FasL-treated mice (Fig
2C). The gut from the control mice undergoing GVHD exhibited a
dilatation, flattening of the villi, and elevation and atrophy of the
crypts, which are characteristics of intestinal GVHD (Fig 2F). Similar
changes were observed in the gut of anti-FasL-treated mice, although
structural integrity of the villi was partially improved as compared
with the GVHD control (Fig 2H). In contrast, all these lesions were almost absent in the anti-TNF-treated mice (Fig 2G).
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| Fig 2.
Histopathological examination. Induction of lethal acute
GVHD and administration of anti-FasL and/or anti-TNF MoAb
were performed as described in Fig 1. On day 19 for the GVHD group or
day 21 for the other groups, 3 mice in each group were killed. Paraffin section of the liver (A through E), intestine (F through J), skin (K
through O), and spleen (P through T) were stained by hematoxylin and
eosin. Sections from age-matched normal CBF1 are also represented. The
specimens shown are representatives of 3 mice in each group with
similar histology. Original magnification × 100.
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The skin from the control mice undergoing GVHD exhibited severe
inflammatory infiltrates with intraepidermal lymphocytes and dyskeratotic cells, ulceration, loss of hair follicles, and destruction of rete ridges (Fig 2K). Such changes were not observed in either anti-FasL-treated (Fig 2M) or anti-TNF-treated (Fig 2L) mice.
The spleen from the control GVHD mice showed a marked lymphoid atrophy,
structural disorganization, and focal necrosis (Fig 2P). Such changes
were minimal in either anti-FasL-treated (Fig 2R) or
anti-TNF-treated (Fig 2Q) mice. In the recipients treated with both
anti-FasL and anti-TNF MoAbs, no apparent lesion was observed in the
liver (Fig 2D), intestine (Fig 2I), skin (Fig 2N), or spleen (Fig 2S)
as compared with normal mice (Fig 2E, J, O, and T).
Effect on GVHD-associated lymphoid hypoplasia.
Cell numbers of CD4+ T, CD8+ T, and
B220+ B cells of recipient
(H-2Kd+Kb+) or donor
(H-2KdKb+) origin in the spleen of
normal CBF1, GVHD, or MoAb-treated mice on day 21 were calculated from
the total numbers of recovered and the percentages of each
subpopulation were determined using three-color flow cytometric
analysis (Table 1). In the splenocytes from
GVHD mice, both CD4+ and CD8+ T cells and
B220+ B cells of host origin were severely decreased as
compared with normal CBF1 mice. The treatment with either anti-FasL or
anti-TNF MoAb alone partially but substantially prevented the loss
of all these lymphocyte subpopulations, and almost complete protection was achieved by the treatment with both MoAbs. It was also noted that
donor-derived CD4+ and CD8+ T cells were
increased in the anti-FasL- and/or anti-TNF-treated mice
as compared with the GVHD mice, representing a chimeric state of these
recipients. As represented in Table 1, 60% to 67% of T
cells and 47% to 58% of B cells were donor origin. This chimeric state appeared to be stable, because no further change in the numbers
of host and donor lymphocytes was observed on day 60 in the recipients
treated with both anti-FasL and anti-TNF MoAbs (not shown).
| |
DISCUSSION |
In this study, we explored the ameliorating effects of neutralizing
MoAbs against FasL and TNF, both of which have been implicated in
the pathogenesis of GVHD, in a murine model of lethal acute GVHD.
Whereas the treatment with either anti-FasL or anti-TNF MoAb alone
significantly delayed the mortality and improved the weight loss, a
complete protection was achieved by the combination of both MoAbs.
Histological examination indicated differential effects of these MoAbs
on GVHD-associated pathologies.
Recent studies have implied that FasL plays a critical role in the
development of hepatic and cutaneous lesions and lymphoid atrophy.
Baker et al13 showed that, when the FasL-deficient gld mice were used as the T-cell donor in a major
histocompatibility complex (MHC)-matched but
minor-mismatched allogenic BMT model of acute GVHD, only minimal signs
of hepatic and cutaneous GVHD pathology were observed and the lymphoid
atrophy in the spleen was improved. However, intestinal GVHD was not
abrogated and neither weight loss nor mortality was improved. In
contrast, Braun et al15 reported a significantly delayed
mortality in the recipients of FasL-defective T cells in a
MHC-mismatched spleen cell transfer model. We used the parent (B6) to
F1 (CBF1) spleen cell transfer model and found that the treatment with
anti-FasL MoAb delayed the mortality and improved the weight loss,
consistent with the observation by Braun et al.15 The
apparent discrepancy from the observation by Baker et al13
in the FasL contribution to mortality remains to be resolved by testing
the effect of anti-FasL MoAb in the BMT model. Our histological
observations are consistent with those by Baker et al,13
indicating a critical contribution of FasL to the development of
hepatic and cutaneous, but not intestinal, lesions and splenic atrophy.
The ameliorating effect of anti-TNF treatment observed in this study
was essentially consistent with that reported by Piguet et
al.8 They described that the administration of an
anti-TNF polyclonal antibody reduced the mortality at day 40 by 50%
and abolished the weight loss on day 18. In our present study, the administration of an anti-TNF MoAb similarly reduced the mortality and abolished the weight loss. They also showed that the
GVHD-associated pathologies in the skin and gut, but not those in the
liver, were prevented by the anti-TNF treatment. These observations
are also consistent with ours, indicating a critical contribution of
TNF to the development of intestinal and cutaneous, but not hepatic, lesions.
When both anti-FasL and anti-TNF MoAbs were administered in
combination, all of these histological lesions in the liver, intestine,
skin, and spleen were minimal. It was notable that all the recipients
survived more than 60 days and grew well as normal mice without growth
retardation observed in the recipients treated with either anti-TNF
or anti-FasL MoAb alone, which may result from hepatic or intestinal
damage, respectively. These results verified that FasL and TNF
differentially contribute to the GVHD pathologies as follows: (1)
hepatic GVHD is predomonantly mediated by FasL; (2) intestinal GVHD is
predominantly mediated by TNF; and (3) cutaneous GVHD, splenic
atrophy, weight loss, and mortality are mediated by both FasL and
TNF. Importantly, FasL and TNF in combination appear to mostly
account for all these GVHD-associated pathologies observed in the
present study.
In the histological examination, the treatment with either anti-FasL or
anti-TNF MoAb improved the splenic atrophy. Flow cytometric analysis
for the lymphocyte subpopulations indicated that the GVHD-associated
elimination of host lymphocytes (both T and B cells) was prevented
partially by either MoAb alone and almost completely by the combination
of both MoAbs. This suggests that both TNF and FasL contribute to
cytotoxic elimination of host lymphocytes by host-reactive donor T
cells. Alternatively, this may be also due to blocking of suppressive
effects of TNF and FasL on hematopoiesis17-20 (our
unpublished data). It was also noted that donor-derived T
cells were increased in the anti-FasL- and/or
anti-TNF-treated mice as compared with the GVHD mice. This may
result from inhibition of activation-induced apoptosis, in which both
FasL and TNF have been implicated.21 The preservation of
both host and donor lymphocytes represents a chimeric state of the
recipients, which appears to be stable over 60 days in the
anti-FasL/TNF-treated mice. It remains to be determined whether a
tolerance to the host alloantigen has been established in the donor T
cells.
In conclusion, a complete protection was achieved by administration of
both anti-FasL and anti-TNF MoAbs in a murine model of lethal acute
GVHD. Although our observations were made in a parent into F1 model in
which no cytotoxic conditioning was used before the transplant and thus
cannot necessarily be directly extrapolated to allogeneic
transplantation as performed clinically today, our present findings may
provide insights that would be useful for the treatment of GVHD. The
phase I-II clinical trials with a humanized anti-TNF MoAb for the
treatment of refractory acute GVHD have resulted in limited
success.9 We recently succeeded to generate a humanized
version of antihuman FasL MoAb (manuscript in
preparation), which may be useful for the clinical
treatment of severe acute GVHD patients in combination with the
anti-TNF MoAb.
| |
FOOTNOTES |
Submitted December 1, 1997;
accepted January 30, 1998.
Supported by grants from the Ministry of Education, Science and
Culture, and the Ministry of Health, Japan.
Address reprint requests to Ko Okumura, MD, Department of
Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank C. Ushiyama for technical assistance and helpful
suggestions.
| |
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IFN-{{gamma}}/TNF-{{alpha}} Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic {{beta}} Cell Death
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Abstract
Introduction
Abstract