Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1464-1468
Soluble Fas Levels in Sera of Bone Marrow Transplantation
Recipients Are Increased During Acute Graft-Versus-Host Disease But
Not During Infections
By
Linda M. Liem,
Thea van Lopik,
Annemarie E.M. van
Nieuwenhuijze,
Hans C. van Houwelingen,
Lucien Aarden, and
Els Goulmy
From the Department of Immunohematology and Blood Bank and the
Department of Medical Statistics, Leiden University Medical Center,
Leiden, The Netherlands; and the Central Laboratory of the Netherlands
Red Cross Blood Transfusion Service, Amsterdam, the Netherlands.
 |
ABSTRACT |
Graft-versus-host disease (GVHD) and infections are two major
complications of allogeneic bone marrow transplantation (BMT). In the
course of GVHD, one of the pathways that activated cytotoxic T cells
use to execute their killing mechanisms is the Fas/Fas ligand pathway.
This killing mechanism might be accompanied by the release of soluble
Fas (sFas) in the circulation. To examine the association of serum sFas
levels and post-BMT complications, we have analyzed sFas levels in sera
of bone marrow recipients with and without GVHD. Postallogeneic BMT
sFas levels were significantly increased during clinically relevant
acute GVHD (aGVHD; P = .002). However, during infections sFas
levels tended to decrease (P = .088). Yet, the simultaneous
occurrence of GVHD and infections resulted in extreme high sFas levels.
These results suggested that sFas release may be correlated with the
amount of tissue damage, because aGVHD induces more damage than
infections. The presence of significantly increased sFas levels during
aGVHD provides new insights into the GVHD pathogenesis.
| |
INTRODUCTION |
HEMATOLOGICAL MALIGNANCIES can be treated
by bone marrow transplantation (BMT). However, allogeneic BMT can be
complicated by graft-versus-host disease (GVHD) and infections, because
BMT recipients are immunosuppressed.1-3 Moreover, GVHD
enhances the susceptibility for infections and, although they occur
simultaneously, GVHD may be masked.4
Induction of apoptosis is an important T-cell effector mechanism that
is mediated by the interaction of the Fas/APO-1 molecule with its
ligand (FasL).5-7 Fas is a member of the tumor necrosis factor/nerve growth factor receptor (TNFR/NGFR)
superfamily.8-10 Soluble receptors have been described for
other members of the TNFR/NGFR family, which are mainly derived by
proteolytic cleavage.11-14 Soluble forms of the TNF
receptor type I and II are present in human serum and are able to
inhibit TNF
activity.15-19
A soluble splice variant of Fas (sFas) has been identified in the serum
of healthy individuals, of patients with autoimmune disease,20-22 and of patients with B- and T-cell
leukemias.23 Also B- and T-cell lines and activated
peripheral blood mononuclear cells were shown to produce
sFas.23-26 Alternative splice variants of the Fas-gene have
been identified, indicating that sFas is generated by alternative
splicing rather than proteolytic cleavage.20,23,25,27 sFas
has been shown to inhibit apoptosis induction in
vitro.20,24,26,27 Studies in Fas-deficient lpr mice
and in FasL-lacking gld mice indicated that Fas-mediated
cytotoxicity is an important effector mechanism in
GVHD.28-34
To our knowledge nothing is known about the production of sFas during
GVHD or organ transplant rejection in man. We questioned whether there
exists a causal relationship between the putative increased T-cell
activity during GVHD and sFas levels in BMT recipients. Because T cells
are also involved in the immune response during infections, we have
analyzed sFas levels in BMT recipients during acute GVHD (aGVHD) and
infections.
| |
MATERIALS AND METHODS |
Patients.
Fifty-two adult patients who underwent BMT between 1978 and 1990 in the
Leiden University Hospital were included in this study. Thirty-nine
patients received bone marrow from a human leukocyte antigen
(HLA)-identical sibling, 1 patient received bone marrow from her
HLA-identical father, and 12 patients received autologous bone marrow.
Underlying diseases were acute myeloid leukemia (n = 33), chronic
myeloid leukemia (n = 6), non-Hodgkin's lymphoma (n = 4), aplastic
anemia (n = 4), morbus Hodgkin's (n = 3), and acute lymphoblastic
leukemia (n = 2). Patients were conditioned with cyclophosphamide (Cy)
and total body irradiation (TBI; n = 37); Cy and total lymph node
irradiation (n = 4); Cy, campath, and busulphan (n = 3); Cy,
BCNU, and etoposide (n = 3); Cy, TBI, ATG, and Ara-C (n = 2); Cy, BCNU, etoposide, and Ara-C (n = 2); or Cy, TBI, and campath (n = 1). Cyclosporin A (n = 18) or methotrexate (n = 22) was given as GVHD
prophylaxis. Of the patients receiving allogeneic bone marrow (19 women
and 21 men) the mean age was 30 years (range 17 to 47). The mean age of
the patients receiving autologous bone marrow (5 women and 7 men) was
37 (range 20 to 58). Normal levels of sFas were determined in sera
taken from bone marrow donors (n = 41) and healthy blood donors (n = 15) designated as healthy controls.
Complications after BMT.
aGVHD was diagnosed according to clinical and histopathological
criteria.35 In the assessment of GVHD, a grade of 0 or I was considered to indicate absent or clinically unrelevant disease and
a grade of II or higher the presence of clinically relevant disease.
Viral infections (CMV, VZV, and HSV) and fungal infections were
diagnosed on the basis of culture, histopathology, and specific antibody tests and bacterial infections (pneumonia and sepsis) were
diagnosed on the basis of an infiltrate on x-ray and/or
positive bacterial culture from sputum, blood, or bronchoalveolar
lavage.
Sera.
Serum samples were collected before BMT and after BMT. Post-BMT serum
samples were collected systematically for the first 3 months post-BMT
and thereafter incidentally up to 3 years post-BMT. Serum samples were
also collected from BMT donors and from healthy blood donors. All sera
were stored at 
30°C until further use. For this study we
have striven to include at least one sample for every 10-day period
post-BMT until day 100 and during complications.
Serum sFas measurements.
Serum sFas levels were assessed by sandwich enzyme-linked immunosorbent
assay (ELISA) using monoclonal antibodies CLB-CD95/2 and CLB-CD95/6.
Maxisorp microtiter plates (Nunc, Roskilde, Denmark) were coated
overnight with 100 µL/well CLB-CD95/2 (2 µg/mL) in 0.1 mol/L
NaHCO3/Na2CO3 buffer (pH = 9.6) at
room temperature and blocked with 100 µL/well phosphate-buffered
saline (PBS)/2% whole milk for 30 minutes at room temperature. Samples
were diluted 10 times in high performance ELISA buffer (HPE; CLB,
Amsterdam, The Netherlands). A twofold dilution of the standard was
made in HPE, ranging from 1,000 pg/mL to 2 pg/mL. One hundred
microliters of samples and standards and 10 µL biotinylated
CLB-CD95/6 (10 µg/mL) were pipetted into each well and the plate was
incubated for 2 hours at room temperature. After washing vigorously 100 µL/well streptavidine poly-horseradish peroxidase (1:10,000 diluted in PBS/2% milk) was added to the plate, incubated for 30 minutes at
room temperature, and washed vigorously. The ELISA was developed using
0.1 mg/mL 3,5,3
,5-tetramethylbenzidine (Merck, Darmstadt, Germany) and 0.003% H2O2 in 0.11 mol/L NaAc
(pH = 5.5) for 10 minutes. The color reaction was stopped with 100 µL
2M H2SO4 and plates were read at 450 nm in a Titertek Multiskan reader (Labsystems Multiskan
Multisoft, Helsinki, Finland).
sFas levels and liver involvement.
Sixteen patients suffered from moderate to severe GVHD without liver
involvement, and 15 patients suffered from moderate to severe GVHD with
liver involvement. To evaluate the contribution of liver damage to
increased sFas levels, total blood bilirubin levels were used as a
marker for the occurrence of liver damage36 after exclusion
of other causes of hyperbilirubinemia.
Statistical analysis.
For statistical analysis, sFas levels were transformed to their
10log value. To test for differences in sFas levels of
healthy controls and pre-BMT sFas levels of BMT recipients unpaired
t-tests were used. Differences between autologous BMT patients
and allogeneic patients on the changes in sFas levels from pre- to
post-BMT were determined with the repeated measurements multivariate
analysis of variance (MANOVA). For this analysis sFas levels determined in sera, taken from autologous bone marrow recipients (n = 12) and from
allogeneic bone marrow recipients without complications (n = 26) before
BMT and within 30 days post-BMT, were used. The factor "patients"
is included in the analysis to correct for general patient levels.
To determine the correlation of aGVHD or infections with changes in
sFas levels post-BMT within the allogeneic BMT group, these
complications were coded into the following dichotomous variables:
"aGVHD" = grade 0 to I (0) versus grade II to IV (1) and "infection" = absence (0) versus bacterial, viral,
or fungal infection (1). The statement used in the MANOVA is the
following: sFas BY patients (1 40) WITH aGVHD, infection.
Thus, only changes within patients are used and not the differences
between patient groups. This analysis can be seen as an extension of
the well-known paired t-test. The correlation between changes
in sFas levels and changes in bilirubin levels within selected patients
was obtained in a truly multivariate MANOVA with "patients" as
factor and 10log(bili) and sFas as outcome variables.
P values less than .05 were accepted as significant.
| |
RESULTS |
sFas levels in healthy controls and in BMT recipients without
complications.
Control serum sFas levels were determined in healthy controls and
ranged from 112.2 to 2,951.2 pg/mL (median 512.9 pg/mL). The pre BMT
sFas levels of 12 patients receiving autologous BMT ranged between
323.6 and 1,047.1 pg/mL (median 549.5 pg/mL) and did not differ
significantly from sFas levels from healthy controls (P = .92).
sFas levels in autologous bone marrow recipients rose slightly in the
first 30 days post-BMT, although this increase was not significant
(median pre-BMT level = 549.5 pg/mL; median post-BMT level = 724.4 pg/mL; P = .122; Fig 1A).
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| Fig 1.
Box-whisker plots of sFas levels in sera of controls, of
autologous bone marrow recipients pre- and post-BMT (A), and of
allogeneic bone marrow recipients pre- and post-BMT (B). The box
represents the 25% and 75% percentiles, with a line indicating the
median value. The whiskers show minimum and maximum values.
|
|
The pre-BMT levels of 40 allogeneic BMT patients ranged between 166.0 and 4,570.9 pg/mL (median 660.7 pg/mL) and did not differ significantly
from sFas levels of healthy controls (P = .16) or of autologous
patients pre-BMT (P = .32). Allogeneic BMT recipients without
complications showed a significant increase in sFas levels after BMT
(median pre-BMT level = 660.7 pg/mL; median post-BMT level = 1,047.1 pg/mL; P < .001; Fig 1B). sFas levels in both autologous and
allogeneic BMT recipients without complications did not stay elevated,
but returned shortly post-BMT to normal or to slightly elevated levels
(data not shown).
Post-BMT levels during complications in allogeneic BMT recipients.
In patients suffering from complications sFas levels reached higher
levels than in patients without complications. To analyze the effects
of aGVHD and infections on sFas levels, the absence or presence of each
complication was recorded for each sample date.
Table 1 shows the descriptive statistics of
the sFas levels measured in the presence of no to mild aGVHD (grade
0-I) or clinically relevant aGVHD (grade II-IV) and in the absence or
presence of infections. Of each group the number of samples measured
and quartiles (median, 25% percentile and 75% percentile) are given.
Median sFas levels increase during relevant aGVHD but not during
infections. However, in the presence of both relevant GVHD and
infections sFas levels are strongly elevated. The effect of both aGVHD
and infections on sFas levels were analyzed in the repeated
measurements MANOVA analysis as described in the Materials and Methods
section. Statistical analysis of the different complications showed
that during aGVHD (grade II-IV) sFas levels are significantly increased (P = .002), whereas sFas levels tend to decrease during
infections (P = .088; Table 2).
Correlation of sFas and liver GVHD.
To investigate whether liver damage is correlated with increased sFas
levels, total blood bilirubin levels were used as a marker for liver
damage. Sixteen patients suffered from moderate to severe GVHD without
liver involvement, and 15 patients suffered from moderate to severe
GVHD with liver involvement. MANOVA analysis showed a significant
correlation between bilirubin levels and sFas levels (r = .443, P < .001), indicating that sFas levels during GVHD with liver
involvement were significantly different from sFas levels during GVHD
without liver involvement.
| |
DISCUSSION |
In experimental GVHD, Fas-mediated apoptosis is an important effector
mechanism.34,37 A soluble form of Fas (sFas) can be
detected in human serum and is able to inhibit Fas-mediated apoptosis
in vitro.20,26,27 Because activated lymphocytes produce
sFas and lymphocyte activity plays an important role in GVHD, we
questioned whether sFas would play a role in the GVHD pathogenesis in
humans.
Our results showed that BMT treatment already caused an early and
temporary increase in sFas levels. This increase was not correlated to
the occurrence of complications and was more pronounced in allogeneic
BMT recipients than in autologous BMT recipients. Immunologic
disparities between donor and host in allogeneic BMT may cause
immunoreactivity early after allogeneic BMT, which will subside when
the graft is accepted. Thus, the conditioning regimen itself causes an
increase in sFas levels, which is reinforced by immunoreactivity in
allogeneic BMT.
Furthermore, a significant correlation between increased sFas levels
and aGVHD grade II-IV is found but not with infections. In the presence
of both aGVHD and infections, strongly increased sFas levels were
found, indicating that the enhancing effect of aGVHD on sFas levels
dominates over the leveling effect of infections. Increased sFas levels
coincided and in some patients preceded aGVHD episodes.
The source of increased levels of sFas found during GVHD is unknown.
sFas can be produced by activated immune cells and, because Fas has a
wide tissue distribution, it may also be released by damaged target
cells.23-26 Hepatocytes constitutively express Fas and are
a ready target for Fas-mediated apoptosis.38,39 Because the
liver is one of the target organs of GVHD, sFas release by damaged
hepatocytes may contribute significantly to the enhanced serum levels
found during GVHD. Our study showed a significant correlation between
bilirubin levels and sFas levels indicating that liver damage, as
delineated by serum hyperbilirubinemia, is associated with increased
sFas levels. However, because Fas is also expressed in the skin
and gastrointestinal tract, sFas may also be released by these tissues
during GVHD.31
The presence of elevated levels of sFas in the sera of GVHD patients
prompted us to hypothesize on the role of sFas in the pathogenesis of
GVHD. Fas/FasL-induced apoptosis normally serves as a mechanism for the
regulation of an immune response via activation-induced cell death.
Activated lymphocytes express both Fas and FasL and can induce
apoptosis in other activated lymphocytes ("fratricide") or in
themselves ("suicide").40-47 sFas molecules are able
to block Fas/FasL interaction and, thus, prevent apoptosis
induction.20,24,26 Although the levels found in serum are
probably too low to play a role in the prevention of apoptosis, local
levels at the site of the graft-versus-host reaction may be much
higher.20 sFas may play a dual role in GVHD. On the one
hand sFas may inhibit Fas-related cytotoxicity of the effector T cells
on the target cells during GVHD. However, because elevated levels of
sFas are found during active GVHD, this explanation does not seem
plausible. On the other hand sFas may prevent Fas-mediated apoptosis of
the effector T cells themselves. This latter event would result in a
non-self-limiting immune response and may lead to a prolonged graft-versus-host reaction, because effector T cells will still be able
to kill through the perforin/granzyme pathway.33 Support for such a mechanism was described in patients with systemic lupus erythematosus.20
In contrast to the high serum sFas levels found during GVHD, sFas
levels tend to decrease during infections. This may imply that
regulation of the immune response via Fas/FasL during infections is not
blocked by high levels of sFas as opposed to the regulation of the
immune response during GVHD. Recent observations suggest that
membrane-expressed Fas and sFas can be differentially
regulated.23,25 Whereas the regulation of Fas and sFas
expression during infections may reflect the normal immune response,
high levels of sFas found during GVHD may not only result from release
by damaged cells but also by abnormal expression of the sFas splice
variant.
In conclusion, we have shown that increased serum sFas levels in BMT
patients correlate significantly with aGVHD and are further increased
in those cases in which GVHD and infections occur simultaneously. In
cases of solely infections, sFas levels tend to decrease in BMT
patients. The latter finding may have also been of great importance for
solid organ transplantation, because diagnosis between rejection and
infection is difficult and requires, more than in BMT, examination of
biopsy specimens of relevant organs. Furthermore, high local sFas
levels may inhibit Fas-mediated regulation of the immune response,
thereby facilitating development of GVHD.
| |
FOOTNOTES |
Submitted February 24, 1997;
accepted October 8, 1997.
L.M.L. and T.v.L. contributed equally to this report.
Supported by the JA Cohen Institute of Radiopathology and Radiation
Protection (IRS), by EC Grant No. BIO2 CT92 0300, by the MACROPA
Foundation and by Grant No. 95CR841 from the Dutch League Against
Rheumatism.
Address reprint requests to Linda M. Liem, PhD, Department
of Immunohematology and Blood Bank, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Dr R. Willemze, Dr A. Brand, and Mrs L. Huige for the
collection of serum samples of hematological patients. We thank Prof
J.J. van Rood and Drs A. Brand, J. Bruning, F. Claas, and M. Oudshoorn
for critical reading of the manuscript.
| |
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Abstract
Introduction
Abstract
