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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3943-3948
Cytokine Gene Polymorphisms Associating With Severe Acute
Graft-Versus-Host Disease in HLA-Identical Sibling Transplants
By
Peter G. Middleton,
Penelope R.A. Taylor,
Graham Jackson,
Stephen
J. Proctor, and
Anne M. Dickinson
From the Leukaemia Research Fund (LRF) Laboratory, Catherine Cookson
Building, The Medical School, Framlington Place, Newcastle upon Tyne,
UK; and the Department of Haematology and University Department of
Haematology, School of Clinical Laboratory Sciences, Royal Victoria
Infirmary, Queen Victoria Road, Newcastle upon Tyne, UK.
 |
ABSTRACT |
It is now well known that the initial phase of graft-versus-host
disease (GVHD) involves cytokine release during preconditioning of the
recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis
factor  (TNF), in particular, has been implicated in pathological
damage and is released pretransplant due to irradiation and cytotoxic
preconditioning regimens. Interleukin-10 (IL-10), a natural
immunosuppressant of TNF , may be involved in downregulation of
these responses, which may be an individual patient-specific effect. In
this study, we determined the genotype for polymorphisms associated
with TNF and IL-10 in 80 potential allo-BMT recipients and
correlated the genotype with the severity of GVHD in 49 patients for
whom clinical data relating to GVHD was available. The widely studied
TNF  308 polymorphism does not show any significant
associations, but the d3 homozygous allele of the TNFd microsatellite
is preferentially associated with grade III/IV GVHD (7 of 11 patients)
compared with its occurrence in 8 of 38 patients with grade 0/II GVHD
(P = .006). Alleles of the IL-10 1064 promoter
region microsatellite polymorphism that possess greater numbers of
dinucleotide (CA) repeats also significantly associate with more severe
GVHD. This region has been demonstrated to be important in the
regulation of the IL-10 promoter. Eighteen of 38 patients with grade
0-II GVHD possessed alleles with greater numbers (12 or more) of
dinucleotide repeats, compared with 9 of 11 cases with grade III-IV
GVHD (P < .02). Of the 38 patients with grade 0-II GVHD, 3 of
38 had a both TNFd3/d3 and IL-10 (12-15) genotype,
compared with 6 of 11 patients with grade III-IV GVHD (P < .001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P = .43 and .51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine
activation during the pretransplant conditioning regimens, and these
results are the first to suggest a genetic predisposition to this
important transplant-related complication.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE PROINFLAMMATORY cytokines and their
related receptors and inhibitors (interleukin-1 [IL-1], IL-1r,
IL-1ra, IL-2, IL-6, tumor necrosis factor [TNF], and IL-10)
have been implicated in a number of immunological diseases (briefly
reviewed in Daser et al1), including graft-versus-host
disease (GVHD) after allogeneic bone marrow transplantation (BMT). In
GVHD, an initial insult during preconditioning provokes an inflammatory
response and release of IL-1 and TNF. The subsequent cascade of
cytokine production initiates tissue damage, which is compounded by a
second phase involving the activation of alloreactive T cells from the
donor marrow.2,3 Raised TNF levels have been reported
during the initial phase of pretransplant conditioning for allo-BMT and
have been shown to correlate with severe complications and mortality after BMT.3,4 A recent clinical phase II study using
monoclonal antibodies to TNF as part of the conditioning regimen led
to a delay in the onset and severity of the GVHD.5 These
studies suggest a role of recipient TNF production in the subsequent development of GVHD.
The gene encoding the proinflammatory cytokine TNF is located within
the major histocompatibility complex (MHC) locus on chromosome 6, which may account, in part, for the association between
HLA type and some immune diseases. Inducibility of TNF has been
found to be low in HLA DR2 genotypes and high in HLA DR3 and DR4
genotypes,6 suggesting the existence of inherently high or
low TNF producers in the population. A polymorphism in the promoter
region of the TNF gene, the 308 (G/A)
polymorphism of an AP-2 transcription factor binding site, has been
widely studied and is associated with the HLA haplotype (A1, B8,
DR3),7-9 with increased in vitro TNF expression being associated with the uncommon TNF2 (A) allele. It has been suggested that high levels of TNF secretion after mitogen stimulation of peripheral blood lymphocytes from BMT recipients may be associated with
this TNF2 (A) allele.4
A number of microsatellite repeat sequence elements have been mapped
around the TNF gene locus.10 One of these highly
informative dinucleotide (GA) microsatellites, TNFd, has been mapped
downstream of the TNF gene and is located within an intron of the
recently described LST1 gene.11 The d3 allele of this
polymorphism has been associated with higher in vitro TNF production
in cells derived from immune-suppressed heart transplant
recipients.12 Interestingly, this association is
not evident when cells derived from normal, non-immune-suppressed
subjects are stimulated to measure TNF expression, possibly
indicating that the proposed associations may only be manifested after
conventional immunosuppression.
IL-10 is a potent immunosuppressant produced by monocytes and a strong
inhibitor of TNF (for review see Roncarolo13 and Korholz
et al14). Low levels of IL-10 production have been
correlated with increased incidence of both acute and chronic
GVHD.3 The ability of donor as well as host cells to
produce either high or low levels of TNF and IL-10 may influence
transplant outcome. In this regard, heart transplant patients were
shown to be more susceptible to rejection episodes if they produced
high levels of TNF and low levels of IL-10.15,16 A
number of polymorphisms of the IL-10 gene have been described,
including single base (G/A) polymorphism (1082)
associated with altered levels of in vitro IL-10
expression16 and microsatellite polymorphism
(1064) mapping near candidate IL-10 gene control
elements.17 Recent findings suggest a role for some of
these polymorphisms in determining rejection in heart transplant
recipients.15,16
In this present study we have determined the BMT recipient TNF and
IL-10 genotype for gene polymorphisms associated with either reported
cytokine productivity or candidate gene control regions and correlated
results with HLA phenotype and clinical outcome, including the
incidence and severity of posttransplant GVHD.
| |
MATERIALS AND METHODS |
Patients and normal controls for polymorphism studies.
Eighty patients being considered for transplant with underlying
hematological malignancies predominantly acute leukemia (ALL) or
chronic granulocytic leukemia (CGL) were tested for TNF and IL-10
polymorphism allele frequencies and genotype. Twenty-eight normals
(laboratory personnel) were also tested for TNF and IL-10 polymorphism allele frequencies and genotype. The results are included
in Fig 1A and B.
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| Fig 1.
(A) Allele frequencies for the TNFd microsatellite
polymorphism as measured in this study (80 Allo BMT recipients, 160 alleles) and two other published reports (Udalova et al10
and Turner et al12). Results on a panel of 28 unselected
normals (56 alleles) are also shown. The observed allele frequencies
show similar frequencies to those reported elsewhere, indicating that
the appropriate allele designations/identifications were being made.
The frequency of predicted d3/d3 homozygotes of 23.1 (predicted from
the allele frequency by Hardy-Weinberg equilibrium) compared well with
the observed frequency of 26. ( ) HT panel (210); ( ) heart
transplants (44); ( ) BMT (160); () 28 normals (56). (B) Allele
frequencies for the IL-10 1064 microsatellite as
measured in this study (80 allo-BMT recipients, 160 alleles) plus
frequencies from two other studies (Eskdale and Gallagher19
and Worthington et al, personal communication, 1998). The
observed allele frequencies show similar frequencies to those reported
elsewhere, indicating that the appropriate allele
designations/identifications were being made. The frequency of
genotypes predicted from the allele frequencies by Hardy-Weinberg
equilibrium compare well with the observed frequencies (i9/9 predicted
14.45, observed 15; i9/13 predicted 12.75, observed 13). ()
Gallagher (204); () Worthington; () BMT (160).
|
|
Cytokine gene polymorphism studies were performed on all patients,
including the 49 of 80 patients who subsequently underwent BMT from an
HLA- and HLA-DR-matched, mixed lymphocyte culture-negative, sibling
donor. The TNF and IL-10 polymorphism results from these patients
were correlated with incidence and severity of GVHD. These patients
included 32 males and 17 females (median age, 33; age range, 14 to 47 years). All 49 patients received non-T-cell-depleted marrow grafts.
The underlying diseases were CGL (n = 12), acute myeloid leukemia (AML;
n = 18), ALL (n = 15), Hodgkin's disease (HD; n = 1), non-Hodgkin's
lymphoma (NHL; n = 1), and myelodysplastic syndrome (MDS; n = 2).
Conditioning regimens and GVHD prophylaxis.
Before January 1991, standard conditioning for the patients with acute
leukemia was with cyclophosphamide (120 mg/kg) and total body
irradiation (TBI; 12 Gy in 6 fractions in 3 days at 25 cGy/min). Since
January 1991, the TBI dose has remained the same, but melphalan (3 mg/kg) has been substituted for the cyclophosphamide. Patients with MDS
were conditioned with cyclophosphamide alone. Patients with CGL were
usually conditioned with busulphan (4 mg/kg/d for 4 days) and
cyclophosphamide.
The majority of patients were treated with either cyclophosphamide or
melphalan plus TBI (Table 1). The number of
patients treated with these two types of conditioning regimes were
equally distributed between the cohorts of patients developing GVHD
grades 0-II and GVHD III-IV (30 of 38 and 9 of 11, respectively;
 2 = .043; df = 1; P = .835; Tables 1
and 2).
GVHD prophylaxis and therapy.
GVHD prophylaxis was with cyclosporin alone, administered
intraveneously at a dose of 5 mg/kg until oral treatment could be tolerated, when the same dose was administered by mouth. Once clinical
GVHD was diagnosed, standard therapy was administered with high-dose
steroids; if there was no immediate response, this was followed by
increased cyclosporin (5 to 10 mg/kg).
Ethics committee approval and informed consent.
This study was approved by the local ethics committee and informed
consent was obtained from all patients and normal controls under study.
HLA typing.
All patients in this study were tested by conventional serology for HLA
A and B alleles along with low resolution molecular typing of DRB1
using polymerase chain reaction (PCR) sequence-specific primer.18 All tissue typing was routinely performed at the
Northern Blood Transfusion Service (Newcastle, UK).
TNF and IL-10 genotypes.
Patient genotypes were determined for the TNF308,
TNFd microsatellite, and IL-10 1064 microsatellite
polymorphisms essentially as described.7,10,19 PCR products
were separated by gel electrophoresis on polyacrylamide gels (10%,
19:1 acryl:bis) and visualized by silver staining. All PCR products
were compared with a control of known genotype (TNF
308 1/2, TNFd1/d3, IL-10 i9/13) to ensure accurate
interpretation. Allele designations, eg, d1/d3, 9/13 etc, are as
described in the original reports of these
polymorphisms.7,10,19
Statistical analyses.
Comparisons between patient groups were made using the 2
test for heterogeneity.
| |
RESULTS |
Incidence and severity of GVHD.
GVHD was diagnosed and graded according to previously published
criteria.20 Of the 49 patients transplanted, 9 showed no evidence of acute GVHD. Fourteen patients developed grade I GVHD: 10 with skin alone, 3 with skin plus gastrointestinal involvement, and 1 with gastrointestinal involvement alone. Fifteen patients developed
grade II GVHD; all had skin involvement, 4 had hepatic involvement (2 with gastrointestinal disease), and 3 had skin and gastrointestinal
involvement with no evidence of liver disease. Eleven of 49 patients
developed severe (grade III-IV) GVHD. All 9 patients with grade III
disease had skin and gastrointestinal GVHD, together with liver
involvement in 4 patients. In this whole cohort, only 2 patients died
of GVHD (Tables 1 and 2).
TNF308 polymorphism.
Of the 80 patients tested, 3 were homozygous for the uncommon TNF2
allele (the allele frequencies would predict 2.1 homozygotes) and 20 cases were heterozygous (TNF1/2). The allele frequencies of TNF1 and
TNF2, respectively, were 0.838 and 0.162. These results were comparable
with those quoted for a normal Caucasian population (0.84 and 0.16, respectively, measured on 40 individuals [80 alleles]7). In common with other studies, a strong association of the TNF2 allele
with HLA haplotypes containing DR3, and a weaker association with DR4
was observed. (All but 4 of the observed TNF2 alleles were carried by
individuals possessing a DR3 or a DR4 haplotype.)
The rare allele TNF2 did not associate with incidence or severity of
GVHD. Thirteen of 38 patients with GVHD grade 0-II and 2 of 11 patients
with grade III/IV GVHD possessed a TNF2 allele. There was no
association of GVHD with HLA type.
Allele frequencies of the TNFd and IL-10 microsatellite
polymorphisms.
The allele frequencies of TNF and IL-10 microsatellites found in the
80 patients tested, along with those previously reported in other
studies, and a panel of 28 unselected normals are shown in Fig 1A and
B. The observed allele frequencies were similar to those reported
elsewhere, indicating that the appropriate allele designations were
made for patient and normal control cohorts. The frequency of predicted
homozygotes (as predicted by Hardy-Weinberg equilibrium) for the more
common alleles compare with the observed frequencies, suggesting that
homozygous genotypes were being appropriately assigned in the study
group (TNFd3/d3 predicted v observed; 23.1 v 26; IL-10
i9/9 predicted v observed; 14.45 v 15; i9/13 predicted v observed; 12.75 v 13).
TNFd and IL-10 microsatellite polymorphisms and association with
GVHD.
The d3 allele of the TNFd microsatellite was preferentially associated
with grade III/IV GVHD, with 7 of 11 patients possessing the d3/d3
genotype, compared with its occurrence in 8 of 38 patients with grade
0-II (2 = 7.598; df = 1; P < .006; Tables 1
and 2).
Alleles of the IL-10 1064 promoter region
microsatellite polymorphism that possessed greater numbers of
dinucleotide repeats (alleles 12, 13, 14, or 15, as described by
Eskdale and Gallagher19) also significantly associated with
more severe GVHD. Eighteen of 38 patients with grades 0-II GVHD
possessed high repeat number alleles (12-15; Table 1), compared with 9 of 11 patients with grades III-IV GVHD only (2 = 5.443;
df = 1; P < .02; Table 2).
If both TNFd and IL-10 genotypes were considered together, there
appears to be a retrospective association with GVHD severity and
occurrence. Of the 38 patients with grade 0-II GVHD, 3 of 38 had a
TNFd3/d3/IL-10 (12-15) genotype, compared with 6 of 11 patients with
grade III-IV GVHD (2 = 14.11; df = 1; P < .001).
TNFd and IL-10 microsatellite polymorphisms and association with
death and relapse.
The TNFd3/d3 genotype was not associated with increased mortality; 8 of
15 patients with the homozygous genotype died, compared with 14 of 34 patients who did not have this allele (2 = .62; df = 1;
P = .43). Possession of an IL-10 genotype with alleles
containing greater numbers of dinucleotide repeats (alleles 12, 13, 14, or 15) was not associated with mortality; 2 analysis of
its association failed to reach significance (2 = .42;
df = 1; P = .51). Of the 9 patients who died from disease relapse, 8 had grade 0-I GVHD, compared with 1 relapse from the group
of patients with grade II-III-IV GVHD (2 = 7.79; df = 1;
P < .006).
| |
DISCUSSION |
The importance of the cytokine cascade in both the initial
preconditioning and posttransplant phases of GVHD is well established. TNF secretion is of particular importance during the irradiation and
cytotoxic treatment of the recipient before transplant giving rise to
initial endothelial cell damage and aiding T-cell activation by
upregulation of class I, class II, and adhesion molecules. Several
reports have dealt with the measurement of serum TNF and its role in
predicting GVHD. One problem that arises that is independent of the
problems associated with serum measurements of cytokines is that high
levels of TNF are also associated with other transplant-related
complications, including infection and veno-occlusive
disease.3
In this present study, the d3 allele of the TNFd polymorphism was found
to be associated with severe GVHD grades III/IV but not with overall
clinical survival. This result suggests that the effect seen in the
d3/d3 TNFd genotype may be susceptible to immunosuppression as
suggested by Turner et al12 in studies on heart transplant
recipients in which the effect was related to the degree of
immunosuppression. The increased incidence of GVHD in the homozygous
d3/d3 cohort was associated with increased GVHD, but also this
subpopulation was possibly more responsive to the GVHD therapy in the
form of increased cyclosporin and methotrexate and therefore did not
succumb to fatal GVHD. A similar effect may be the explanation for the
lack of correlation with GVHD mortality and IL-10 (12-15) allele
polymorphisms. This hypothesis can only be tested in larger cohorts of
patients with and without increased GVHD prophylaxis and altered
therapy. Our studies have also shown that the 308
polymorphism was not associated with GVHD severity. Mayer et
al4 have recently completed a study on 53 CML allograft recipients indicating a possible role of the 308
polymorphism in severe GVHD. That study was confined to CML patients
and included matched unrelated donor transplants as well as
HLA-identical siblings (personal communication, 1998) and therefore may
not be directly compared with this present study. Our study is also too
small to correlate TNF308 polymorphism with
incidence or severity of GVHD in particular cohorts of leukemia
patients.
A large number of studies have looked unsuccessfully for associations
between TNF2 genotype and disease incidence, severity, or
susceptibility in a range of immunoregulatory disorders. These include
studies on rheumatoid arthritis,21,22 systemic lupus erythematosus,23 inflammatory bowel disease,24
lichen sclerosus,25 and ankylosing
spondylitis.26 An association between the TNF2 allele and
the incidence of insulin-dependent diabetes mellitus has been reported,
but this association is not independent of the HLA type and probably
reflects linkage disequilibrium between the TNF2 polymorphism and the
ancestral HLA haplotype.27 A similar association has been
seen in rheumatoid arthritis patients with systemic lupus
erythematosus.28 An association between disease incidence
and the TNF2 allele that is independent of the HLA type has been
reported in studies on asthma.29 Taken together, these findings indicate that the TNF2 genotype may not be important in
immunoregulatory disorders and that other candidate loci or genetic
elements must be considered.
A proven association of cytokine gene polymorphisms with GVHD would
undoubtedly enable the clinician to modify therapy in those patients
predicted to develop GVHD by virtue of their underlying cytokine
genotype. The study reported here documents the possible role of IL-10
gene polymorphism in GVHD. Analysis of both the TNF and IL-10
polymorphisms and GVHD severity was based on knowledge that grade 0-II
GVHD is more susceptible to therapeutic intervention than grades
III-IV, which are often fatal.18 This increase in risk of
severe GVHD if possessing risk-associated alleles for both the TNF
d3/d3 and IL-10 (12, 13, 14, and 15) genotype was highly significant
(P < .001). However, possession of either genotype alone was
also significant. These results suggest both an interacting role for
TNF and IL-10 and a role for both as independent indicators of
severity of GVHD. This further suggests that other factors undoubtedly
regulate TNF and IL-10 production and play a role in the ultimate
degree of GVHD.
The extension of these studies to include other indicators/predictors
of GVHD in HLA-identical siblings, such as minor histocompatibility testing,30 HTLp frequency analysis,31 cytokine
production,32 and/or predicting GVHD using a skin
explant model,33 may allow the development of an individual
risk index for GVHD. Such a risk index would allow for improved
management for GVHD, which is still the major cause of morbidity and
mortality after allogeneic BMT.
Recent approaches to therapy include engineering a shift in cytokine
profiles before BMT as a way to attenuate inflammatory processes of
GVHD.3,5 These approaches include the possible use of
anti-TNF antibodies and recombinant IL-10, a strong inhibitor of
TNF. The finding of 8 of 9 deaths from disease relapse in the grade
0-I GVHD group suggests that prior knowledge of a patient's risk
status for cytokine production might be of value not only in
attenuating the effects of GVHD in high-risk individuals, but also in
potentially upregulating the response in GVHD low-risk individuals to
manipulate the graft-versus-leukemia (GVL) effect. Such management
options would only become reality if accurate GVHD/GVL predictions for
an individual patient could be made.
| |
ACKNOWLEDGMENT |
The authors thank the Blood Transfusion Service (Barrack Road,
Newcastle, UK) for HLA typing data and Jane Worthington (ARC Epidemiology Research Unit, Manchester, UK) for advice on the IL-10
microsatellite. We also thank Jim Cavet for critical reading of the
manuscript.
| |
FOOTNOTES |
Submitted April 15, 1998;
accepted July 7, 1998.
Supported by a Tyneside Leukaemia Research Association Programme Grant.
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.
Address reprint requests to Peter G. Middleton, PhD, LRF
Laboratory, Catherine Cookson Building, University of Newcastle,
Medical Molecular Biology Group, Floor 4, The Medical School,
Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
| |
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Top
Abstract
Introduction