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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3941-3946
Recipient Tumor Necrosis Factor- and Interleukin-10 Gene
Polymorphisms Associate With Early Mortality and Acute
Graft-Versus-Host Disease Severity in HLA-Matched Sibling Bone
Marrow Transplants
By
James Cavet,
Peter G. Middleton,
Miriam Segall,
Harriet Noreen,
Stella M. Davies, and
Anne M. Dickinson
From the University Department of Haematology, School of Clinical and
Laboratory Sciences, The Medical School, University of Newcastle Upon
Tyne, Newcastle Upon Tyne, UK; and the Department of Bone Marrow
Transplantation and Clinical Research, University of Minnesota,
Minneapolis, MN.
 |
ABSTRACT |
The proinflammatory cytokine tumor necrosis factor- (TNF-) is
strongly implicated in graft-versus-host disease (GVHD) and other acute
bone marrow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL-10) antagonizes TNF- and reduces GVHD. We previously showed association of recipient TNF (TNFd) and IL-10 (IL-10 1064) gene polymorphisms with acute GVHD severity
in matched sibling BMT using only cyclosporin A monotherapy. The
current study tested association of GVHD with TNFd and
IL-101064/-1082 polymorphisms in a large cohort (144 matched sibling donor/recipient pairs) given both cyclosporine A (CyA)
and methotrexate (MTX) prophylaxis. Genotype results were correlated
with acute and chronic GVHD and mortality. Patients homozygous for the
TNFd microsatellite allele 3 had higher early mortality: 23.7% of
TNFd3/d3 homozygotes died before day 30, compared with 6.80% of
non-d3/d3 recipients (P = .013). Recipients possessing longer
IL-101064 microsatellite alleles developed more severe
acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed
grade III to IV GVHD, versus 3.92% of those with smaller alleles
(P < .01). Other recipient or donor genotypes tested did not
significantly affect GVHD or mortality. We conclude that recipient TNFd
and IL-101064 polymorphisms associate with early
mortality and severe acute GVHD in matched sibling BMT with dual
prophyaxis. This supports the hypothesis of genetic predisposition
towards GVHD and other BMT complications other than histocompatibility
antigen disparity.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
GRAFT-VERSUS-HOST DISEASE (GVHD) remains
the most common allogeneic bone marrow transplant (BMT) complication;
mild acute GVHD (aGVHD) does not necessarily affect survival, but
severe aGVHD, especially grades III to IV, increases
mortality,1 and once established, often responds poorly to
therapy.2 Prophylaxis with immunosuppressive drugs and/or
T-cell depletion has side effects of increasing infection and
decreasing the graft-versus-leukemia (GVL) effect.3
Currently there are no widely established approaches to individualized
targeting of GVHD prophylaxis.
Cytokines are important GVHD mediators and regulators.4,5
Although conditioning exerts an antineoplastic effect, increased total
body irradiation (TBI) intensity causes accelerated aGVHD and more
infections.6 TBI and chemotherapy damage host cells, releasing proinflammatory cytokines including tumor necrosis factor- (TNF-).7 Gastrointestinal mucosal injury allows
bacterial lipopolysaccharide to stimulate monocyte TNF-
secretion.8 TNF- increases major histocompatibility
complex (MHC) expression,9 facilitates cell-mediated
cytotoxicity and is itself cytotoxic via apoptosis.10
TNF- release during conditioning precedes severe aGVHD1
and other early inflammatory transplant-related complications (TRC),
including venoocclusive disease (VOD) and septic shock, and is
predictive of high mortality.11 However, TNF- release
before conditioning is not linked to increased aGVHD, possibly via
desensitization.12 Clinical studies show anti-TNF- antibodies during conditioning decrease aGVHD,13 but
established aGVHD responds only transiently.14
The TNF- gene maps within the MHC class III region on chromosome 6 near many polymorphisms, several of which associate with inflammatory
disease.15 TNFd, a (GA)n-repeat microsatellite sequence,16 maps downstream of the TNF- gene within
intron 3 of the nearby leukocyte-specific transcript (LST)-1
gene.17 The most commonest allele, TNFd3, associates with
higher in vitro TNF- production,18 and TNFd3/d3
homozygous cardiac-transplant recipients have increased
rejection.19 We recently demonstrated that TNFd3/d3
homozygosity associated with grade III to IV aGVHD in HLA-matched
sibling BMT using prophylactic cyclosporine A (CyA) monotherapy.20
The antiinflammatory cytokine interleukin-10 (IL-10)21
inhibits monocyte production of proinflammatory
cytokines,22 including TNF-, and decreases apoptosis
induced by lipopolysaccharide and irradiation.8 IL-10 also
reduces MHC expression and attenuates recognition by cytotoxic
lymphocytes.23 A recently described IL-10-dependent
CD4+ T-cell subset, the T-regulatory 1 (Tr1)-cell, can
induce antigen-specific tolerance.24,25 In BMT, IL-10
production preconditioning protects from TNF- release, aGVHD,
and other TRC.26 Cells from patients with acute or
chronic GVHD (cGVHD) produce less IL-10 in
vitro.27,28 The IL-10 gene regulatory region includes 2 microsatellite polymorphisms, which associate with differential in
vitro IL-10 production.29 An excess of allele 13 of the
IL-101064 (CA)n-repeat polymorphism occurs in
systemic lupus erythematosus.30 Recently, we demonstrated
that greater IL-101064 repeat number in the
recipient associated with severe aGVHD in CyA-treated matched sibling
BMT and that this association operates in parallel to that of
TNFd3/d3.20 The nearby IL-101082
(G/A)-polymorphism A allele associates with lower in vitro IL-10 production.31 Possession of both TNFd3/d3 genotype and
IL-101082 A allele associates with greater cardiac
rejection.19
The current study was designed to test association of acute and chronic
GVHD with TNFd and IL-101064 genotypes of both
donors and recipients in a larger population given combined
CyA/methotrexate (MTX) prophylaxis32 and to examine potential association of the neighboring IL-101082
polymorphism. Genotypes for TNFd and
IL-101064/1082 polymorphisms were
determined for CyA/MTX-treated matched sibling BMT donor/recipient
pairs. These genotypes were correlated with clinical outcomes including
GVHD severity and mortality. We hypothesize that recipient genetic
factors are important in determining the severity of transplant
complications. In this study, we strengthen that hypothesis, showing
that recipient TNF and IL-10 polymorphisms associate with early
mortality and aGVHD after matched sibling donor BMT.
| |
MATERIALS AND METHODS |
BMT patient characteristics.
A total of 144 sibling donor/recipient pairs who had undergone
HLA-matched (serologically for HLA-A/-B antigens; by high resolution molecular typing for HLA-DRB1) BMT at the University of Minnesota were
genotyped, while blinded to clinical outcomes
(Table 1). All patients or their guardians
signed consent forms approved by the University of Minnesota
Institutional Review Board. Conditioning comprised of cyclophosphamide
(60 mg/kg × 2) followed by fractionated TBI (165 cGy twice daily
for 4 days; total 1,320 cGy); except for 2 patients who received 125 cGy 3 times daily for 3 days and twice daily on the fourth day (total
1,375 cGy), and 4 pediatric patients who received 200 cGy twice daily
for 3 days (total 1,200 cGy), followed by cyclophosphamide (60 mg/kg × 2). All grafts were non-T-cell depleted and GVHD prophylaxis
consisted of CyA from day  3 (maintaining levels between 200 to
400 ng/mL assayed by high-performance liquid chromatography) and short
course MTX (15 mg/m2 day 1 and 10 mg/m2 days 3, 6, and 11).
TNF- and IL-10 genotypes.
Donor/recipient genotypes for the TNFd and IL-101064
/1082 polymorphisms were determined as previously
described16,30,31 using stored DNA or crude cell-lysates
where purified DNA was unavailable. Some samples contained insufficient
intact DNA to act as polymerase chain reaction (PCR) template for all
polymorphisms, despite phenol/chloroform extraction and ethanol
precipitation. PCR products were resolved by polyacrylamide gel
electrophoresis (8%; 19:1 acrylamide:bisacrylamide) and visualized by
silver staining. Control DNA heterozygous for each common allele was
used to ensure accuracy. As TNFd is within the MHC complex, TNFd
genotype acted as a control for donor/recipient pair matching.
IL-10 haplotypes were determined in an IL-101082
allele-specific PCR including the IL-101064
microsatellite in the product, thereby ascertaining the
IL-101064 allele together with its associated
IL-101082 G or A allele. Primers were
5'-AGCAACACTCCTCGTCGCAAC-3' (JW-F) with
5'-CCTATCCCTACTTCCCCC-3' (B1) or
5'-CCTATCCCTACTTCCCCT-3' (B2). Reactions contained 20 µmol/L of each primer, 0.5 U Taq polymerase (Bioline, London, UK) and
200 µmol/L deoxyribonucleoside triphosphates (dNTP) mixture with 1.5 mmol/L MgCl2 in 1x NH4 Buffer (Bioline) in
addition to test DNA, to a final volume of 25 µL. Amplification was
performed on Perkin-Elmer thermal-cycler (Norwalk, CT)
with 30 cycles of: 94°C for 30 seconds; 60°C for 60 seconds; 72°C for 60 seconds; followed by a final extension of 72°C for 7 minutes.
Statistical analysis.
Data were analyzed in contingency tables by Fisher's exact test (other
than Kaplan-Meier survival-curve comparison by  2), using
GraphPad Prism 2 software (GraphPad Software Inc, San Diego, CA), with
P values (all 2-sided) less than .05 regarded as statistically significant.
| |
RESULTS |
TNFd polymorphism frequencies.
A total of 562 TNFd alleles was analyzed; 8 samples could not be typed.
Allele frequency distribution did not differ significantly from
previous reports,16,19,20 with homozygote frequencies comparable to those predicted by the Hardy-Weinberg equilibrium (eg,
TNFd3/d3: predicted = 72 pairs; observed = 76). One pair exhibited a
single TNFd mismatch (donor genotype d3d4; recipient d4d5).
IL-10 polymorphism haplotypes.
A total of 574 IL-101064 alleles was ascertainable;
allele frequency distribution did not differ significantly from
previous reports,20,29,30 with comparable homozygote
frequencies to those predicted (eg, IL-101064
i9/i9: predicted = 45 pairs, observed = 51). The
IL-101082 (G/A)-polymorphism was ascertained for 430 alleles, with comparable frequencies to previous reports (Table
2).19,31 Haplotype analysis
showed IL-101064 alleles possessing greater numbers
of dinucleotide repeats, referred to as i(12-16), to be preferentially
associated with IL-101082 A. One hundred sixty-three
of 276 IL-101064 i(7-11) alleles were associated
with a G allele at IL-101082, and 101 of 154 IL-101064 i(12-16) alleles associated with
IL-101082 A (P < .001). This is consistent
with findings from both normal subjects and the previously analyzed
Northern UK BMT cohort (P.G.M., unpublished observation, February
1999).
Clinical outcomes.
Of the 144 patients, 16 died before day 30, hence 128 were evaluable
for aGVHD grade. Twelve of these 16 had sepsis (6 fungal), 6 diffuse
alveolar/pulmonary hemorrhage, 3 multisystem organ failure (MSOF), 2 hyperammonemia, 1 acute respiratory distress syndrome, and 1 VOD.
Eighty-eight patients developed aGVHD (grading according to Glucksberg
et al33): 26 grade I, 43 grade II, 17 grade III, and 2 grade IV aGVHD. A further 18 patients died before day 100, leaving 110 evaluable for cGVHD grade. Presence of aGVHD showed a
trend toward correlation with cGVHD risk: 11 of 32 patients without
aGVHD surviving >100 days developed de novo cGVHD, while 44 of 78 with grade I to IV aGVHD went on to develop cGVHD (P = .058).
Of the 55 patients developing cGVHD, 4 had limited and 51 had extensive
disease (grading according to Atkinson et al34).
Median follow-up duration was 869 days. Overall survival was 47.2% (76 deaths) and showed significant correlation with presence of aGVHD: 62 of 109 (57.8%) patients with grade 0 to II aGVHD survived, compared
with 6 of 19 (31.6%) with grade III to IV aGVHD (P = .049).
cGVHD presence did not correlate with overall survival (P = 1.0). If the 6 patients who received nonstandard conditioning were
excluded, the rates of mortality and GVHD were no different, as none of
these patients died before day 30 nor did they develop severe aGVHD.
Early mortality.
TNFd3/d3 genotype (shared by donor and recipient) was significantly
associated with early mortality: 23.7% (9 of 37) of TNFd3/d3 homozygotes died before day 30, compared with 6.80% (7 of 96) of
nond3/d3 recipients (P = .013)
(Table 3). Possession of only 1 TNFd3
allele was not associated with early death (P = .56). Early
death was not associated with recipient status at either IL-101064 or 1082 polymorphism.
Acute GVHD.
TNFd3/d3 genotype was not associated with severe aGVHD (grade III to
IV) in those surviving more than 30 days (P = .24)
(Table 4). Recipient
IL-101064 alleles with larger numbers of
dinucleotide repeats were significantly associated with severe aGVHD:
22.3% (17 of 76) of recipients possessing 1 or more i(12-16) allele
developed grade III to IV aGVHD, while 3.92% (2 of 51) of recipients
with only i(7-11) alleles developed grade III to IV aGVHD (P = .0045). Recipient IL-101082 or donor IL-10 genotypes
did not associate with aGVHD.
Chronic GVHD.
Neither donor nor recipient TNFd or IL-10 polymorphisms were associated
with cGVHD (Table 5).
Overall mortality.
TNFd3/d3 homozygotes had lower overall survival, but not to a
significant degree, despite increased early mortality: 42.1% (16 of
38) of TNFd3/d3 homozygotes were survivors, and 49.5% (51 of 103)
non-TNFd3/d3 recipients survived (P = .45)
(Table 6). Median TNFd3/d3 homozygous
recipient survival was 373 days compared with 467 days for non-d3/d3
recipients (Kaplan Meier 2, P = .29). Recipient
IL-101064 polymorphism length did not correlate with
overall survival, despite association with aGVHD severity: 40 recipients with i(12-16) and 27 recipients with only i(7-11) survived,
while 45 recipients with i(12-16) and 31 recipients with only i(7-11)
died (P = 1.0). Recipient IL-101082 or donor
IL-10 polymorphisms did not associate with overall mortality.
| |
DISCUSSION |
Preliminary studies led us to hypothesize that recipient cytokine gene
polymorphism was related to inflammatory complications of BMT,
including GVHD; the results of this study are consistent with this
hypothesis. Transplant recipients who were homozygous for the TNFd3
allele had significantly higher early mortality, suggesting genetic
susceptibility to fatal acute inflammatory TRC. Of the 9 TNFd3d3
homozygotes dying within the first month, 3 had diffuse alveolar
hemorrhage associated with sepsis, 2 developed MSOF in association with
severe sepsis, 2 succumbed to fungal infection, 1 to respiratory
syncitial virus pneumonia, and 1 to Citrobacter septicemia. TNF-
release is implicated in pathogenesis of aGVHD, VOD, MSOF, and septic
shock35 The association of fatal early TRC and TNFd3d3
polymorphism is consistent with the hypothesis that recipient genetic
variation in cytokines influences BMT outcome. The association between
TNFd3/d3 genotype and inflammatory TRC including aGVHD probably
reflects increased TNF- release as demonstrated in cardiac allograft
recipients.18 However, the TNFd microsatellite lies within
the neighboring LST-1 gene, the function of which is unknown, and
another mechanism cannot currently be excluded. As the study was
retrospective, no TNF- levels were available.
In our previous study using CyA monotherapy, TNFd3/d3 homozygotes had
increased severe aGVHD.20 In this current cohort given combined CyA/MTX prophylaxis, TNFd3/d3 homozygotes who survived the
initial month did not exhibit more severe aGVHD. The differences observed between the 2 studies may reflect increased prophylaxis (overall rate of grade III to IV aGVHD 22.4% in the monotherapy study
compared with 14.8% in the current cohort given CyA/MTX). The addition
of MTX may have reduced TNF-'s influence on aGVHD without
modulating that of IL-10, which is not mediated solely via
TNF--antagonism; similar differential effects of MTX on cytokine release have been described in systemic lupus
erythematosus.36 Alternatively, TNFd3/d3 homozygotes who
died early might otherwise have subsequently developed severe aGVHD.
The previous study was not designed to assess early transplant
outcomes, as only those recipients who had aGVHD grade ascertainable
were analyzed.20
TNFd3d3 homozygous recipients' overall median survival was decreased,
but not to a significant degree, despite a significantly increased
early mortality. This may reflect the fact that other causes of death
such as relapse make a large contribution to overall survival, and the
fact that TNFd3d3 homozygotes constitute only 25% of the population.
Knowledge of a genetic predisposition to inflammatory TRC might aid
pretransplant assessment and counselling. TNFd genotyping may
facilitate targeting of experimental TNF- antagonists, such as
anti-TNF- antibodies13 or
soluble-TNF-receptors,7 toward recipients with the
high-risk TNFd3/d3 genotype. Alternatively, recipients might benefit
from alteration in conditioning; however, as only 6 patients differed
from the routinely used TBI dose, it is not possible to determine if
the association of TNFd3d3 with TRC was dependent on the conditioning regimen.
Recipients possessing IL-101064alleles with greater
(CA)n repeat numbers had more severe aGVHD, in agreement with previous
findings in recipients given CyA alone.20 The associations
of TNFd and IL-101064 genotype with grade III to IV
aGVHD demonstrated in the CyA monotherapy BMT cohort could be combined
to show cumulative risk of severe GVHD.20 However, in the
current study, TNFd3 homozygosity was associated with fatal early TRC
and hence assessment of TNFd3d3 in conjunction with
IL-101064 genotype in relation to aGVHD was not
possible. No association of either of the IL-10 polymorphisms tested
with GVHD was found in donors.
Linkage of the IL-10 polymorphisms examined to neighboring genes is
unlikely to account for the observed relationship, as no other genes
currently implicated in GVHD map to chromosome 1q. In normal subjects,
the IL-101082 polymorphism A allele associates with
lower in vitro IL-10 production by concanavalin A-stimulated
lymphocytes.31 IL-10 haplotyping (Table 2) indicates that
longer IL-101064 alleles associate preferentially
with the IL-101082 A allele. Similar alleleic
linkage has been observed in other populations (P.G.M., unpublished
observation, February 1999). Hence, longer IL-101064
alleles may associate with lower in vitro lymphocyte IL-10 release. However, the IL-101064 allele 14 is reported to
associate with higher in vitro IL-10 release from
lipopolysaccharide-stimulated whole blood.29 Differences in
composition of cell population and stimulating mitogens make extrapolation from such in vitro to in vivo data difficult.
cGVHD did not associate with either IL-10 polymorphism, despite cGVHD
usually occuring after preceeding aGVHD.37 Although cGVHD
has been linked to reduced IL-10,27
IL-101064/1082 genotype is not
informative with respect to cGVHD in this study.
Pretransplant IL-101064 genotyping may allow more
individually tailored prophylaxis, with increased immunosuppression
administered only to patients with high aGVHD risk-associated
genotypes. Typing recipients may aid decisions regarding those who
could benefit most from experimental antiinflammatory cytokines such as
recombinant IL-10.38 Reduced prophylaxis for recipients
with low aGVHD risk-associated genotypes transplanted for malignancy
might permit enhanced GvL effect, hence reducing risk of
relapse without adding to aGVHD morbidity and mortality.
A combination of established GVHD risk factors in HLA-matched siblings,
such as skin explant analysis,39 minor histocompatibility antigen incompatibility,40 and herpes/cytomegalovirus
status,1 with genotyping for TNF and IL-10 polymorphisms
(and other potential genotypic risk factors) could allow the creation
of a GVHD risk index. Such an index would facilitate accurate
individual risk calculation, permitting adjustment of prophylaxis
accordingly. Although IL-10 genotype's influence on aGVHD has been
demonstrated in cohorts given differing prophylaxis, further studies of
both TNF and IL-10 polymorphisms' role in modulating GVHD will be
important in building such a risk index, together with investigation of other candidate immunogenetic polymorphisms.
Our findings support the hypothesis that recipient response during BMT
conditioning is critical in subsequent outcome and that this involves a
substantial genetic component. Recipient cytokine genotype could be
used to guide more appropriate GVHD prophylaxis, both established and
experimental, particularly in combination with other risk factors.
| |
ACKNOWLEDGMENT |
We acknowledge Gretchen Radloff (Department of Bone Marrow
Transplantation, Minneapolis, MN) for assistance with samples and clinical data and Jane Worthington (School of Biological Sciences, University of Manchester) for the IL-10 JW-F primer.
| |
FOOTNOTES |
Submitted April 6, 1999; accepted July 20, 1999.
Supported by grants from the Leukaemia Research Fund (to J.C.) and the
Tyneside Leukaemia Research Association (to A.M.D.).
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 James Cavet, MBBS, MRCP, Department of
Haematology, Royal Victoria Infirmary, Victoria Rd, Newcastle Upon
Tyne, NE1 4LP, UK.
| |
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INTRODUCTION