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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2169-2176
Evidence That CD31, CD49b, and CD62L Are Immunodominant Minor
Histocompatibility Antigens in HLA Identical Sibling Bone Marrow
Transplants
By
Etsuko Maruya,
Hiroh Saji,
Shigeki Seki,
Yasuhiko Fujii,
Koji Kato,
Syunro Kai,
Akira Hiraoka,
Keisei Kawa,
Yasutaka Hoshi,
Kazuhiko Ito,
Shigeki Yokoyama, and
Takeo Juji
From the Department of Research, Kyoto Red Cross Blood Center, Kyoto,
Japan; the Department of Internal Medicine, Saku Central Hospital,
Nagano, Japan; the Department of Transfusion Medicine, Yamaguchi
University Hospital, Yamaguchi, Japan; the Division of
Hematology/Oncology, Japanese Red Cross Nagoya First Hospital, Nagoya,
Japan; the Department of Transfusion Medicine, Hyogo Medical College,
Nishinomiya, Japan; the Department of Internal Medicine, Osaka Medical
Center for Cancer and Cardiovascular Disease, Osaka, Japan; the
Department of Pediatrics, Osaka Medical Center and Research Institute
for Maternal and Child Health, Osaka, Japan; the Department of
Transfusion Medicine, Tokyo Jikei University School of Medicine, Tokyo,
Japan; the Department of Transfusion Medicine, Kyoto University
Hospital, Kyoto, Japan; and the Japanese Red Cross Central Blood
Center, Tokyo, Japan.
 |
ABSTRACT |
Despite complete matching of siblings for the HLA loci, after bone
marrow transplantation (BMT), approximately 20% develop graft-versus-host disease (GVHD). This is presumably due to
incompatibility of minor histocompatibility antigens (mHa). We
investigated the polymorphisms of 14 adhesion molecules (CD2, CD28,
CD31, CD34, CD36, CD42, CD44, CD48, CD49b, CD54, CD62L, CD86, CD102,
and CD106) in Japanese subjects and their association with the
occurrence of GVHD after allogeneic HLA identical BMT. Six molecules
(CD2, CD31, CD42, CD49b, CD54, and CD62L), which were found to be
polymorphic, were then examined in 118 HLA identical sibling donors and
recipients who had undergone BMT. Association of the incompatibility of
the polymorphic molecules with the presence or absence of GVHD was examined. In these six, we observed a significant correlation between
acute GVHD and the compatibility of CD31 (codons 563/670) (Pcorrected = .018), and CD31 (codons 563/670) + CD62L (Pcorrected = .018) in patients with
the HLA-B44-like superfamily. In patients with the HLA-A3-like
superfamily, the compatibility of CD62L (Pcorrected = .03) and CD62L + CD49b (P = .004, Pcorrected = .078) was associated with acute
GVHD. Therefore, CD31, CD49b, and CD62L might be candidates for
immunodominant mHa.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
ACUTE GRAFT-VERSUS-HOST disease (GVHD) is
a major cause of morbidity and mortality after bone marrow
transplantation (BMT).1 Incompatibility of the major
histocompatibility complex (MHC) is a primary cause of GVHD. Most
recipients of marrow from HLA-mismatched donors develop
GVHD.2,3
Even if the bone marrow (BM) donor and recipient have identical MHC
antigens, the two major complications of allogeneic BMT, GVHD and
leukemia relapse, may still occur. GVHD occurs in 10% to 35% of HLA
genotypically identical BMT pairs.4-6 T-cell depletion of
BM graft to prevent GVHD is associated with an increased risk of
leukemia relapse, and GVHD itself is associated with the decrease of
leukemia relapse after BMT. Donor-derived T lymphocytes that cause GVHD
may also be effectors of GVL reactivity.7-11
In HLA-genotypically identical BMT, antihost alloreactive donor T cells
are, by definition, directed against minor histocompatibility antigens
(mHa) presented by the host.12-14 These antigens are
recognized in the context of molecules encoded by the
MHC.15-17 Snell et al18,19 were the first to
observe transplantation antigens that were identified as mHas. Goulmy
et al12,20 have identified certain types of mHas, such as
the male-specific mHa (H-Y), and non-Y-linked mHas (HA-1 to HA-5), by
isolating cytotoxic T-cell clones from lymphocyte populations in the
blood of patients with severe GVHD. HA-1, -2, -4, and -5 are found only
in individuals expressing HLA-A2, whereas HA-3 is restricted to
HLA-A1.21 The nine amino acid peptide corresponding to HA-2
appears to be derived from a nonfilamentous class I myosin
protein.22 Goulmy et al21 observed a
significant relationship between GVHD and recipient/donor mismatch at
HA-1 alone or at HA-1 plus one or more mismatches of HA-2, -4, and -5. They referred to clinically significant mHa as "major" mHa.
Behar et al23 reported an association between GVHD and
mismatch at an amino acid polymorphism (leucine or valine at codon 125)
within the adhesion molecule CD31 or platelet endothelial cell adhesion
molecule-1 (PECAM-1).23 Sixty-seven percent of the
recipients who had received a transplant from HLA-identical sibling
donors with CD31 genotypes that were incompatible to the donor's
genotype developed GVHD, as compared with 22% of the recipients with
compatible CD31 genotypes (P = .03). However, Nichols et al24 recently reported no significant association between
CD31 (codon 125) mismatch and the development of severe GVHD in 301 patients who received BMT from HLA identical siblings.
We screened polymorphisms in adhesion molecules that are expressed as
the sites of main injury in acute GVHD, such as vascular endothelial
cells, skin, liver and lymphoid organs, and blood cells. We then
examined the relationship between the compatibility of adhesion
molecules and the development of acute GVHD in the case of BMT between
HLA-identical siblings. We detected amino acid diversities in seven of
14 adhesion molecules: CD2 (lymphocyte function-associated antigen-2
[LFA-2], CD31 (PECAM-1), CD42 (glycoprotein [GP] Ib),
CD49b (GPIa), CD54 (intracellular adhesion molecule [ICAM]-1), CD62L (leukocyte endothelial adhesion
molecule-1 [LECAM-1]), and CD102 (ICAM-2). In
particular, CD31 exhibited amino acid diversities not only in exon 3 at
codon 125, but also at codon 80, in exon 8 and 12 at codon 563 and 670. We analyzed the association between acute GVHD and incompatibility of
adhesion molecules.
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MATERIALS AND METHODS |
DNAs.
Forty-eight genomic DNAs were selected at random for the first
screening of polymorphisms in adhesion molecules. A total of 209 genomic DNAs from unrelated healthy Japanese panels were used for
detecting gene frequencies of polymorphisms in the adhesion molecules.
Twenty-eight families (112 haploides) were used to determine CD31
alleles. DNAs of 118 BMT recipients and their genotypically HLA
identical sibling donors were used to analyze the association between
compatibility of adhesion molecules and acute GVHD. Patients' blood
was collected before transplantation.
Patients.
We studied 118 recipients of BM and their HLA identical sibling donors.
The recipients were patients at Saku Central Hospital (Nagano),
Japanese Red Cross Nagoya First Hospital (Nagoya), Hyogo College of
Medicine Hospital (Nishinomiya), Yamaguchi University Hospital
(Yamaguchi), Osaka Medical Center Hospital for Cancer and
Cardiovascular Disease (Osaka), Osaka Medical Center and Research Institute for Maternal and Child Health (Osaka), Tokyo Jikei University Hospital (Tokyo), Kyoto City Hospital (Kyoto), Kyoto Prefectural Medical College Hospital (Kyoto), Kyoto University Hospital (Kyoto) and
Tohoku University Hospital (Sendai). The group comprised 61 pairs of
adults and 57 pairs of children under age 16. The recipients had
undergone BMT between 1993 and 1997 for acute lymphocytic leukemia,
acute myelocytic leukemia, chronic myelocytic leukemia, non-Hodgkin's
lymphoma, or aplastic anemia. None of the recipients had received BM
depleted of T cells. As prophylaxis against GVHD, they had received
methotrexate (one patient), cyclosporine (one patient), or both (116 patients). GVHD had been diagnosed and graded as a consensus of the
opinions of the attending transplant physicians according to previously
published standard clinical criteria.25,26
The screening of adhesion molecule polymorphisms.
Exon-specific amplifications of targeted adhesion molecules were
performed using exon specific primers. Twelve DNA mixtures mixed with
four genomic DNAs (48 DNAs in all) were amplified using polymerase
chain reaction (PCR) with 1.25 U of Taq DNA polymerase. The reaction
mixture (50 µL) contained 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl,
1.5 mmol/L MgCl2, 0.2 mmol/L dNTP, and 20 pmol/L of each amplification primer. First, the reaction mixture was
denatured at 95°C for 5 minutes, followed by 35 cycles of denaturation at 95°C for 1 minute, annealing at 59°C for 1 minute, and a final incubation at 72°C for an additional 5 minutes
to complete the final extension step after the last cycle, using an
automated PCR thermal sequencer (Gene Amp PCR system 9600; PE Applied
Biosystems, Foster City, CA). PCR products were analyzed using low
sonic strength-single-stranded conformation polymorphism (LIS-SSCP),
which has been described.27 Briefly, 1 µL of PCR product
was added to 20 µL of low ionic strength (LIS) solution (10%
saccharose, 0.01% bromophenol blue, and 0.01% xylene cyanol FF). The
mixture was denatured at 97°C for 2 minutes, and 4 to 10 µL of
the mixture was applied to 10% polyacrylamide gel on a mini gel
electrophoresis apparatus with a constant temperature control system.
Electrophoresis proceeded in a buffer of 45 mmol/L Tris-borate
(pH8.0)/1 mmol/L EDTA at 15 mA for 1.5 to 2.5 hours. To evaluate the
optimal electrophoresis conditions, we performed electrophoresis under
four different conditions by varying the running temperature between
22°C and 4°C and adding or not adding 10% glycerol to the
polyacrylamide gel. The SSCP profiles in the gel were detected using
silver staining. For the second screening, the PCR amplified fragments
whose nucleotide mutations had been detected using LIS-SSCP were
sequenced using the cycle-sequencing method with an automated DNA
sequencer (Type 373A; PE Applied Biosystems). Both strands were
sequenced. Nonsynonymous amino acid substitutions were selected using
translation from nucleotide sequences to amino acid sequences with the
DNASIS program (Hitachi Software Engineering Co, Ltd, Tokyo,
Japan). To confirm mutated nucleotide sequences, PCR
products that exhibited amino acid polymorphism were digested
independently with each restriction enzyme. For the third screening, a
population study of mutated amino acids was performed using 209 randomly selected DNAs. The 28 family studies were performed to
determine the combination of mutated codons in CD31. The association
between the compatibility of adhesion molecule and acute GVHD was
analyzed in 118 patients who had received BM from HLA-identical
siblings.
Statistical analysis.
The direct count method was used for allele frequency and linkage
disequilibrium of polymorphic sites of CD31. The significance of
differences between groups in Table 3 was calculated using Fisher's
exact test with the aid of JMP software (SAS Institute Inc, Cary,
NC). When multiple comparisons are found to be
significant, associations may arise by chance. To avoid such errors
P values were corrected with the number of characters compared
(three for HLA-superfamily of A and B loci, two for CD31 of codon 125 and codons 563/670, six for combination analysis of two adhesion
molecules). If the P value reached values of less than .05, then they were corrected for the total number of tests performed using
the formula: Pcorrected = 1  (1 p)n, where p is the original P value and n
is the number of tests performed. Odds ratios were computed using
standard methods.28
| |
RESULTS |
We screened for polymorphisms within the coding regions of human
adhesion molecules that were mainly expressed on target tissues of GVHD
or blood cells. Of 14 screened adhesion molecules, we observed amino
acid mutations in seven: CD2 (LFA-2), CD31 (PECAM-1), CD42 (GPIb),
CD49b (GPIa), CD54 (ICAM-1), CD62L (LECAM-1), and CD102 (ICAM-2). Amino
acid mutations and their gene frequencies are shown in
Table 1. CD31 is the most polymorphic
adhesion molecule in the seven, in which we detected amino acid
polymorphisms. CD31 had four amino acid mutations. These mutations were
located in exon 3 at codon 80 (Val  Met), in exon 3 at codon
125 (Val Leu), in exon 8 at codon 563 (Asn Ser),
and in exon 12 at codon 670 (Gly Arg). All mutations were
detected for the first time in this study, except for the mutation in
exon 3 at codon 125, which has been reported by Behar et
al.23 We performed 28 family studies to determine the
substituted amino acids in each codon on the same haploid of CD31. We
defined five CD31 alleles based on four amino acid mutations. The
allele frequencies of CD31 in the Japanese population based on the data
from 112 haploides are shown in Table 2.
Mutation at codon 80 from valine to methionine was rare. We could
detect this mutation in 209 randomly selected DNAs, but not in 28 families (113 DNAs). When the amino acid at codon 563 was serine
(asparagine), the amino acid of codon 670 was always arginine
(glycine). They were linked completely. The amino acid at codon 125, valine, showed a strong linkage disequilibrium with asparagine at codon
563, but did not show complete linkage. Their nucleotide sequences are
shown in Fig 1.
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| Fig 1.
Nucleotide sequence variations of CD31 alleles (A-E). The
dashes indicate identity with PECAM-B/C or B/D/E. The alleles (A-E)
were tentatively named in the present study (see Table 2). Only those
alleles observed have been illustrated here.
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We analyzed the relationship between the compatibility of adhesion
molecules that exhibited amino acid polymorphism in the coding region,
except CD102, which showed a low mutation rate (0.5%), and acute GVHD
in 118 HLA-identical sibling transplants with respect to HLA
restriction. The mutations of CD31 at codons 563 and 670 showed
complete linkage, and thus were referred to as codons 563/670. The
mutated codons 125 and 563/670 of CD31 were analyzed separately, as
these showed incomplete linkage. We divided HLA antigens of patients
into groups of superfamilies based on similarities of their
peptide-binding motifs,29 such as HLA-A2-like, A3-like,
and other for HLA-A locus antigens, and HLA-B7-like, B44-like, and
other for the HLA-B locus. Patients without GVHD were compared with
acute GVHD (grade 1 or above). We found that BMT pairs in the
HLA-A3-like superfamily (HLA-A3, A11, A31, A33, and A*6801) showed a
100% occurrence of acute GVHD in CD49b and CD62L incompatible
recipients, but showed 50% and 45% in compatible recipients,
respectively. The association between the compatibility of CD62L and
acute GVHD was statistically significant (P = .01, Pcorrected = .03) and odds ratio was 18.2. Even if
CD49b showed a high odds ratio (7.0), there was no statistically
significant correlation between incompatibility and acute GVHD
(Table 3). CD49b (VLA-2, GPIa) is expressed
mainly on platelets, monocytes, and endothelial cells, and amino acid
substitutions were detected at codon 505, glutamic acid (gene frequency = 0.97) versus lysine (gene frequency = 0.03). This polymorphism is
known as HPA-5.30 CD62L (LECAM-1) is expressed mainly by
neutrophils, monocytes, natural killer (NK) cells, and
subpopulations of B and T lymphocytes, and amino acid substitutions
were detected at codon 213, proline (gene frequency = 0.8) versus
serine (gene frequency = 0.2).
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Table 3.
Association Between Compatibility of Adhesion Molecules
and Acute GVHD in BMT of HLA-Identical Siblings and Their
Restriction to HLA Superfamilies
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We analyzed the association between the compatibility of combination
for adhesion molecules and acute GVHD in the HLA-A3-like superfamily.
The definition of compatibility is as follows. It was found in the case
of combination of CD49b and CD62L. In incompatible pairs, ie, pairs (n = 8) in which any CD49b or CD62L alleles found in the recipient were
not repeated in the donor, GVHD occurred at a rate of 100%. On the
other hand, in compatible pairs, ie, pairs (n = 39) in which the
recipient had no CD49b and CD62L alleles that were foreign to those of
the donor, GVHD occurred at a rate of 44%. The association between the
compatibility of CD62L + CD49b and acute GVHD showed a significant
P value (P = .004), but after correcting, it was not
statistically significant (Pcorrected = .07),
however the odds ratio was the highest (21.8) in the present test
(Table 4). We did not find other
significant correlations in the HLA-A3-like superfamily.
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Table 4.
Significant Association Between Compatibility of
Adhesion Molecules and Acute GVHD in BMT of HLA-Identical Siblings
and Their Restriction to HLA Superfamilies
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We found the correlation between the compatibility of codons 563/670
amino acid polymorphism of CD31 with acute GVHD in patients in the
HLA-B44-like superfamily (HLA-B37, B41, B44, B45, B47, B49, B50, B60,
and B61). The occurrence of acute GVHD in incompatible pairs (n = 16)
was 88%, and in compatible pairs (n = 41), it was 44%. This
difference between two groups based on compatibility was statistically
significant (Pcorrected = .018, Table 4). However, the compatibility of exon 3 at codon 125 for acute GVHD was not statistically significant (Table 3). CD31 (PECAM-1) is expressed mainly
on vascular endothelial cells, myeloid cells, platelets, and certain
lymphocyte subsets.31,32 Moreover, we found the occurrence
of acute GVHD in CD62L incompatible patients was much higher than in
compatible patients, but it was not statistically significant
(P = .27).
We performed the combination analysis of two adhesion molecules and
acute GVHD in the HLA-B44-like superfamily. The compatibility was
defined the same way as in the case of CD49b + CD62L. The association
between the compatibility of CD31 codons 563/670 + CD62L and acute GVHD
was significant (P = .001, Pcorrected = .018, Table 4). GVHD occurred in incompatible pairs (n = 23) at a rate of 83% and in compatible pairs (n = 34) at a rate of 38%. We found no
statistically significant association with other combinations.
| |
DISCUSSION |
In this study, we screened each exon of 14 adhesion molecules using the
LIS-SSCP method, and we found amino acid polymorphism within seven of
them: CD2 (LFA-2), CD31 (PECAM-1), CD42 (GPIb), CD49b (GPIa), CD54
(ICAM-1), CD62L (LECAM-1), and CD102 (ICAM-2). The most polymorphic
adhesion molecule was CD31, in which we detected four amino acid
substitutions, which lead to five alleles, located at codons 80, 125, 563, and 670. The other adhesion molecules showed only one amino acid
substitution in each of the coding regions.
We postulated that polymorphisms of adhesion molecules on target
tissues or blood cells might be related to the occurrence of GVHD
and/or GVL, and candidates of mHa. We analyzed the association between the compatibility of these adhesion molecules and acute GVHD in
the context of HLA restriction. The effect of incompatibility of mHas
on the development of GVHD is best studied in pairs of siblings who are
genotypically HLA identical. In such pairs, the effect of the disparity
would not be diminished by unknown mismatches of major
histocompatibility antigens. Siblings discordant for mHas are possible
only in families in which both parents are heterozygotes or one parent
is heterozygous and the other homozygous for the mHa
allele.33 An incompatible pair for development of GVHD is one in which the donor is homozygous and the recipient is heterozygous or homozygous for the mHa allele, but not identical with the donor. An
mHa is of clinical interest only if it is immunogenic and has a
somewhat frequent distribution in the population.
In this study, we wanted to identify candidates for mHa. Therefore, we
used grade  1 acute GVHD as the positive biologic
reaction in humans. We observed significant correlation between the
compatibility of CD62L and acute GVHD in patients in the HLA-A3-like
superfamily (HLA-A3, A11, A31, A33, and A*6801) and between acute GVHD
and the compatibility of CD31 codons 563/670, and CD31 codons 563/670 + CD62L in patients in the HLA-B44-like superfamily (HLA-B37, B41, B44,
B45, B47, B49, B50, B60, and B61). The association between the
compatibility of CD62L + CD49b and acute GVHD in the HLA-A3-like superfamily was not significant (P = .004, Pcorrected = .07) because of the small number of
incompatible pairs, however odds ratio was the highest (21.8).
Therefore, CD49b might be a candidate for an immunodominant mHa.
For more relevant clinical correlation, we should use grade 2 acute
GVHD. However, the aim in our study was the identification of
candidates for immunodominant mHa and not actual clinical predictions. It is necessary to accumulate samples with more detailed clinical information in order to evaluate clinical applications for BMT.
We analyzed the association between the compatibility of adhesion
molecule and acute GVHD in adults and children separately, and the
results showed the same tendency as the total results (data not shown).
We also analyzed the correlation between survival and compatibility of
adhesion molecules. In the patients with the HLA-A3-like superfamily,
incompatible pairs of CD49b (100%) and CD62L (86%) had slightly
higher survival rates than compatible pairs (75% and 75%,
respectively). In the patients with the HLA-B44-like superfamily,
incompatible pairs of CD31 codons 563/670 (69%) and CD62L (66%) had
slightly lower survival rates than compatible pairs (78% and 77%,
respectively). The differences between the two groups were not
statistically significant in either case.
There are two contradictory reports23,24 about the
association between the compatibility of CD31 at codon 125 (Val/Leu) and acute GVHD. Behar et al23 reported that CD31
polymorphism is a risk factor for acute GVHD, and Nichols et
al24 reported that compatibility of CD31 polymorphism is
not associated with the occurrence of acute GVHD. Our results supported
the results of Nichols et al. However, Nichols et al observed the
effect of CD31 polymorphism at codon 125 only. Our data showed that
CD31 is more polymorphic, and that polymorphism at codons 563/670 is a
risk factor of acute GVHD in the HLA-B44-like superfamily of antigens.
Amino acid mutation of codon 125 is incompletely linked to codons
563/670. The findings of Behar et al might be the result of linkage
disequilibrium between codon 125 and codons 563/670. We
could not find a statistically significant correlation between the
compatibility of amino acids at codons 563/670 and acute GVHD without
HLA restriction. However, in this situation, our data suggested a
tendency toward increased risk of GVHD in the recipients of BM from
donors whose amino acids were incompatible.
Cytotoxic T lymphocytes (CTLs) that are specific for recipient mHa
trigger GVHD after BMT from donors who are genotypically HLA-identical.34 CTLs react in a classical MHC-restricted
fashion.35 Sidney et al29,36-38 grouped HLA
class I alleles into superfamilies based on similarities of their
peptide-binding motifs. The capacity of a peptide to bind multiple MHC
molecules and, consequently, to be immunogenic in the context of
individuals from different MHC types has been referred to as degeneracy
at the MHC or T-cell level. Recognition of cells that present the same
peptide in the context of different MHC molecules has been termed
promiscuous recognition. This phenomenon has been described with CTL
lines specific for melanoma-associated antigens within the A2-like
superfamily39 and for human immunodeficiency virus
(HIV)-1-specific peptide within the A3-like superfamily.40
These data validated the concept of HLA class I superfamilies. In this
study, the HLA restriction of mHas was mainly analyzed using HLA class
I superfamilies. Our data suggested that CD31 and CD62L, which were the
candidates for immunodominant mHa based on the occurrence of acute GVHD
in BMT of HLA-identical siblings, were restricted to the HLA-B44-like superfamily, and CD49b and CD62L were restricted to the HLA-A3-like superfamily.
We searched for putative peptides that were included in the polymorphic
sites and were derived from these adhesion molecules (CD49b, CD31, and
CD62L). Table 5 shows the supermotifs of
HLA superfamilies and the putative peptides derived from these adhesion molecules. The amino acid polymorphisms within B pocket (which is
normally occupied by the side-chain of the position 2 residue of bound
peptides) and F pocket (which is normally occupied by the C-terminal
residue of bound peptides) of the HLA class I binding groove were
shared between HLA antigens of the same superfamily. The putative
peptide from CD49b fit into the A3-like supermotif of bound peptides
carrying somewhat hydrophobic residues at position 2 and positively
charged residues in the C-terminal. Interestingly, the polymorphic
amino acid of CD49b is the C-terminal residue. In CD31, the putative
peptide that fit into the B44-like supermotif was found in exon 12, which is the cytoplasmic domain. In CD62L, the putative peptide that
fit into the B44-like supermotif was also found. However, we could not
define the putative peptide that fit into the A3-like supermotif of
CD62L, even though the correlation between CD62L and acute GVHD in the
HLA-A3-like superfamily was shown. This might be due to the presence
of amino acid polymorphism in a position that could not be detected by
our method and had complete linkage to the polymorphism of CD62L at
codon 213.
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Table 5.
HLA Supermotifs and Putative Peptides of Adhesion
Molecules Which Are the Candidate of Immunodominant mHa
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In conclusion, our data demonstrate that amino acid polymorphism of
adhesion molecules occurred frequently, in seven of 14 adhesion
molecules. An association between compatibility of CD31 (codons
563/670), CD49b, and CD62L and acute GVHD in HLA-identical BMT in
different HLA superfamilies was observed. Our results suggest that CD31
(codons 563/670), CD49b, and CD62L might be candidates for
immunodominant mHa. Further studies are needed to confirm our results,
such as the establishment of mHa-specific CTL clones in multiple
members of a single HLA superfamily, and the extraction of mHa peptides
from their restricted HLA molecules.
| |
FOOTNOTES |
Submitted November 24, 1997;
accepted May 5, 1998.
Address reprint requests to Etsuko Maruya, BS, 644 Sanjusangendo Mawarimachi, Higashiyamaku, Kyoto 605, Japan; e-mail:
maruya{at}mbox.kyoto-inet.or.jp or emaruya{at}hla.cbc.jrc.or.jp.
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 |
We thank Dr P.I. Terasaki (UCLA, Los Angeles, CA) and Dr
K. Tokunaga (Tokyo University, Tokyo, Japan) for giving us useful discussion and suggestions, Dr H. Hiraga (Saku Central Hospital), Dr A. Sasada (Kyoto University, Kyoto), Dr M. Ohotake (Sendai City Hospital,
Sendai), Dr Y. Wakazono (Kyoto Katsura Hospital, Kyoto), Dr T. Sakurai
(Ishimaki Red Cross Hospital), Dr T. Shishido (Ishimaki Red Cross
Hospital), Dr M. Iga (Shimane University, Shimane), Dr Y. Takahashi
(Kyoto Prefectural Medical College Hospital, Kyoto), Dr H. Ohno (Kyoto
University, Kyoto), Dr M. Itoh (Kyoto University, Kyoto), Dr K. Nishikawa (Tottori University Hospital, Tottori), Dr K. Tubaki (Kinki
University, Osaka), Dr T. Nakao, Dr T. Egawa, Dr T. Torino (Osaka
Medical Center Hospital for Cancer and Cardiovascular Disease, Osaka),
Dr M. Naya, Dr M. Houjou, Dr H. Kajimoto (Kyoto City Hospital, Kyoto),
Dr A. Miura (National Sendai Hospital, Sendai), Dr M. Minegishi (Tohoku
University, Sendai), Dr Y. Akiyama (Kyoto University, Kyoto), Dr H. Nakagawa (Kyoto Red Cross First Hospital, Kyoto), and Dr I. Kawamura
(Kurashiki Central Hospital, Kurashiki) for providing the patient
samples.
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Abstract
Introduction
Abstract