|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4864-4871
Molecular Typing Shows a High Level of HLA Class I
Incompatibility in Serologically Well Matched Donor/Patient Pairs:
Implications for Unrelated Bone Marrow Donor Selection
By
Iain Scott,
John O'Shea,
Mike Bunce,
Jean-Marie Tiercy,
J. Rafael Argüello,
Helen Firman,
John Goldman,
H. Grant Prentice,
Ann-Margaret Little, and
J. Alejandro Madrigal
From the Anthony Nolan Research Institute and the Department of
Haematology, The Royal Free Hospital, London, UK; the Department of
Haematology, Imperial College School of Medicine, London, UK; The
Nuffield Department of Surgery, Oxford Transplant Centre, Churchill
Hospital, Oxford, UK; and the Transplantation Immunology Unit, Hopital
Cantonal Universitaire, Geneva, Switzerland.
 |
ABSTRACT |
In comparison with HLA-matched sibling bone marrow transplants,
unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due
to HLA incompatibilities not identified by current matching strategies.
High resolution DNA-based typing methods for HLA class II loci have
improved donor selection and treatment outcome in unrelated donor bone
marrow transplantation. By using DNA-based typing methods for HLA-A and
-B on a cohort of 100 potential bone marrow donor/patient pairs, we
find that serological typing for HLA class I is limited in its ability
to identify incompatibilities in unrelated pairs. Furthermore, the
incompatibilities identified are associated with the presence at high
frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing
also indicates that HLA-C mismatches are common in HLA-A and -B
serologically matched pairs. Such mismatches appear to be significantly
less immunogenic with respect to cytotoxic T-lymphocyte recognition,
but are expected to influence natural killer cell activity. Thus,
improved resolution of HLA class I shows many previously undisclosed
mismatches that appear to be immunologically functional. Use of high
resolution typing methods in routine matching is expected to improve
unrelated donor selection and transplant outcome.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
ALLOGENEIC BONE MARROW transplantation
(BMT) involves a unique immunological assault on the recipient. HLA
differences between individuals can lead to the expansion of high
frequency alloreactive T cells, often leading to severe
graft-versus-host disease (GVHD) in the allogeneic BMT
setting.1 An HLA genotypically identical sibling is
therefore the donor of choice. However, because such a donor is
available to only about 30% of patients, alternative donors, such as
partially HLA-matched related and phenotypically HLA matched unrelated
donors, are increasingly used. Although single HLA differences may be
tolerated in related donor transplants, especially in younger
recipients,2 such donors are rare, and increased disparity
is associated with greatly reduced transplant success.3
Consequently, HLA-matched unrelated donor transplants are often used in
the treatment of a range of hematological disorders.
HLA matching is complex involving at least three highly polymorphic
loci, HLA-A, -B, and -DRB1, encoding more than 400 alleles.4 In siblings, this complexity is reduced, because
matching simply involves distinguishing the inherited from noninherited
haplotypes. However, unrelated donor/patient pairs must be matched for
each antigen and/or allele and, due to the extensive
polymorphism of the HLA system, the chance of unrelated individuals
being HLA identical is remote.5 It is only with the
establishment of large international registers of HLA-typed individuals
(currently >4.6 million potential donors have been recruited
worldwide) that identification of a suitable unrelated donor is
practical. Compared with HLA genotypically identical sibling
transplants, HLA phenotypically matched unrelated donor transplants are
commonly associated with increased risk of GVHD
posttransplant6 and failure to engraft. It is likely that
the increase in such posttransplant complications is at least in part
due to the presence of HLA alloantigens not discriminated in the
current matching procedure.
HLA typing for DRB1 and DQB1 is now performed using DNA-based methods
allowing the routine identification of most Caucasoid alleles. However,
until recently, matching for HLA-A and -B has been dependent on
serological techniques. Serological resolution was thought to be
adequate, because, in contrast to the typing of HLA-DR and -DQ
serology, serological typing for HLA-A and -B identifies a greater
number of antigens and a high level of heterozygosity at each locus.
Despite this, there are limitations in the use of HLA class I
serological data for matching, as cellular,7 biochemical,8 and sequencing strategies show.9
Although the importance of such differences in BMT remains to be fully defined, case studies have implicated alloresponses due to a single amino acid difference in HLA-B44 subtypes in both graft
rejection10 and GVHD.11
Although matching at HLA-A and -B loci is known to be important, the
impact of HLA-C on transplantation is unclear. HLA-C is the third
classical class I locus to be described, but, due to its low level of
cell surface expression and reduced polymorphism, has been considered
as less immunologically relevant.12 However, HLA-C-restricted virus-specific,13
tumor-specific,14 and allospecific cytotoxic T lymphocytes
(CTLs)15 are found, indicating that HLA-C has a role to
play in a range of T-cell immune responses.
Interest in HLA-C and transplantation has been stimulated by recent
exposition of its role in modulating natural killer (NK) cell activity.
Interaction of self-MHC with receptors on a subset of NK cells is
crucial for the protection from NK cell-mediated lysis.16
In humans, this interaction has been mapped to a dimorphic epitope at
residues 77 and 80 on the  1 domain of HLA-C, each epitope
interacting with a distinct killer inhibitory receptor (KIR).17 Those cells expressing HLA-C molecules with a
motif shared with HLA-Cw*0303 (Ser77/Asn 80) are protected from lysis by NK clones expressing KIR2DL2/3, whereas expression of a motif shared
with HLA-Cw*0401 (Asn77/Lys80) inhibits lysis by NK clones expressing
KIR2DL1.18 Alloreactive NK cells can be generated against
stimulators expressing the opposite motif to that of the responder.19 The implications for BMT may be seen in mouse
experiments in which NK cells of an irradiated F1 hybrid are able to
reject parental bone marrow20 that lacks expression of
self-MHC class I molecules.21 Recent reports suggest
increased likelihood of graft failure in HLA-C-mismatched
BMT,22,23 which may be analogous to the mouse hybrid
resistance model.
The frequency of such serologically undetected mismatches and their
impact on transplantation have yet to be fully assessed. In a previous
report, we described that high CTL precursor (CTLp) frequencies were
common in HLA-A, -B serologically and biochemically matched unrelated
pairs, suggesting that undetected mismatches are common.24
We have applied high resolution HLA class I typing techniques to study
the true level of HLA compatibility in conventionally matched unrelated
patient/donor pairs. Comparison of CTLp frequencies and DNA typing
information may allow the assessment of the functional significance of
such mismatches in allorecognition.
| |
MATERIALS AND METHODS |
Patients and donors.
Seventy-six patients and 100 potential unrelated bone marrow donors
were included in this study. Donors were selected as the best available
matches for patients on the basis of matching for HLA-A and -B by
serology and DRB1 identity by DNA-based typing. All patient/potential
donor pairs were also analyzed for alloreactive CTLp frequency in the
graft-versus-host direction.
Initial HLA typing for donor selection.
HLA-A and -B typing was performed by the standard complement-dependent
microcytotoxicity test, using a combination of local and commercial
(Biotest, Germany) serological typing trays. HLA-DR and -DQ types were
assigned initially using commercial serological typing trays (Biotest).
DNA from 97 of 100 pairs was then typed by a combination of polymerase
chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) and
polymerase chain reaction-sequence-specific primers
(PCR-SSP) for DRB1 and similarly 95 of 100 for DQB1, as previously described.25 Where fully HLA compatible
unrelated donors were not found on international volunteer registers,
donors with minor HLA mismatches were considered. Minor mismatches were defined as either an HLA-A or -B subtype of a serologically related group as defined by the World Health Organization (WHO) nomenclature committee or mismatched at the molecular level for serologically defined HLA-DR1-14 specificities. Three pairs were serologically mismatched for HLA-A and 9 pairs for HLA-B, and 14 pairs were originally mismatched at the molecular level for HLA-DRB1. In total,
mismatches were detected between 23 pairs at HLA-A, -B, and/or
-DRB1.
Limiting dilution analysis.
Limiting dilution analysis was performed in the graft-versus-host
direction as described by Kaminski et al26 to determine the
frequency of patient-specific donor CTL precursors. A high CTLp
frequency was taken to be greater than 1:105 peripheral
blood mononuclear cells (PBMCs), because this correlates with poor transplant outcome.27 Low CTLp frequency was
taken as being between 1:105 and 5:106, with
CTLp frequencies less than this being regarded as negative.
DNA typing for HLA-A, -B, and -C.
To identify the presence of serologically undetected incompatibilities,
a combination of DNA-based typing methods were used. HLA-A and -B were
typed by previously described PCR-SSOP methods28,29 to
confirm serotypes. Locus-specific oligotyping enabled the subtyping of
most common HLA-A and -B serotypes to varying levels of resolution. The
resolution offered by these techniques was dependent on the combination
of alleles present, because heterozygosity often hindered allele-specific assignment. B locus oligotyping resolution was improved
by using 3 primers D1 and D2 separately where appropriate to
amplify and analyze each allele individually.29 In total, the B locus alleles were amplified separately in 30% of pairs.
The polymorphisms within the serological specificities HLA-A2, -B35,
and -B44 were further defined using a combination of group-specific
amplification and oligotyping as described previously.30,31 HLA-C typing was performed using either PCR-SSP32 or
PCR-SSOP33 as described.
Reference strand-mediated conformation analysis (RSCA) matching of
patient/donor pairs.
Because PCR-SSOP typing resolution is limited both by the number of
probes used and ambiguities caused by heterozygosity, a
conformation-dependent technique has been used on selected pairs. RSCA
has recently been described as a method of identifying HLA alleles on
the basis of mobility of a heteroduplex formed between the sense strand
of a reference allele and the antisense strand of the unknown
allele.34
Briefly, HLA-A, -B, or -C amplification of a fragment containing exon
2, intron 2, and exon 3 was performed using locus-specific primers
described previously.35 Reference strand amplification was
performed from cell line DNA homozygous for the appropriate HLA allele
using the same primers except with the sense primer labeled at the
5 end with the Cy5 fluorochrome (Pharmacia Biotech, Uppsala,
Sweden). Amplified reference and sample products were mixed at a 1:3 ratio and hybridized as previously
described.34 Duplexes were separated by polyacrylamide gel
electrophoresis (PAGE) using an ALFexpress automated
sequencer (Pharmacia Biotech), and the mobility of the fluorescent
duplex bands was analyzed using Fragment manager software (Pharmacia
Biotech). By comparison with the mobilities of known heteroduplexes, it
was possible to assign allelic specificities. Reference alleles used
were as previously described,36 with the exception of
HLA-B*1501 (amplified from DNA from IHW 9072 cell line) for
confirmation of matching HLA-B62 seropositive donor/patient pairs.
| |
RESULTS |
Identification of serologically undetected HLA-A and -B
incompatibilities.
To determine the level of HLA-A and -B undetected mismatching in
serologically matched patient/donor pairs, samples were analyzed using
higher resolution DNA-based methods. Patient/donor pairs were initially
fully matched for HLA-A in 97% of cases
(Fig 1). DNA typing of the patient/donor
pairs confirmed the mismatches identified by serology. Two further
patient/donor pairs were found to be incompatible using oligotyping for
HLA-A, one indicating an HLA-A*02 subtype mismatch and the other an
HLA-A*0301 versus -A*0302 mismatch (Table
1). Specific subtyping confirmed the HLA-A*02 incompatibility as
HLA-A*0201 versus -A*0205 and that 55 further HLA-A2 seropositive pairs
were matched at the subtype level. That 91 of 92 HLA-A2 seropositive
individuals were encoded by HLA-A*0201 reflects the dominance of this
subtype in North European Caucasoids.37 RSCA matching
indicated two further mismatches at A locus, an HLA-A*30 subtype
mismatch and an HLA-A*03 heterozygote donor (A*0301, *03v) and
HLA-A*0301 homozygous patient.
View larger version (14K):
[in this window]
[in a new window]
| Fig 1.
Level of matching achieved by conventional typing
methods. Patients and potential donors were typed by serological
methods for HLA-A and -B and DNA-based methods for HLA-DRB1 and -DQB1.
Limiting dilution analysis was performed in the graft-versus-host
direction to assess the frequency of host specific CTL precursors.
Pairs with a high CTLp frequency (>1:105 PBMC) were
judged to be mismatched at the cellular level.
|
|
Original serological testing showed that 91% of patient/donor pairs
were matched for HLA-B. A greater level of mismatching was found for
HLA-B using DNA-based typing techniques. Discrepancies may occur
between serological techniques due to the cross-reactivity of
alloantisera, limitations in the alloantisera used, or the lack of
expression of an allele. HLA-B SSOP found 3 samples to be misassigned
by serology. In one case, HLA-B58 was missed and in another the same
antigen was misassigned HLA-B57. In both cases, HLA-B62 was the second
serotype expressed and errors in serological typing were likely due to
serological cross-reactivity for HLA-B15 and -B17 groups. In the third,
an HLA-B38 was not originally identified by serology. However, retyping
by serology confirmed the presence of HLA-B38 as being expressed and
not a null allele.
By using group-specific oligotyping methods,30,31 we
identified heterogeneity within the HLA-B35 and -B44 serotypes. Four HLA-B*35 subtypes were identified at varying frequencies within the 27 individuals tested (Table 1). Importantly, 40% of the HLA-B35
seropositive patient/donor pairs tested were mismatched at the subtype
level. HLA-B*44 subtyping indicated two common subtypes, HLA-B*4402 and
-B*4403, in a 3:2 ratio. Despite the presence of these two common
subtypes, only 4 of 25 (16%) of HLA-B44 seropositive pairs were
mismatched at the subtype level. This low percentage is likely due to
the HLA-B*44 subtypes commonly segregating on different
haplotypes38 and matching for other loci fortuitously
results in frequent HLA-B*44 subtype compatibility.
Oligotyping was limited in its resolution by the number of probes used
and the heterozygosity exhibited by most samples. Two PCR primer mixes
were used for HLA-B SSOP, which enabled the separate typing of each
allele in a proportion of allelic combinations. However, RSCA was
useful in identifying polymorphisms not detected by oligotyping and
also in confirming homogeneity in potentially heterogeneous serotypes.
Three HLA-B*51 subtypes and two commonly occuring HLA-B*39 subtypes
were identified by this technique (Table 1) as well as those HLA-B*35
and -B*44 subtypes identified by SSOP. In contrast, only one subtype
was detected in 45 HLA-B7 and 40 HLA-B8 seropositive individuals.
Furthermore, HLA-B62, a serotype shown to be encoded by many distinct
alleles,4 was identified as B*1501 in all 16 cases tested.
After molecular typing methods were applied, mismatching for HLA-A and
-B increased to 7% and 27% of pairs, respectively. In total, those
matched for HLA-A and -B decreased from 89% as initially detected by
serology to 70% of pairs (Fig 2). The
higher level of HLA-B mismatching reflects the limitations in
serological resolution at this locus.
View larger version (14K):
[in this window]
[in a new window]
| Fig 2.
HLA matching for bone marrow donor selection. DNA based
typing ( ) showed an increased level of mismatching for HLA-A and -B
over that defined by serology ( ). Although no HLA-C serology was
performed for original typing, DNA-based typing indicated a high level
of incompatibility.
|
|
Molecular HLA-C typing.
Unlike HLA-A and -B, no account was taken of HLA-C match status in the
selection of donors for final stage testing. However, because HLA-B and
HLA-C are in strong linkage disequilibrium, some level of matching was
expected. To measure the level of matching at HLA-C and so determine
its impact on the match status of patient donor pairs, PCR-SSP and
PCR-SSOP typing methods were used. DNA-based typing identified HLA-C
mismatching in 33 of 84 pairs tested (39%), a higher level than that
seen for HLA-A or -B (Fig 2), with 8 pairs mismatched for both HLA-C
alleles. Importantly, 24 of the 33 (73%) HLA-C mismatched pairs had
further HLA-A and/or -B incompatibilities identified at the
molecular level, indicating that HLA-C is a useful marker for other
mismatches on the haplotype. The utility of HLA-C type as an indicator
of HLA-B compatibility was allele dependent. HLA-B*4402 and B*4403 were
predominantly associated with restricted HLA-C locus alleles, Cw*0501
and Cw*1601, respectively. In contrast, HLA-B*5101 was associated with
a wide range of HLA-C alleles, as reported previously.15,39
Thus, mismatching at HLA-C was not predictive of further mismatches for
all haplotypes. Overall, 22 of 25 potential donor/patient pairs
mismatched at HLA-B were also mismatched at HLA-C.
Mismatching for the HLA-C encoded motifs that interact with KIRs, thus
influencing NK cell allorecognition, was next assessed. Each individual was classified as being positive for the Asn77 and
Lys80 (group 1) and/or Ser77 and Asn80 (group 2) HLA-C
molecules.18 We then calculated whether the HLA-C
mismatched donor/patient pairs were also mismatched for this motif.
Twenty-two of the 33 (67%) HLA-C mismatched pairs were also mismatched
at the level of KIR binding motif. However, no mismatched pairs were
homozygous for opposite KIR binding motifs, and so NK cell
allorecognition would be expected to be unidirectional. Nine of the 22 mismatches may be expected to influence allorecognition in the
graft-versus-host direction and 13 in the host-versus-graft direction.
Cellular recognition.
It has been reported that HLA-A and -B mismatches detected by serology
and at the DNA level are recognized in vitro by high frequency
CTL.24,40 In total, 86% of all donor/patient pairs mismatched for HLA-A or -B in the graft-versus-host direction fell into
the high CTLp frequency group. Although the range of CTLp frequencies
was broad, there was no evidence that mismatches detected by DNA typing
were less immunogenic than those typed by serological methods,
suggesting they may be as functionally relevant. In contrast to HLA-A
and -B mismatches, 40% of HLA-C incompatible pairs fell into the low
or negative CTLp frequency group. This suggests that HLA-C alloantigens
may be less immunogenic than HLA-A or -B. To further investigate this,
the donor/patient pairs were divided into those with only HLA-C
mismatches and those with HLA-C plus other HLA class I
incompatibilities. Mean CTLp frequencies differed significantly between
both groups (P = .0004), with 82% of pairs with only HLA-C
mismatches being in the low or negative CTLp frequency
group (Fig 3). Only four
donor/patient pairs were identified with HLA-A or -B mismatches in the
graft-versus-host direction without HLA-C incompatibility. For these
four pairs, a mean CTLp frequency of 1:30,000 was obtained (range,
1:23,000 to 1:36,000).
View larger version (12K):
[in this window]
[in a new window]
| Fig 3.
The effect of HLA-C mismatching on CTLp frequency. CTLp
frequencies of 30 pairs with patient HLA-C locus incompatibilities are
shown above. Mean CTLp frequencies differed significantly between those
with only HLA-C mismatches (1:316,500) and those with further HLA class
I mismatches (1:47,110). This indicates that HLA-C alloreactive T cells
are found at a lower frequency than those at HLA-A and -B. The limit of
sensitivity of this assay is 1 patient-specific donor CTLp/5 × 105 or higher. Mean CTLp frequencies differed
significantly between groups according to the Mann-Whitney test.
|
|
Previous studies have indicated undetected HLA class I mismatches to be
responsible for high CTLp frequencies. Despite using DNA-based HLA-A,
-B, and -C matching for serologically matched pairs, 24 of 47 pairs
(51%) with a high CTLp frequency had no discernible mismatch at HLA
class I (Fig 4). Furthermore, only 2 DRB1
and 4 DQB1 mismatches were detected in the 24 pairs in the high CTLp
and no HLA class I mismatch group.
View larger version (23K):
[in this window]
[in a new window]
| Fig 4.
DNA-based typing shows many HLA class I mismatches in the
high CTLp frequency group not identified using serological methods.
() Matched pairs; () those with detected HLA class I mismatches.
Forty-seven donors had high (>1:105) patient-specific
CTLp frequencies. Only 8 (17%) of these had HLA class I mismatches
detected by serological typing, reflecting the low overall number of
HLA class I serological mismatched pairs. The proportion of HLA class I
mismatched pairs in the high CTLp frequency group increased to 23 (49%) after DNA-based typing, with 21 pairs mismatched at the HLA-B
and/or -A locus. However, 24 pairs (51%) with high CTLp
frequencies appear to be compatible for HLA class I.
|
|
Overall level of matching.
Donors were selected on the basis of being closely matched for HLA-A
and -B by serological methods and -DRB1 (and DQB1) by molecular
methods. Using molecular typing methods for HLA-A and -B and including
HLA-C typing data, the level of matching was seen to be greatly
reduced. Of 89 pairs (89 donors for 76 patients) studied, 63% were
originally regarded as fully matched. After DNA-based typing, this
figure was reduced to 46%. However, single detected mismatches
indicate mismatched haplotypes and increase the chances of there being
incompatibilities at other loci. By using high resolution class I
typing, we have found 43% of donor patient pairs with two or more
mismatches and 17% with three or more (Fig
5).
View larger version (17K):
[in this window]
[in a new window]
| Fig 5.
Multiple mismatches are shown by high resolution HLA
class I typing. () Original matching level; () the matching level
obtained after DNA typing for HLA class I. After serological testing
for HLA-A, -B and DNA typing for HLA-DRB1, -DQB1, 92% of pairs fell in
the 0 or 1 mismatch group. This was reduced to 69% after DNA typing of
HLA-A, -B, and -C. The increase in pairs with 3 or more mismatches
increased from 2% to 16%, reflecting the association of HLA subtypes
on different haplotypes.
|
|
| |
DISCUSSION |
Unrelated donor BMT has only been made practical by the establishment
of large volunteer registries and implementation of HLA typing
techniques with sufficient resolution for matching. Although
HLA-matched siblings can be identified by a combination of a mixed
lymphocyte reaction (MLR) assay and serological typing, this
combination of tests has not proven effective in predicting GVHD in the
unrelated donor setting.41 DNA-based typing methods have
therefore been developed to allow accurate matching of HLA class II
loci and are now used routinely for selection of matched unrelated
donors, with improved transplant results.42 In contrast, HLA-A and -B specificities have until recently only been defined using
classical serological methods. We have implemented DNA typing methods
for HLA-A, -B, and -C to study the deficiencies of current HLA class I
typing in accurately matching unrelated pairs. It is only by
identifying the precise level of matching in BMT that the importance of
serologically undefined differences can be assessed.
By using DNA-based typing for HLA class I, we have been able to
identify many more serologically undetected mismatches in HLA-B than
HLA-A. It appears that most HLA-A serotypes in our population are
encoded for by one dominant allele as indicated by HLA-A2 subtyping
(Table 1). In contrast, several HLA-B serotypes were encoded by
multiple alleles. Although the incompatibilities identified by
DNA-based typing involved molecular differences of as little as one
amino acid, these are likely to be in positions on the HLA molecule
expected to interact with bound peptide and/or T-cell
receptor.43,44 Such small differences have been shown to
generate vigorous alloreactive CTL responses in the BMT setting leading
to severe complications.10,11 To further emphasize the
functional relevance of these mismatches, high CTLp frequencies were
detected in 86% of HLA-A, -B mismatched pairs.
We have confirmed that HLA-C incompatibilities are frequent in
serologically HLA-A, -B matched unrelated pairs.15,45
However, due to the distribution of polymorphic residues within HLA-C
antigens and their reduced cell surface expression, it has been
suggested that HLA-C may not be as immunologically relevant as the
other classical class I loci.46 It has previously been
suggested that HLA-C incompatibilities do correlate with high CTLp
frequency,47 although in that study HLA-A and -B typings
had not been determined using high resolution methods. In contrast, we
have demonstrated that, whereas HLA-A and -B mismatches correlate with
a high CTLp frequency, this was not so for HLA-C mismatching. By using
high resolution matching techniques, we show that, of all the C locus mismatched pairs with high CTLp frequency, 89% had other class I
differences. Furthermore, 82% of those with no other HLA class I
mismatch were found to have a low or negative CTLp frequency (Fig 4).
This supports the view that HLA-C may be of less immunological relevance than HLA-A and -B with respect to CTL surveillance.
Whereas HLA-C incompatibilities may not be a major target for
alloreactive CTLs, certain mismatches will result in differential expression of the motifs responsible for modulating alloreactive NK
cell activity. Mismatching for the HLA-C encoded NK resistance motifs
was seen in 67% of those mismatched at this locus and 26% of all
pairs studied. Because HLA phenotype appears to play an important role
in defining the KIR repertoire of an individual,19,48 potentially alloreactive NK cells are likely to be present in a
significant proportion of unrelated donor transplants and their possible impact should be considered. A phenomenon in the mouse known
as hybrid resistance in which bone marrow from an MHC homozygous parent
is rejected by its F1 hybrid offspring has been shown to be mediated by
NK cells.20 It is now known that the lack of self-MHC
molecules on murine donor bone marrow cells leaves them vulnerable to
recipient NK-mediated lysis.21 An analogous situation has
been demonstrated in vitro in the human, with HLA-C playing a key role
in the protection from NK lysis.49
The detection of high CTLp frequency has been hypothesized to be a
useful indicator of HLA class I incompatibilities not identified by
serological methods.24,50,51 However, the range of CTLp frequencies for the same HLA mismatch may be large between unrelated individuals (Breur-Vriesendorp et al52 and unpublished
data). Whether the absolute frequency or the qualitative
properties of alloreactive CTLs calculated in vitro is important is not
clear. Evidence suggests the CTLs involved in GVHD are not the same as those generated in vitro.51 Despite the use of high
resolution HLA matching techniques, a significant number of pairs in
the high CTLp frequency group (51%) had no detected mismatches in the
GVHD direction. In such cases, full HLA-A, -B, and -C sequencing would
be useful in confirming patient/donor HLA matching. A possible explanation for such CTL activity is that the peptide repertoire varies
sufficiently between unrelated individuals to induce a strong
alloreactive CTL response in vitro. In fact, serological reagents have
been used to distinguish HLA-B antigens in the absence of allelic
differences.53,54 CTLp frequency is often used as a
criterion for selection of a suitable unrelated donor. It will therefore be important to assess the functional significance of high
CTLp frequencies in the absence of HLA incompatibilities.
The term minor HLA mismatch is commonly used in reference to an HLA-A,
-B mismatch of the same serological cross-reactive group or HLA class
II allele encoding a product of the same serological group. Matching
for HLA-B serological splits has been shown to be of little benefit in
renal transplantation.55 However, evidence suggests that
these incompatibilities are of major importance to the outcome of
allogeneic BMT. Serologically undetected HLA class I mismatches are
recognized efficiently by alloreactive CTL correlating with poor
transplant outcome.27,40,56,57
By improving the resolution of HLA class I matching, the number of
perfectly matched pairs has significantly decreased. Furthermore, many
pairs were found to have multiple mismatches, which has been shown to
increase the risk of posttransplant complications. Thus, the problem
created by high resolution typing of HLA loci is a reduction in the
number of matched donors that can be provided. However, this study has
demonstrated that many of the HLA mismatches identified are on
haplotypes frequent in the Caucasoid population. Therefore, the
likelihood increases that several unrelated donors will be matched at
the serological level at HLA class I. The development of techniques
such as RSCA will allow the convenient, rapid, and accurate screening
of a large number of such potential donors. By using such a strategy,
HLA matching levels should improve. However, there will remain a
significant number of patients without fully HLA matched donors and we
need to assess carefully what level of HLA mismatching can be
acceptable for a beneficial outcome to BMT. Retrospective analyses of
unrelated donor transplants using high resolution typing have been
performed by several groups in an attempt to identify those mismatches
best tolerated,58,59 and indications that mismatched
transplants can be successful, especially for younger patients, are
encouraging. The hope is that such studies will allow the rational
selection of the most appropriate mismatched bone marrow donor.
| |
ACKNOWLEDGMENT |
The authors thank I. Anthony Dodi and Steven G.E. Marsh for critical
review of the manuscript and the staff of the Anthony Nolan
Tissue-typing Laboratories for excellent technical assistance.
| |
FOOTNOTES |
Submitted April 22, 1998;
accepted August 13, 1998.
Supported by The Anthony Nolan Bone Marrow Trust. J.R.A.
is a recipient of a fellowship from the Consejo Nacional de Ciencia y
Tecnologia, Mexico and Overseas Research Students Awards (CVCP) U.K.
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 J. Alejandro Madrigal, MD, PhD, The Anthony
Nolan Research Institute, The Royal Free Hospital, Pond Street, London,
NW3 2QG, UK; e-mail: madrigal{at}rfhsm.ac.uk.
| |
REFERENCES |
1.
Kaminski E, Hows J, Man S, Brookes P, Mackinnon S, Hughes T, Avakian O, Goldman JM, Batchelor JR:
Prediction of graft versus host disease by frequency analysis of cytotoxic T cells after unrelated donor bone marrow transplantation.
Transplantation
48:608, 1989[Medline]
[Order article via Infotrieve]
2.
Beatty PG, Anasetti C, Hansen JA, Longton GM, Sanders JE, Martin PJ, Mickelson EM, Choo SY, Petersdorf EW, Pepe MS, Appelbaum FR, Bearman SI, Buckner CD, Clift RA, Peterson FB, Singer J, Stewart PS, Storb RF, Sullivan KM, Tesler MC, Witherspoon RP, Thomas ED:
Marrow transplantation from unrelated donors for treatment of hematologic malignancies: Effect of mismatching for one HLA locus.
Blood
81:249, 1993[Abstract/Free Full Text]
3.
Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, Sanders JE, Stewart P, Buckner CD, Storb R, Thomas ED:
Marrow transplantation from related donors other than HLA-identical siblings.
N Engl J Med
313:765, 1985[Abstract]
4.
Bodmer JG, Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Charron D, Dupont B, Erlich HA, Fauchet R, Mach B, Mayr WR, Parham P, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI:
Nomenclature for factors of the HLA System, 1996.
Hum Immunol
53:98, 1997[Medline]
[Order article via Infotrieve]
5.
Speiser DE, Tiercy JM, Rufer N, Chapuis B, Morell A, Kern M, Gmur J, Gratwohl A, Roosnek E, Jeannet M:
Relation between the resolution of HLA-typing and the chance of finding an unrelated bone marrow donor.
Bone Marrow Transplant
13:805, 1994[Medline]
[Order article via Infotrieve]
6.
Beatty PG, Hansen JA, Longton GM, Thomas ED, Sanders JE, Martin PJ, Bearman SI, Anasetti C, Petersdorf EW, Mickelson EM, Pepe MS, Appelbaum FR, Buckner CD, Clift RA, Petersen FB, Stewart PS, Storb RF, Sullivan KM, Tesler MC, Witherspoon RP:
Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies.
Transplantation
51:443, 1991[Medline]
[Order article via Infotrieve]
7.
Brenner MB, McLean J, Yang SY, van der Poel JJ, Pious D, Strominger JL:
Clonal T lymphocyte recognition of the fine structure of the HLA-A2 molecule.
J Immunol
135:384, 1985[Abstract]
8.
Ragupathi G, Cereb N, Yang SY:
The relative distribution of B35 alleles and their IEF isotypes in a HLA-B35-positive population.
Tissue Antigens
46:24, 1995[Medline]
[Order article via Infotrieve]
9.
Fleischhauer K, Kernan NA, Dupont B, Yang SY:
The two major subtypes of HLA-B44 differ for a single amino acid in codon 156.
Tissue Antigens
37:133, 1991[Medline]
[Order article via Infotrieve]
10.
Fleischhauer K, Kernan NA, O'Reilly RJ, Dupont B, Yang SY:
Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44.
N Engl J Med
323:1818, 1990[Medline]
[Order article via Infotrieve]
11.
Keever CA, Leong N, Cunningham I, Copelan EA, Avalos BR, Klein J, Kapoor N, Adams PW, Orosz CG, Tutschka PJ, Baxter-Lowe LA:
HLA-B44-directed cytotoxic T cells associated with acute graft-versus-host disease following unrelated bone marrow transplantation.
Bone Marrow Transplant
14:137, 1994[Medline]
[Order article via Infotrieve]
12.
Lawlor AD, Warren E, Ward FE, Parham P:
Comparison of class I MHC alleles in humans and apes.
Immunol Rev
113:147, 1990[Medline]
[Order article via Infotrieve]
13.
Chen BP, Lam V, Kraus EE, DeMars R, Sondel PM:
Restriction of Epstein-Barr virus-specific cytotoxic T cells by HLA-A, -B, and -C molecules.
Hum Immunol
26:137, 1989[Medline]
[Order article via Infotrieve]
14.
van der Bruggen P, Szikora JP, Boel P, Wildmann C, Somville M, Sensi M, Boon T:
Autologous cytolytic T lymphocytes recognize a MAGE-1 nonapeptide on melanomas expressing HLA-Cw*1601.
Eur J Immunol
24:2134, 1994[Medline]
[Order article via Infotrieve]
15.
Grundschober C, Rufer N, Sanchez-Mazas A, Madrigal A, Jeannet M, Roosnek E, Tiercy JM:
Molecular characterization of HLA-C incompatibilities in HLA-ABDR-matched unrelated bone marrow donor-recipient pairs. Sequence of two new Cw alleles (Cw*02023 and Cw*0707) and recognition by cytotoxic T lymphocytes.
Tissue Antigens
49:612, 1997[Medline]
[Order article via Infotrieve]
16.
Ljunggren H-S, Karre K:
In search of the `missing self': MHC molecules and NK cell recognition.
Immunol Today
11:237, 1990[Medline]
[Order article via Infotrieve]
17.
Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R, Barbaresi M, Ciccone E, Moretta L:
P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities.
J Exp Med
178:597, 1993[Abstract/Free Full Text]
18.
Ciccone E, Pende D, Viale O, Than A, Di Donato C, Orengo AM, Biassoni R, Verdiani S, Amoroso A, Moretta A, Moretta L:
Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: Expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2).
J Exp Med
176:963, 1992[Abstract/Free Full Text]
19.
Colonna M, Brooks EG, Falco M, Ferrara GB, Strominger JL:
Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C.
Science
260:1121, 1993[Abstract/Free Full Text]
20.
Bennett M:
Biology and genetics of hybrid resistance.
Adv Immunol
41:333, 1987[Medline]
[Order article via Infotrieve]
21.
Yu YYL, George T, Dorfman JR, Roland J, Kumar V, Bennet M:
The role of Ly49A and 5E6(Ly49C) molecules in hybrid resistance mediated by murine natural killer cells against normal T cell blasts.
Immunity
4:67, 1996[Medline]
[Order article via Infotrieve]
22.
Bishara A, Amar A, Brautbar C, Condiotti R, Lazarovitz V, Nagler A:
The putative role of HLA-C recognition in graft versus host disease (GVHD) and graft rejection after unrelated bone marrow transplantation (BMT).
Exp Hematol
23:1667, 1995[Medline]
[Order article via Infotrieve]
23.
Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, McKinney SK, Smith AG, Martin PJ, Hansen JA:
Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors.
Blood
89:1818, 1997[Abstract/Free Full Text]
24.
O'Shea J, Madrigal A, Davey N, Brookes P, Scott I, Firman H, Lechler R, Goldman J, Batchelor R:
Measurement of cytotoxic T lymphocyte precursor frequencies reveals cryptic HLA class I mismatches in the context of unrelated donor bone marrow transplantation.
Transplantation
64:1353, 1997[Medline]
[Order article via Infotrieve]
25.
Jordan F, McWhinnie AJ, Turner S, Gavira N, Calvert AA, Cleaver SA, Holman RH, Goldman JM, Madrigal JA:
Comparison of HLA-DRB1 typing by DNA-RFLP, PCR-SSO and PCR-SSP methods and their application in providing matched unrelated donors for bone marrow transplantation.
Tissue Antigens
45:103, 1995[Medline]
[Order article via Infotrieve]
26.
Kaminski E, Hows J, Goldman J, Batchelor R:
Optimising a limiting dilution culture system for quantitating frequencies of alloreactive cytotoxic T lymphocyte precursors.
Cell Immunol
137:88, 1991[Medline]
[Order article via Infotrieve]
27.
Spencer A, Brookes PA, Kaminski E, Hows JM, Szydlo RM, van Rhee F, Goldman JM, Batchelor JR:
Cytotoxic T lymphocyte precursor frequency analyses in bone marrow transplantation with volunteer unrelated donors. Value in donor selection.
Transplantation
59:1302, 1995[Medline]
[Order article via Infotrieve]
28.
Oh SH, Fleischhauer K, Yang SY:
Isoelectric focusing subtypes of HLA-A can be defined by oligonucleotide typing.
Tissue Antigens
41:135, 1993[Medline]
[Order article via Infotrieve]
29.
Middleton D, Williams F, Cullen C, Mallon E:
Modification of an HLA-B PCR-SSOP typing system leading to improved allele determination.
Tissue Antigens
45:232, 1995[Medline]
[Order article via Infotrieve]
30.
Tiercy JM, Djavad N, Rufer N, Speiser DE, Jeannet M, Roosnek E:
Oligotyping of HLA-A2, -A3, and -B44 subtypes. Detection of subtype incompatibilities between patients and their serologically matched unrelated bone marrow donors.
Hum Immunol
41:207, 1994[Medline]
[Order article via Infotrieve]
31.
Gauchat-Feiss D, Rufer N, Speiser D, Jeannet M, Roosnek E, Tiercy JM:
Heterogeneity of HLA-B35. Oligotyping and direct sequencing for B35 subtypes reveals a high mismatching rate in B35 serologically compatible kidney and bone marrow donor/recipient pairs.
Transplantation
60:869, 1995[Medline]
[Order article via Infotrieve]
32.
Bunce M, Barnardo MC, Welsh KI:
Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including definition of HLA-Cw9 and Cw10 and a new allele HLA-"Cw7/8v".
Tissue Antigens
44:200, 1994[Medline]
[Order article via Infotrieve]
33.
Kennedy LJ, Poulton KV, Dyer PA, Ollier WE, Thomson W:
Definition of HLA-C alleles using sequence-specific oligonucleotide probes (PCR-SSOP).
Tissue Antigens
46:187, 1995[Medline]
[Order article via Infotrieve]
34.
Argüello RJ, Little A-M, Pay AL, Gallardo D, Rojas I, Marsh SGE, Goldman JM, Madrigal JA:
Mutation detection and typing of polymorphic loci through double-strand conformation analysis.
Nat Genet
18:192, 1998[Medline]
[Order article via Infotrieve]
35.
Cereb N, Maye P, Lee S, Kong Y, Yang SY:
Locus-specific amplification of HLA class I genes from genomic DNA: locus-specific sequences in the first and third introns of HLA-A, -B, and -C alleles.
Tissue Antigens
45:1, 1995[Medline]
[Order article via Infotrieve]
36.
Argüello J, Little A-M, Bohan E, Gallardo D, O'Shea J, Dodi I, Goldman JM, Madrigal JA:
A high resolution HLA class I and class II matching method for bone marrow donor selection.
Bone Marrow Transplant
22:527, 1998[Medline]
[Order article via Infotrieve]
37.
Krausa P, Brywka M III, Savage D, Hui KM, Bunce M, Ngai JLF, Teo DLT, Ong YW, Barouch D, Allsop CEM, Hill AVS, McMichael AJ, Bodmer JG, Browning MJ:
Genetic polymorphism within HLA-A*02: significant allelic variation revealed in different populations.
Tissue Antigens
45:223, 1995[Medline]
[Order article via Infotrieve]
38.
Petersdorf EW, Setoda T, Smith AG, Hansen JA:
Analysis of HLA-B*44 alleles encoded on extended HLA haplotypes by direct automated sequencing.
Tissue Antigens
44:211, 1994[Medline]
[Order article via Infotrieve]
39.
Bunce M, Barnardo MC, Procter J, Marsh SG, Vilches C, Welsh KI:
High resolution HLA-C typing by PCR-SSP: Identification of allelic frequencies and linkage disequilibria in 604 unrelated random UK Caucasoids and a comparison with serology [corrected and republished article originally printed in Tissue Antigens 48:680, 1996].
Tissue Antigens
50:100, 1997[Medline]
[Order article via Infotrieve]
40.
Speiser DE, Loliger CC, Siren MK, Jeannet M:
Pretransplant cytotoxic donor T-cell activity specific to patient HLA class I antigens correlating with mortality after unrelated BMT.
Br J Haematol
93:935, 1996[Medline]
[Order article via Infotrieve]
41.
Mickelson EM, Longton G, Anasetti C, Petersdorf E, Martin P, Guthrie LA, Hansen JA:
Evaluation of the mixed lymphocyte culture (MLC) assay as a method for selecting unrelated donors for marrow transplantation.
Tissue Antigens
47:27, 1996[Medline]
[Order article via Infotrieve]
42.
Petersdorf EW, Longton GM, Anasetti C, Martin PJ, Mickelson EM, Smith AG, Hansen JA:
The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation.
Blood
86:1606, 1995[Abstract/Free Full Text]
43.
Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC:
The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens.
Nature
329:512, 1987[Medline]
[Order article via Infotrieve]
44.
Bjorkman PJ, Parham P:
Structure, function, and diversity of class I major histocompatibility complex molecules.
Annu Rev Biochem
59:253, 1990[Medline]
[Order article via Infotrieve]
45.
Santamaria P, Reinsmoen NL, Lindstrom AL, Boyce-Jacino MT, Barbosa JJ, Faras AJ, McGlave PB, Rich SS:
Frequent HLA class I and DP sequence mismatches in serologically (HLA-A, HLA-B, HLA-DR) and molecularly (HLA-DRB1, HLA-DQA1, HLA-DQB1) HLA-identical unrelated bone marrow transplant pairs.
Blood
83:280, 1994[Abstract/Free Full Text] (erratum 83:3834, 1994)
46.
Lawlor DA, Zemmour J, Ennis PD, Parham P:
Evolution of class-I MHC genes and proteins: From natural selection to thymic selection.
Annu Rev Immunol
8:23, 1990[Medline]
[Order article via Infotrieve]
47.
Barnardo MC, Davey NJ, Bunce M, Brookes PA, Lechler RI, Welsh KI, Batchelor JR:
A correlation between HLA-C matching and donor antirecipient CTL precursor frequency in bone marrow transplantation.
Transplantation
61:1420, 1996[Medline]
[Order article via Infotrieve]
48.
Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D'Andrea A, Phillips JH, Parham P:
Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors.
Immunity
7:739, 1997[Medline]
[Order article via Infotrieve]
49.
Moretta L, Ciccone E, Mingari MC, Biassoni R, Moretta A:
Human natural killer cells: Origin, clonality specificity, and receptors.
Adv Immunol
55:341, 1994[Medline]
[Order article via Infotrieve]
50.
Rufer N, Tiercy JM, Speiser DE, Helg C, Gratwohl A, Chapuis B, Jeannet M, Roosnek E:
Characterization of pretransplant CTL activity in "perfectly matched" unrelated bone marrow donor/recipient combinations.
Bone Marrow Transplant
11:20, 1993 (suppl 1)
51.
Rufer N, Helg C, Tiercy JM, Barbey C, Gratwohl A, Chapuis B, Jeannet M, Roosnek E:
Recognition of major histoincompatibilities after transplantation with marrow from HLA closely matched donors.
Transplantation
63:1833, 1997[Medline]
[Order article via Infotrieve]
52.
Breur-Vriesendorp BS, Vingerhoed J, Schaasberg WP, Ivanyi P:
Variations in the T-cell repertoire against HLA antigens in humans.
Hum Immunol
27:1, 1990[Medline]
[Order article via Infotrieve]
53.
Domena JD, Arnett KL, Marsh SG, Bodmer JG, Parham P:
Alloantibodies can discriminate three populations of HLA-B40 molecules encoded by B*4002.
Tissue Antigens
44:57, 1994[Medline]
[Order article via Infotrieve]
54.
Adams EJ, Scott I, Shah A, Arnett KL, Marsh SG, Madrigal JA, Parham P:
Homogeneity of allelic sequence for serological variants of HLA-B53.
Tissue Antigens
46:330, 1995[Medline]
[Order article via Infotrieve]
55.
Sanfilippo F, Vaughn WK, Light JA, LeFor WM:
Lack of influence of donor-recipient differences in subtypic HLA-A, B antigens (splits) on the outcome of cadaver renal transplantation.
Transplantation
39:151, 1985[Medline]
[Order article via Infotrieve]
56.
Roosnek E, Hogendijk S, Zawadynski S, Speiser D, Tiercy JM, Helg C, Chapuis B, Gratwohl A, Gmur J, Seger R, Jeannet M:
The frequency of pretransplant donor cytotoxic T cell precursors with anti-host specificity predicts survival of patients transplanted with bone marrow from donors other than HLA-identical siblings.
Transplantation
56:691, 1993[Medline]
[Order article via Infotrieve]
57.
Keever-Taylor CA, Passweg J, Kawanishi Y, Casper J, Flomenberg N, Baxter-Lowe LA:
Association of donor-derived host-reactive cytolytic and helper T cells with outcome following alternative donor T cell-depleted bone marrow transplantation.
Bone Marrow Transplant
19:1001, 1997[Medline]
[Order article via Infotrieve]
58.
Madrigal JA, Arguello R, Scott I, Avakian H:
Molecular histocompatibility typing in unrelated donor bone marrow transplantation.
Blood Rev
11:105, 1997[Medline]
[Order article via Infotrieve]
59.
Hansen JA, Petersdorf E, Martin PJ, Anasetti C:
Hematopoietic stem cell transplants from unrelated donors.
Immunol Rev
157:141, 1997[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
B. E. Shaw, T. A. Gooley, M. Malkki, J. A. Madrigal, A. B. Begovich, M. M. Horowitz, A. Gratwohl, O. Ringden, S. G. E. Marsh, and E. W. Petersdorf
The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation
Blood,
December 15, 2007;
110(13):
4560 - 4566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Flomenberg, L. A. Baxter-Lowe, D. Confer, M. Fernandez-Vina, A. Filipovich, M. Horowitz, C. Hurley, C. Kollman, C. Anasetti, H. Noreen, et al.
Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome
Blood,
October 1, 2004;
104(7):
1923 - 1930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. M. Heemskerk, M. Hoogeboom, R. A. de Paus, M. G. D. Kester, M. A. W. G. van der Hoorn, E. Goulmy, R. Willemze, and J. H. F. Falkenburg
Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region
Blood,
November 15, 2003;
102(10):
3530 - 3540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Cao, B. Lo, E. A. Ranheim, F. C. Grumet, and J. A. Shizuru
Variable hematopoietic graft rejection and graft-versus-host disease in MHC-matched strains of mice
PNAS,
September 30, 2003;
100(20):
11571 - 11576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. D. Ottinger, S. Ferencik, D. W. Beelen, M. Lindemann, R. Peceny, A. H. Elmaagacli, J. Husing, and H. Grosse-Wilde
Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors
Blood,
August 1, 2003;
102(3):
1131 - 1137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Finke, C. Schmoor, H. Lang, K. Potthoff, and H. Bertz
Matched and Mismatched Allogeneic Stem-Cell Transplantation From Unrelated Donors Using Combined Graft-Versus-Host Disease Prophylaxis Including Rabbit Anti-T Lymphocyte Globulin
J. Clin. Oncol.,
February 1, 2003;
21(3):
506 - 513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Raziuddin, D. L. Longo, M. Bennett, R. Winkler-Pickett, J. R. Ortaldo, and W. J. Murphy
Increased bone marrow allograft rejection by depletion of NK cells expressing inhibitory Ly49 NK receptors for donor class I antigens
Blood,
September 26, 2002;
100(8):
3026 - 3033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Mutis, E. Blokland, M. Kester, E. Schrama, and E. Goulmy
Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation
Blood,
June 28, 2002;
100(2):
547 - 552.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Morishima, T. Sasazuki, H. Inoko, T. Juji, T. Akaza, K. Yamamoto, Y. Ishikawa, S. Kato, H. Sao, H. Sakamaki, et al.
The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors
Blood,
May 13, 2002;
99(11):
4200 - 4206.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. R. Drobyski, J. Klein, N. Flomenberg, D. Pietryga, D. H. Vesole, D. A. Margolis, and C. A. Keever-Taylor
Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen- disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts
Blood,
February 1, 2002;
99(3):
806 - 814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Fleischhauer, E. Zino, B. Mazzi, E. Sironi, P. Servida, E. Zappone, E. Benazzi, and C. Bordignon
Peripheral blood stem cell allograft rejection mediated by CD4+ T lymphocytes recognizing a single mismatch at HLA-DP{beta}1*0901
Blood,
August 15, 2001;
98(4):
1122 - 1126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Raziuddin, M. Bennett, R. Winkler-Pickett, J. R. Ortaldo, D. L. Longo, and W. J. Murphy
Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2b bone marrow cell allografts
Blood,
June 15, 2000;
95(12):
3840 - 3844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction