Biology Reference
In-Depth Information
The role of classical HLA in unrelated donor
hematopoietic cell transplantation
Among phenotypically matched patients and unrelated donors, DNA-
based typing methods can detect allelic differences that are clinically rel-
evant
[39-44]
. Based on extensive worldwide data, HLA matching of the
patient and the unrelated donor for HLA-A, C, B, DRB1 and DQB1 alleles is
associated with lower post-transplant risks and higher survival compared
to mismatching
[43-46]
.
When allele-matched donors are not available, the criteria for prioritizing
the selection of mismatched donors indicates that an isolated HLA-DQB1
mismatch is better tolerated than mismatching at HLA-A, C, B or DRB1
[44,45]
. The impact of mismatching at a single HLA locus also depends
on non-genetic factors that influence transplant outcome. Of these non-
genetic factors, the stage of disease at the time of transplantation remains a
strong factor for risk of disease recurrence and survival. Among good (low)-
risk patients, the risks associated with donor HLA mismatching appear to
be higher than those in patients with high-risk disease
[44,47]
. These obser-
vations are likely due to the cumulative effects of genetic and non-genetic
factors. Given the importance of an efficient search
[48,49]
, careful con-
sideration should be taken for extending a search when no HLA-matched
donors are available.
25
Alleles and antigens
Antigens are defined by serological reagents in microcytotoxicity assays
[50]
. Alleles are defined by DNA-based methods that permit ascertainment
of selected nucleotide positions of exons or full-length sequences. Since
the definition of alleles and antigens is, in part, methodological, intense
efforts have been made to determine whether there are biological differ-
ences associated with HLA mismatches that are detectable using serology
(“antigen-level” or “low-resolution” mismatches) apart from mismatches
that can only be detected using DNA-based methods (“allele-level” or “high
resolution” mismatches). One of the earliest demonstrations that alleles
can be highly immunogenic came from observations in the setting of graft
rejection following transplantation of a B*44:03 donor for a B*44:02 patient
[51]
. Donor-derived cytotoxic T lymphocytes could selectively recognize
the patient's HLA-B*44:02 allele. Following this report, the application of
molecular methods were used to identify HLA-C allele mismatching and its
role in graft failure
[52]
. These early studies firmly placed DNA-based typing
methods at the forefront of clinical testing.
Subsequently, large retrospective analyses have extended those findings to
other HLA loci
[44,45]
. In a study from the NMDP-CIBMTR
[44]
, survival
was decreased by 10% for each mismatched HLA-A, HLA-B, HLA-C or HLA-
DRB1 locus. Allele mismatches were as detrimental as antigen mismatches
with the exception being HLA-C, where antigen mismatches were more det-
rimental than allele mismatches. In peripheral blood stem cell transplanta-
tion
[53]
, pronounced differences in mortality among patients mismatched
with their donors for alleles versus antigens were found for HLA-C, but not
for other loci.
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