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Tyr9-Phe9 of HLA-A and for Tyr9-Ser9, Asn77-Ser77, Lys80-Asn80, Tyr99-
Phe99, Leu116-Ser116 and Arg156-Leu156 of HLA-C were identified in
Japanese patients to be associated with increased risk of acute GVHD [66] .
Since HLA-C serves as a ligand for the natural killer inhibitory receptor
(KIR), (refer to section below), HLA-C mismatched pairs were further evalu-
ated for the presence of residues that could be associated with GVHD risk
beyond the two positions that define KIR receptor binding (positions 77 and
80); donor-recipient mismatching at positions 9, 99, 156 and 163 strongly
correlated with GVHD risk. In a subsequent analysis, certain HLA-C and
HLA-DPB1 mismatch combinations were associated with both relapse and
GVHD [67] . This study demonstrates that risks are not necessarily the same
for every HLA mismatch; future studies are needed to separate mismatch
combinations involved in graft-versus-leukemia (GVL) from those influ-
encing GVHD. To this end, the use of statistical and structural modeling has
been explored to identify HLA alleles with diverse peptide binding reper-
toires [68,69] .
The studies described above have used statistical analysis tools to identify
the most likely residues involved in host-versus-graft and graft-versus-host
allorecognition. A parallel effort has been made by way of in vitro cytotox-
icity assays to identify the most immunogenetic epitopes. Among those
studies, HLA-DP has served as a model locus [70-76] . Population studies
have shown that HLA-DP is unique among other HLA genes because of very
weak LD between HLA-DP and HLA-A, HLA-B, HLA-C, HLA-DR and HLA-
DQ. As a result, less than 20% of HLA-A, HLA-B, HLA-C, HLA-DRB1 and
HLA-DQB1-matched unrelated donor pairs are also matched for HLA-DP.
Retrospective examination of HLA-DP has required very large transplant
populations so that sufficient numbers of HLA-DP-matched pairs can
be compared with mismatched pairs. Furthermore, the measured effects
attributed to single loci in early studies likely measured additive effects of
HLA-DP with HLA-A, HLA-B and HLA-DR. HLA-DP does function as a clas-
sical transplantation antigen with respect to GVHD [75-77] . Mismatching
for two DPB1 alleles increases the risk of acute GVHD compared to one or
no HLA-DP mismatch [71] .
27
Given that 80% of HLA 10/10 allele matched donors are DPB1-mismatched,
the frequencies suggest that for patients with common HLA haplotypes who
can identify several HLA-A, C, B, DRB1, DQB1-matched donors, that one of
five donors could be DPB1-matched. Hence, the patients who are likely to
benefit from prospective evaluation of DPB1 are patients who have common
HLA haplotypes and for whom transplantation is not urgent. Considering
that every patient has a DPB1-mismatched donor, studies have addressed
whether all DPB1 mismatches are equally detrimental. These analyses
have focused on the identification of donor-recipient mismatching at spe-
cific T-cell epitopes (TCE) defined by exon 2 sequence variation, that are
most closely associated with GVHD risk [70] . Using T-cell clones to identify
DPB1 alleles that generate high cytotoxic potential, a schema for predict-
ing high immunogenetic combinations of DPB1 alleles is possible. Inde-
pendent validation of the TCE definition in a large cohort of HLA-matched
and -mismatched unrelated donor transplants from the International His-
tocompatibility Working Group (IHWG) in Hematopoietic Cell Transplanta-
tion (HCT) has validated the TCE concept as a clinically practical approach
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