Page 1811 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 105 Unrelated Donor Hematopoietic Cell Transplantation 1615

ligand mismatches that were low-expression had similar risks as outcome. The map of the MHC continues to be refined for both
HLA-C matches. simple variation such as that represented by SNPs to more complex
The 3′ untranslated region of the HLA-DPB1 locus is resident to variation, including insertions and deletions (http://www.sanger.ac.uk/
a single nucleotide polymorphism that affects the level of expression HGP/Chr6?MHC). The content of several common HLA haplo-
of HLA-DP allotypes, and the ability of hepatitis B−infected indi- types, including HLA-A1, B8, DR3 and HLA-A2, B DR15, show-
viduals to control infection from this virus. In unrelated donor cases the extreme levels of sequence conservation over long stretches
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transplantation, an HLA-DPB1 mismatch between a low-expression of the MHC, upward of 4 Mb in some haplotypes. This work
HLA-DPB1 donor allele and a high-expression HLA-DPB1 recipient importantly shows the need for similarly dense sequence information
allele was recently identified as a risk factor for severe acute GVHD. on common as well as rare haplotypes in all ethnicities and racial
These data demonstrate that polymorphisms that reside within regu- populations to understand how such variation may be clinically
latory regions of HLA genes have clinical significance, and underscore relevant.
a need for a more complete understanding of HLA expression in How can knowledge of haplotype content facilitate the discovery
defining permissible HLA mismatches. Taken together, the results of new transplantation determinants? The available sequence align-
offer a new approach for understanding HLA-mediated immune ments demonstrate that the classic HLA loci serve as robust markers
responses in transplantation, infectious diseases, and autoimmune for the undetected linked variation on the haplotype. To test the
disorders. hypothesis that the HLA haplotype serves as a tool for querying such
areas outside of classic loci, a novel long-range phasing technique has
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BEYOND CLASSIC HLA: MAJOR HISTOCOMPATIBILITY been developed. By physically linking HLA-A with HLA-B with
HLA-DR on the same strand of DNA, this technique has been
COMPLEX RESIDENT VARIATION applied to test the hypothesis that HLA-identical unrelated donors
and recipients encode different HLA haplotypes, and furthermore,
Currently, gene-by-gene matching between recipients and unrelated haplotype mismatching is associated with increased posttransplant
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donors is performed to approximate the haplotype matching that risks conferred by variation that is linked to the different haplotypes.
is feasible between genotypically identical sibling pairs. However, In this study, a homogeneous population of HLA-A, HLA-B, HLA-C,
HLA-matched unrelated donors and recipients are not related to HLA-DRB1, HLA-DQB1 allele-matched unrelated transplants were
one another; therefore they are described as identical by state. This characterized using the phasing method. Of these pairs, 20% were
opens the possibility that genes other than classic HLA may be found to have different physical linkage of HLA-A, HLA-B, and
clinically relevant. The major histocompatibility complex (MHC) is HLA-DR. Haplotype mismatching was associated with a significantly
the most diverse region in the human genome known to date. More increased risk of grade III−IV acute GVHD. The increased risk of
than 300 loci have been verified within the extended 7.6-megabase GVHD was offset by lower relapse, leading to similar overall survival.
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(Mb) MHC region have immune function. Hence, current donor This study demonstrates that variation linked to the haplotype is
matching is performed for less than 5% of the total gene content of functional and that the HLA haplotype can be used as a surrogate
the MHC. marker for GVHD risk.
In addition to the classic HLA loci, the MHC is residence to the Fine mapping will entail comprehensive analysis of both simple
nonclassic HLA-E, HLA-F, HLA-G, MICA, and MICB genes. Data and complex MHC variation. In this way, comparative sequences
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suggest a role for HLA-E in transplant outcome. Increased risk for analysis of common and rare haplotypes continues to be an important
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bacterial infections and corresponding TRM at day 180 posttrans- research area. The JMDP carried out an extensive analysis of three
plant were found in recipients transplanted from HLA-E*01:01,01:01 commonly observed HLA haplotypes in their transplant popula-
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homozygous unrelated donors. HLA-E*01:03,01:03 homozygosity tion. This work has provided invaluable information on the degree
among HLA-identical siblings conferred protection against acute of conservation within and across haplotypes of the Japanese popula-
GVHD and TRM, leading to increased overall survival. These data tion and provides insight into the possible genetic basis for differences
point to the potential involvement of the innate immune system in in GVHD risk among Japanese patients compared with white
GVHD. New information on MICA in transplantation has become patients. In North American populations, SNPs, the most common
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available. In a retrospective study of 236 patients transplanted from and simplest form of human genetic variation, have been used to
HLA-matched and HLA-mismatched unrelated donors, 8.4% were identify candidate regions within the MHC that may harbor novel
mismatched for MICA. The presence of MICA disparity was associ- variants that have functional consequences in unrelated donor trans-
ated with higher risk of overall grades II−IV acute GVHD and higher plantation. 63,64 In HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-
gastrointestinal GVHD independent of HLA mismatching. Because DQB1−matched transplantation, two novel markers have been
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the gastrointestinal epithelium is the sole organ where MICA is validated as determinants of survival and acute GVHD. In single-
expressed, the data suggest that MICA serves as a classic transplanta- locus mismatched unrelated donor transplantation, candidate markers
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tion antigen. have been identified and validation is underway. The data in HLA-
Mapping with microsatellite (Msat) markers was among the earliest mismatched transplantation provides new information on suscepti-
approaches for discovering disease-causing variation in many model bility genes but also sheds light on the risks associated with
systems, including autoimmunity and cancer. Msats provide indirect mismatching for classic HLA genes. When the effects of SNP geno-
information because Msats themselves are not functional. Their LD type or mismatching are accounted, comparison of mismatching at
with putative functional genes, however, provides the basis for its HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 relative to HLA-C
application in estimating optimal donor registry size and composition demonstrates the deleterious nature of HLA-A, and HLA-C mis-
and for donor selection. Studies have used Msats to query the MHC matching, but also highlights the permissive nature of HLA-DQB1
region for novel determinants. Tumor necrosis factor variation within mismatches. These data point towards new understanding of the
the class III region of the HLA complex has recently been identified alloimmunogenecity of HLA in unrelated donor transplantation.
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as a risk factor for transplant outcomes. These studies provide key
evidence that variation outside of the classic HLA genetic loci both
exist and are potentially functional in transplantation. FUTURE DIRECTIONS
More recently, with the availability of a complete sequence of the
MHC, mapping with the use of single-nucleotide polymorphisms The HLA genetic system regulates the transplantation barrier. Clini-
(SNPs) has provided investigators with a robust tool for disease cal outcome after unrelated donor transplantation can be achieved
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mapping. The MHC is characterized by LD of discrete segments with donor matching for the highly polymorphic HLA loci. When
or blocks of sequences that reside between HLA genes. Although the HLA disparity cannot be avoided, judicious selection of a donor with
specific content of these blocks is under investigation, donor−recipient the fewest HLA mismatches and avoidance of certain loci may
matching for these regions is associated with superior clinical provide patients with the opportunity for lifesaving transplantation.