The HLA system in hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 28

The pairs were further defined by their HLA-DPB1 match status. The pres-
ence of DPB1 mismatching concurrent with TNFd alleles was associated
with increased GVHD risk and poorer overall outcome compared to their
absence. This study suggests that variation within the class III TNF-defined
region has clinical relevance. Furthermore, negative additive effects can be
measured at both the TNF and the DP loci.

The application of microsatellite markers paved the way for the use of state-
of-the-art single nucleotide polymorphism (SNP) platforms to understand
haplotype content [94] . In a recent study by the Japanese Marrow Donor
Program [95] , HLA 10/10 matched patient-donor pairs were characterized
using an SNP-based genotyping platform. Three high frequency Japanese
haplotypes were fully characterized for SNP content and LD. Interestingly,
the Japanese patients and donors displayed a very high degree of SNP con-
servation across the MHC and precluded an analysis of the effect of SNP
mismatching. However, a high frequency of HLA homozygosity permitted
the presence of certain haplotypes to be analyzed for associated trans-
plant risks. Three major haplotypes were identified, each having a differ-
ent association to post-transplant complications. This study highlights the
fundamental role of haplotypes and their associated variants in transplant
outcome.

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Future efforts to identify clinically relevant MHC region variants will require
very large, well-characterized patient populations. The diversity of haplo-
types in certain populations may permit donor-recipient mismatching of
non-HLA variants to be more fully defined. The characterization of both
common and rare haplotypes for the entire MHC region will greatly facili-
tate mapping efforts to localize novel transplantation determinants.

The clinical significance of non-classical HLA genes:
HLA-E, (HLA-F), HLA-G and MIC genes

The measurement of transplant-associated risks conferred by the non-
classical HLA genes has been successful in selected sibling cohorts that
limit the confounding effects of the classical HLA genes; however, due to the
inherent long-range LD of the MHC, the number of sibling transplant pairs
required to analyze the differential effect of the non-classical HLA genes is
necessarily high in order to reach sufficient statistical power [32,96] .

HLA-E in HCT: GVH

The effect of HLA-E*01:03 homozygosity was first assessed in a cohort of 187
HLA-matched genotypically identical siblings from a single institution and
revealed a protective effect for acute GVHD and transplant-related mortal-
ity (TRM) [97] . Patients with HLA-E*01:01,01:01 or 01:01,01:03 genotypes
showed a higher incidence of acute GVHD compared with patients with
the HLA-E*01:03,01:03 genotype. This protective role was subsequently
confirmed [98] . Similarly a significant reduction of TRM was associated
with HLA-E*01:03 homozygosity in a cohort of 83 related and unrelated
HLA-matched transplants and translated into better overall survival [99] .
The role of the HLA-E was confirmed in a study in 124 patients receiving
an unrelated donor HCT, showing a decreased risk of acute GVHD, but no