Page 1810 - Hematology_ Basic Principles and Practice ( PDFDrive )

1614 Part X Transplantation

approaches have been taken including understanding whether there define killer-cell immunoglobulin-like receptor (KIR) ligands,
are differences in risks associated with patient–donor mismatching donor−recipient mismatching at positions 9, 99, 156, and 163 were
for (1) DNA-defined alleles (“high-resolution mismatches”) com- found to correlate strongly with GVHD risk. This study demonstrates
pared with antigens (“low-resolution mismatches”); (2) specific that mismatching for positions of HLA-A or HLA-C that participate
amino acid positions, or groups of alleles defined by T-cell reactivity in peptide binding is functional and provides a basis for defining
(“T-cell epitope” or TCE mismatches), and (3) low- or high-expression nonpermissive HLA allele mismatches. Of the 10 mismatch combi-
HLA allotypes. nations associated with GVHD risk, the JMDP explored whether the
same mismatch combinations were involved in both GVHD and
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relapse (GVL effects) or only one. In a population of 4643 trans-
Alleles and Antigens plants, 10 mismatch combinations (4 for HLA-C and 6 for HLA-
DPB1) were statistically significantly associated with lowered relapse;
With the availability of molecular methods for defining the HLA however, only a subset were also involved in GVHD.
alleles of transplant recipients and donors, it now is possible to A recent CIBMTR analysis of HLA-matched and HLA-
evaluate the impact of the location and number of mismatched amino mismatched unrelated donor transplants performed in the United
acid residues as potential factors defining the permissibility of a States has identified three critical amino acid substitutions of class I
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mismatch. In a single-center study of graft failure after myeloablative and their role in GVHD. Patient–donor mismatching at residue
unrelated HCT, donor−recipient mismatching for HLA-A, HLA-B, 116 of HLA-C is associated with severe acute GVHD, and mismatch-
or HLA-C antigens conferred greater risk for graft failure than ing at residue 99 with increased transplant-related mortality. Residue
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did single allele mismatches at these loci. The allele and antigen 9 of HLA-B was identified as a susceptibility position, associated with
mismatches represented in this study population differed in the increased risk of chronic GVHD. These results suggest that HLA
number of nonsynonymous substitutions (a change in amino acids) mismatches do not confer equivalent risks to GVHD and relapse and
and in the location of the mismatch in the α 1 and α 2 domains of the that approaches for separating GVH from GVL may be possible
molecule, suggesting that multiple mismatches for residues that affect through selected HLA combinations. Statistic models have been
peptide binding and T-cell receptor contact might have been instru- developed to predict peptide binding of HLA molecules as an
mental in evoking T-cell responses that led to graft failure in these approach to predict HLA alleles that lead to diverse binding of
patients. peptide and that may consequently affect T-cell recognition of HLA
Single-center and registry-based studies have examined allele and and its minors.
antigen mismatches and the risks conferred by each kind of mismatch Initial observations suggested a role for HLA-DPB1 mismatching
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on TRM and survival (see Table 105.6). In an early CIMBTR analy- in graft failure. The importance of T-cell epitope (TCE) recognition
sis, each HLA-A, HLA-B, HLA-C, or HLA-DRB1 mismatch was of HLA-DPB1 mismatches in GVHD, relapse, and mortality was
found to confer a 9% to 10% lower overall survival compared with subsequently elucidated in a large population of unrelated donor
4
a baseline of 8/8 allele matches. A follow-up registry analysis of transplants. In this retrospective analysis of 8539 transplants per-
patients receiving growth factor mobilized peripheral blood stem cell formed worldwide, HLA-DPB1 TCE groups were assigned according
transplants confirms the high-risk nature of HLA-C antigen mis- to alloreactive T-cell cross-reactivity patterns established in a patient
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matches, more so than HLA-C allele mismatches. Among HLA-C with graft failure after transplantation for thalassemia. 49,50 Compared
allele mismatches, the high frequency mismatch between C*03:03 with permissive HLA-DPB1 mismatches (i.e., outcomes similar for
and C*03:04 appears to be associated with risks comparable with mismatches compared with matches), nonpermissive HLA-DPB1
HLA-C−matching, described in detail later in the section entitled mismatches (i.e., outcomes associated with mismatches were worse
The Level of HLA Expression. These data are consistent with the than those associated with other mismatches or matches) were associ-
graft failure study discussed earlier in which a predominance of ated with significantly higher risks of severe acute GVHD, nonrelapse
HLA-C mismatches and allele disparities did not contribute to morality, and overall mortality. The TCE concept that mismatching
increased risk. These studies demonstrate that avoidance of HLA-A, at certain amino acid positions of HLA class I and II molecules may
HLA-B, HLA-C, and HLA-DRB1 allele mismatches lowers the risks affect transplant outcomes differently than mismatching at other
of posttransplant complications. amino acid positions, has recently been validated by the NMDP/
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CIBMTR. In this large US study of 8003 transplants, nonpermis-
Mismatching at Amino Acid Residues sive HLA-DPB1 mismatching was associated with higher transplant-
related mortality compared with permissive mismatches or
and T-Cell Epitopes HLA-DPB1 matches.

The hypothesis that donor−recipient mismatching at certain amino
acid substitutions in the class I HLA molecule may be associated with THE LEVEL OF HLA EXPRESSION
higher posttransplant risks compared with mismatching at other resi-
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dues was first tested by Ferrara et al. Amino acid mismatching at HLA expression has recently emerged as a key feature of alloimmunity
residue 116 was found to be associated with significantly increased in infections and autoimmune diseases including HIV-AIDS and
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risks of acute GVHD and TRM compared with matching at this Crohn disease. The level of expression of HLA-C and HLA-DP
residue. Following these intriguing findings, the JMDP evaluated allotypes has recently been found to be an important feature of the
5210 Japanese recipients of unrelated donor transplants to identify permissivity of donor–recipient mismatching at these two loci.
mismatched residues of HLA-A, HLA-B, HLA-C, HLA-DRB1, Whereas high expression of HLA-C is associated with low viral set-
HLA-DQB1, or HLA-DPB1 molecules that correlate with clinical point in HIV-AIDS, high expression of HLA-C is associated with
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outcome. Analysis of each allele-defined mismatch yielded four increased risk of Crohn disease. In a recent analysis of unrelated
HLA-A, one HLA-B, seven HLA-C, two HLA-DR/DQ, and two donor transplants mismatched for only a single HLA-C determinant,
HLA-DP mismatch combinations to be significantly associated with the level of HLA-C expression was found to be informative for per-
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increased posttransplant complications. Each allele was subsequently missive and nonpermissive HLA-C mismatches. As the level of
defined by its putative amino acid sequence, and all polymorphic expression of the patient’s mismatched HLA-C allotype increased, the
donor−recipient mismatched positions at each locus were individu- risks of acute GVHD and nonrelapse mortality also increased. When
ally analyzed for associations. Donor−recipient mismatching for mismatches were examined for C*03 and 07 (allotypes expressed at
Tyr9−Phe9 of HLA-A and for Tyr9−Ser9, Asn77−Ser77, Lys80−Asn80, the lowest levels) and C*01 and 14 (allotypes expressed at the highest
Tyr99−Phe99, Leu116–Ser116, and Arg156−Leu156 of HLA-C levels), mismatching for high-expression mismatches was associated
were identified to be clinically significant. When the study group was with increased risk when the HLA-C mismatch was also mismatched
restricted to pairs matched at HLA-C for positions 77 and 80 that at residue 116 and for natural KIR ligands. Residue 116 and KIR