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Frequent HLA class I and DP sequence mismatches in serologically (HLA- A,
HLA-B, HLA-DR) and molecularly (HLA-DRB1, HLA-DQA1, HLA-DQB1) HLA-
identical unrelated bone marrow transplant pairs [published erratum appears
in Blood 1994 Jun 15;83(12):3834]
P Santamaria, NL Reinsmoen, AL Lindstrom, MT Boyce-Jacino, JJ Barbosa, AJ Faras, PB McGlave and SS Rich
Institute of Human Genetics, University of Minnesota, Minneapolis.
The rates of graft-versus-host disease (GVHD) and rejection are
significantly higher among recipients of unrelated donor marrow (BM) than
in recipients of marrow from HLA-identical siblings, even when donors and
recipients are mixed lymphocyte culture (MLC) compatible and serologically
and Dw identical. It has been hypothesized that phenotypically silent HLA
class I and DP sequence mismatches might be associated with these
differences, but little is known about their incidence. We have sequenced
the HLA-A, HLA-B, HLA-C, HLA-DPA1, and HLA- DPB1 genes expressed by 12
unrelated marrow transplant pairs, 11 of whom were molecularly matched at
DRB, DQA1, and DQB1 loci. Nine of these pairs were also HLA-A and HLA-B
matched by serology. Six of these nine "HLA-identical" pairs were HLA-A (2
of 6), HLA-B (1 of 6), and HLA- C (6 of 6) mismatched at the sequence
level. The mismatched class I alleles of all these pairs had strikingly
different sequence motifs in the six specificity pockets of their antigen
recognition site, and in five pairs they also had sequence differences at
positions implicated in T-cell receptor (TCR) binding. Two of the three
pairs who were serologically mismatched for one HLA-A or HLA-B antigen were
also sequence mismatched at HLA-C. Finally, 10 of 11 pairs tested expressed
different DP sequences. These data indicate that HLA class I, especially
HLA-C, and DP sequence mismatches are frequent among unrelated subjects
defined as HLA identical by current typing methods. We speculate that these
sequence differences may explain, at least in part, the higher incidence of
acute GVHD and rejection in unrelated BM transplantation as opposed to
transplantation between HLA-identical siblings. Because of their high
frequency, the role of HLA-A, HLA-B, HLA-C, and HLA-DP mismatches in
transplantation outcome is now amenable to direct study.
Volume 83,
Issue 1,
pp. 280-287,
01/01/1994
Copyright © 1994 by The American Society of Hematology
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