MHC haplotype matching for unrelated hematopoietic cell transplantation.
BACKGROUND
Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.


RESULTS
We isolated DNA strands extending across 2 million base pairs of the MHC to determine the physical linkage of HLA-A, -B, and -DRB1 alleles in 246 HCT recipients and their HLA-A, -B, -C, -DRB1, -DQB1 allele-matched unrelated donors. MHC haplotype mismatching was associated with a statistically significantly increased risk of severe acute GVHD (odds ratio 4.51; 95% confidence interval [CI], 2.34-8.70, p < 0.0001) and with lower risk of disease recurrence (hazard ratio 0.45; 95% CI, 0.22-0.92, p = 0.03).


CONCLUSIONS
The MHC harbors genes that encode unidentified transplantation antigens. The three-locus HLA-A, -B, -DRB1 haplotype serves as a proxy for GVHD risk among HLA-identical transplant recipients. The phasing method provides an approach for mapping novel MHC-linked transplantation determinants and a means to decrease GVHD-related morbidity after HCT from unrelated donors.
Petersdorf
Effie W
EW
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. epetersd@fhcrc.org
Malkki
Mari
M
Gooley
Ted A
TA
Martin
Paul J
PJ
Guo
Zhen
Z
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D008040:Genetic Linkage; D006086:Graft vs Host Disease; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007223:Infant; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009026:Mortality; D012008:Recurrence; D016896:Treatment Outcome
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains