Prediction of graft-versus-host disease in humans by donor gene-expression profiling.
BACKGROUND
Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be "stronger alloresponders" than others, and consequently more likely to elicit GVHD.


RESULTS
To this end, we measured the gene-expression profiles of CD4(+) and CD8(+) T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation.


CONCLUSIONS
These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.
Baron
Chantal
C
Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
Somogyi
Roland
R
Greller
Larry D
LD
Rineau
Vincent
V
Wilkinson
Peter
P
Cho
Carolyn R
CR
Cameron
Mark J
MJ
Kelvin
David J
DJ
Chagnon
Pierre
P
Roy
Denis-Claude
DC
Busque
Lambert
L
Sékaly
Rafick-Pierre
RP
Perreault
Claude
C
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016002:Discriminant Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000175:diagnosis*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous
C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D051900:Smad3 Protein; D054353:Perforin