Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes.
OBJECTIVE
Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA.


METHODS
We developed an algorithm based on genetic disparities between Y chromosome-encoded and X chromosome-encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome-derived, HLA A*0201-restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A*0201 positive.


RESULTS
Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A*0201-restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A*0201, each patient responded to a unique set of peptides.


CONCLUSIONS
Novel HLA A*0201-restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia.
Division of Hematologic Malignancies, Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Yishai
Y
Ofran
Haesook T
HT
Kim
Vladimir
V
Brusic
Loren
L
Blake
Michael
M
Mandrell
Catherine J
CJ
Wu
Stefanie
S
Sarantopoulos
Roberto
R
Bellucci
Derin B
DB
Keskin
Robert J
RJ
Soiffer
Joseph H
JH
Antin
Jerome
J
Ritz
D000328:Adult; D000465:Algorithms; D041322:Chromosomes, Human, Y / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006648:Histocompatibility / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D055815:Young Adult
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015778:Minor Histocompatibility Antigens