A human minor histocompatibility antigen specific for B cell acute lymphoblastic leukemia.
Human minor histocompatibility antigens (mHags) play an important role in the induction of cytotoxic T lymphocyte (CTL) reactivity against leukemia after human histocompatibility leukocyte antigen (HLA)-identical allogeneic bone marrow transplantation (BMT). As most mHags are not leukemia specific but are also expressed by normal tissues, antileukemia reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Here, we describe a novel mHag, HB-1, that elicits donor-derived CTL reactivity in a B cell acute lymphoblastic leukemia (B-ALL) patient treated by HLA-matched BMT. We identified the gene encoding the antigenic peptide recognized by HB-1-specific CTLs. Interestingly, expression of the HB-1 gene was only observed in B-ALL cells and Epstein-Barr virus-transformed B cells. The HB-1 gene-encoded peptide EEKRGSLHVW is recognized by the CTL in association with HLA-B44. Further analysis reveals that a polymorphism in the HB-1 gene generates a single amino acid exchange from His to Tyr at position 8 within this peptide. This amino acid substitution is critical for recognition by HB-1-specific CTLs. The restricted expression of the polymorphic HB-1 Ag by B-ALL cells and the ability to generate HB-1-specific CTLs in vitro using peptide-loaded dendritic cells offer novel opportunities to specifically target the immune system against B-ALL without the risk of evoking GVHD.
Dolstra
H
H
Department of Hematology, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands. h.dolstra@chl.azn.nl
Fredrix
H
H
Maas
F
F
Coulie
P G
PG
Brasseur
F
F
Mensink
E
E
Adema
G J
GJ
de Witte
T M
TM
Figdor
C G
CG
van de Wiel-van Kemenade
E
E
D000595:Amino Acid Sequence; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology; D002051:Burkitt Lymphoma / Q000276:immunology*; D002460:Cell Line; D002999:Clone Cells / Q000276:immunology; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D010375:Pedigree; D010446:Peptide Fragments / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics; D017421:Sequence Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018076:DNA, Complementary; D006680:HLA Antigens; D015235:HLA-B Antigens; C117270:HMHB1 protein, human; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments