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Harry Dolstra^*, Hanny Fredrix^*, Frans Maas^*, Pierre G. Coulie, Francis Brasseur^||, Ewald Mensink^*, Gosse J. Adema, Theo M. de Witte^*, Carl G. Figdor, and Elly van de Wiel-van Kemenade^*

From the ^* Department of Hematology and the Department of Tumor Immunology, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands; and the Cellular Genetics Unit and the ^|| Ludwig Institute for Cancer Research, Université Catholique de Louvain, B-1200 Brussels, Belgium

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.

Key Words: bone marrow transplantation • cytotoxic T lymphocytes • minor histocompatibility antigens • B cell acute lymphoblastic leukemia • tumor immunity

Abbreviations used: B-ALL, B cell acute lymphoblastic leukemia; BMT, bone marrow transplantation; C_T, threshold cycle; LCL, lymphoblastoid cell line; mHag, minor histocompatibility antigen; Mo-MuLV, Moloney's murine leukemia virus; ORF, open reading frame.

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