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Identification of 4 novel HLA-B*40:01 restricted minor histocompatibility antigens and their potential as targets for graft-versus-leukemia reactivity.
- Source :
-
Haematologica [Haematologica] 2012 Aug; Vol. 97 (8), pp. 1196-204. Date of Electronic Publication: 2012 Mar 14. - Publication Year :
- 2012
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Abstract
- Background: Patients with hematologic malignancies can be successfully treated with donor lymphocyte infusion after HLA-matched allogeneic hematopoietic stem cell transplantation. The effect of donor lymphocyte infusion is mediated by donor T cells recognizing minor histocompatibility antigens. T cells recognizing hematopoietic restricted minor histocompatibility antigens may induce selective graft-versus-leukemia reactivity, whereas broadly-expressed antigens may be targeted in graft-versus-host disease.<br />Design and Methods: We analyzed in detail CD8(+) T-cell immunity in a patient with relapsed chronic myelogenous leukemia who responded to donor lymphocyte infusion with minimal graft-versus-host disease of the skin. CD8(+) T-cell clones specific for 4 HLA-B*40:01 restricted minor histocompatibility antigens were isolated which were identified by screening a plasmid cDNA library and whole genome association scanning. Detailed T-cell reactivity and monitoring experiments were performed to estimate the clinical and therapeutic relevance of the novel antigens.<br />Results: Three antigens were demonstrated to be expressed on primary leukemic cells of various origins as well as subtypes of non-malignant hematopoietic cells, whereas one antigen was selectively recognized on malignant hematopoietic cells with antigen presenting cell phenotype. Skin derived fibroblasts were only recognized after pre-treatment with IFN-γ by two T-cell clones.<br />Conclusions: Our data show evidence for different roles of the HLA-B*40:01 restricted minor histocompatibility antigens in the onset and execution of the anti-tumor response. All antigens may have contributed to a graft-versus-leukemia effect, and one minor histocompatibility antigen (LB-SWAP70-1Q) has specific therapeutic value based on its in vivo immunodominance and strong presentation on leukemic cells of various origins, but absence of expression on cytokine-treated fibroblasts.
- Subjects :
- Animals
CD8-Positive T-Lymphocytes immunology
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Library
Hematopoietic Stem Cell Transplantation
Humans
Leukemia genetics
Leukemia immunology
Leukemia therapy
Middle Aged
Polymorphism, Single Nucleotide
T-Lymphocytes immunology
T-Lymphocytes metabolism
Transplantation, Homologous
Graft vs Host Disease genetics
Graft vs Host Disease immunology
HLA-B40 Antigen genetics
HLA-B40 Antigen immunology
Minor Histocompatibility Antigens genetics
Minor Histocompatibility Antigens immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 97
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 22419570
- Full Text :
- https://doi.org/10.3324/haematol.2011.049478