UTY-specific TCR-transfer generates potential graft-versus-leukaemia effector T cells.
Immunotherapeutic approaches that target antigens that are differentially recognized on haematopoietic and non-haematopoietic cells may specifically enhance the graft-versus-leukaemia (GVL) effect of donor lymphocyte infusion. In this study, we have characterized a new HLA-B*5201-restricted epitope of the UTY gene. Unusually, presentation of this epitope was restricted to lymphoblasts. As a result, a T cell clone specific to this epitope recognized normal and malignant male B and T lymphoblasts, while showing little reactivity towards male HLA-B*5201+ fibroblasts. Transfer of its T cell receptor (TCR) into donor T cells led to the generation of large numbers of T cells, which acquired the specificity of the original clone, its avidity and the differential pattern of reactivity towards lymphoblasts and fibroblasts. Remarkably, the specific response of TCR-transferred T cells was significantly higher than that of the original clone. This is the first demonstration of the possibility to preserve the specific pattern of a T cell response to a differentially expressed antigen after TCR-transfer and to augment the amplitude of this response concomitantly. These results indicate that it may be feasible to enhance the GVL effect of donor lymphocyte infusions in lymphoproliferative malignancies by the transfer of TCRs specific to epitopes that are differentially recognized on lymphoblasts.
Ivanov
Roman
R
Jordan Laboratory for Haemato-Oncology, Department of Haematology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Hol
Samantha
S
Aarts
Tineke
T
Hagenbeek
Anton
A
Slager
Elisabeth H
EH
Ebeling
Saskia
S
D018929:Cell Culture Techniques; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005240:Feasibility Studies; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D017710:Lymphocyte Transfusion; D008297:Male; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000276:immunology; D011506:Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C484453:UTY protein, human; D007371:Interferon-gamma