1. Identification of phosphatidylinositol 4-kinase type II beta as HLA class II-restricted target in graft versus leukemia reactivity.
- Author
-
Griffioen M, van der Meijden ED, Slager EH, Honders MW, Rutten CE, van Luxemburg-Heijs SA, von dem Borne PA, van Rood JJ, Willemze R, and Falkenburg JH
- Subjects
- 1-Phosphatidylinositol 4-Kinase chemistry, Amino Acid Sequence, Base Sequence, CD4-Positive T-Lymphocytes immunology, Cell Separation, Clone Cells, DNA, Complementary genetics, Epitopes chemistry, Epitopes immunology, HLA-DQ Antigens immunology, HLA-DQ beta-Chains, Hematopoietic System cytology, Hematopoietic System immunology, Histocompatibility Antigens Class II chemistry, Humans, Molecular Sequence Data, Organ Specificity, Peptides chemistry, Peptides immunology, 1-Phosphatidylinositol 4-Kinase immunology, Graft vs Host Reaction immunology, Histocompatibility Antigens Class II immunology, Leukemia enzymology, Leukemia immunology
- Abstract
Patients with hematological malignancies can be successfully treated with HLA-matched T cell-depleted allogeneic stem cell transplantation (alloSCT) and subsequent donor lymphocyte infusions (DLIs). The efficacy of DLI is mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on malignant recipient cells. Because HLA class II molecules are predominantly expressed on hematopoietic cells, mHag-specific CD4(+) T cells may selectively mediate graft versus leukemia (GvL) reactivity without graft versus host disease (GvHD). In this study, we used a recombinant bacteria cDNA library for the identification of the first autosomal HLA class II (HLA-DQB1*0603)-restricted mHag LB-PI4K2B-1S encoded by the broadly expressed phosphatidylinositol 4-kinase type II beta gene. A polyclonal CD4(+) T cell response against LB-PI4K2B-1S was demonstrated in a patient with relapsed chronic myeloid leukemia (CML) who responded to DLI after HLA-matched alloSCT. LB-PI4K2B-1S-specific CD4(+) T cells recognized and lysed the CD34(+) CML cells of the patient and other leukemic cells as well as high HLA-DQ-expressing normal hematopoietic cells. HLA-DQ expression on normal cells of nonhematopoietic origin was moderately up-regulated by IFN-gamma and not sufficient for T cell recognition. We hypothesize that LB-PI4K2B-1S-specific CD4(+) T cells contributed to the antitumor response by both directly eliminating malignant cells as effector cells and stimulating CD8(+) T cell immunity as helper cells.
- Published
- 2008
- Full Text
- View/download PDF