11 results on '"Willemze, Roel"'
Search Results
2. High-throughput characterization of 10 new minor histocompatibility antigens by whole genome association scanning.
- Author
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Van Bergen CA, Rutten CE, Van Der Meijden ED, Van Luxemburg-Heijs SA, Lurvink EG, Houwing-Duistermaat JJ, Kester MG, Mulder A, Willemze R, Falkenburg JH, and Griffioen M
- Subjects
- Anemia, Refractory blood, Anemia, Refractory etiology, Anemia, Refractory surgery, CD8-Positive T-Lymphocytes immunology, Cells, Cultured, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Female, Genome, Human genetics, Hematopoietic Stem Cell Transplantation methods, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive surgery, Male, Myelodysplastic Syndromes complications, Polymerase Chain Reaction, Sequence Analysis, DNA, Transplantation, Homologous, CD8-Positive T-Lymphocytes metabolism, Genome-Wide Association Study methods, Minor Histocompatibility Antigens genetics, Polymorphism, Single Nucleotide
- Abstract
Patients with malignant diseases can be effectively treated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Polymorphic peptides presented in HLA molecules, the so-called minor histocompatibility antigens (MiHA), play a crucial role in antitumor immunity as targets for alloreactive donor T cells. Identification of multiple MiHAs is essential to understand and manipulate the development of clinical responses after allo-SCT. In this study, CD8+ T-cell clones were isolated from leukemia patients who entered complete remission after allo-SCT, and MiHA-specific T-cell clones were efficiently selected for analysis of recognition of a panel of EBV-transformed B cells positive for the HLA restriction elements of the selected T-cell clones. One million single nucleotide polymorphisms (SNP) were determined in the panel cell lines and investigated for matching with the T-cell recognition data by whole genome association scanning (WGAs). Significant association with 12 genomic regions was found, and detailed analysis of genes located within these genomic regions revealed SNP disparities encoding polymorphic peptides in 10 cases. Differential recognition of patient-type, but not donor-type, peptides validated the identification of these MiHAs. Using tetramers, distinct populations of MiHA-specific CD8+ T cells were detected, demonstrating that our WGAs strategy allows high-throughput discovery of relevant targets in antitumor immunity after allo-SCT., (Copyright © 2010 AACR.)
- Published
- 2010
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3. Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity.
- Author
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Stumpf AN, van der Meijden ED, van Bergen CA, Willemze R, Falkenburg JH, and Griffioen M
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- Antigens, CD genetics, Antigens, CD immunology, DNA, Complementary, Enzyme-Linked Immunosorbent Assay, Epitopes, Fibroblasts immunology, Fibroblasts metabolism, Focal Adhesion Kinase 2 genetics, Focal Adhesion Kinase 2 immunology, Hematopoietic Stem Cell Transplantation, Hematopoietic System cytology, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Humans, Lectins, C-Type genetics, Lectins, C-Type immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Methylenetetrahydrofolate Dehydrogenase (NADP) genetics, Methylenetetrahydrofolate Dehydrogenase (NADP) immunology, Polymorphism, Single Nucleotide, Receptors, Cell Surface genetics, Receptors, Cell Surface immunology, Skin cytology, Skin immunology, Skin metabolism, Transplantation, Homologous, Tumor Cells, Cultured, CD4-Positive T-Lymphocytes immunology, Graft vs Host Disease immunology, Graft vs Leukemia Effect immunology, HLA-DR Antigens immunology, Hematopoietic System immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Minor Histocompatibility Antigens immunology
- Abstract
Potent graft-versus-leukemia (GVL) effects can be mediated by donor-derived T cells recognizing minor histocompatibility antigens (mHags) in patients treated with donor lymphocyte infusion (DLI) for relapsed hematologic malignancies after HLA-matched allogeneic stem cell transplantation (alloSCT). Donor-derived T cells, however, may not only induce GVL, but also mediate detrimental graft-versus-host disease (GVHD). Because HLA-class II is under noninflammatory conditions predominantly expressed on hematopoietic cells, CD4+ T cells administered late after alloSCT may selectively confer GVL without GVHD. Although a broad range of different HLA-class I-restricted mHags have been identified, the first 2 autosomal HLA-class II-restricted mHags have only recently been characterized. By screening a recombinant bacteria cDNA expression library, we identified 4 new HLA-class II-restricted mHags recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia who achieved long-term complete remission and experienced only mild GVHD of the skin after DLI. All CD4+ T cells were capable of recognizing the mHags presented by HLA-DR surface molecules on primary hematopoietic cells, but not on skin-derived (cytokine-treated) fibroblasts. The selective recognition of hematopoietic cells as well as the balanced population frequencies and common HLA-DR restriction elements make the novel mHags possible targets for development of immunotherapeutic strategies.
- Published
- 2009
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4. Kinetic preservation of dual specificity of coprogrammed minor histocompatibility antigen-reactive virus-specific T cells.
- Author
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van Loenen MM, Hagedoorn RS, Kester MG, Hoogeboom M, Willemze R, Falkenburg JH, and Heemskerk MH
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- Humans, Kinetics, Receptors, Antigen, T-Cell physiology, Cytomegalovirus immunology, Minor Histocompatibility Antigens immunology, Neoplasm Proteins immunology, T-Lymphocytes immunology
- Abstract
Adoptive transfer of antigen-specific T cells is an attractive strategy for the treatment of hematologic malignancies. It has been shown that T cells recognizing minor histocompatibility antigens (mHag) selectively expressed on hematopoietic cells mediate antileukemic reactivity after allogeneic stem cell transplantation. However, large numbers of T cells with defined specificity are difficult to attain. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of mHag-specific T-cell receptors (TCR). TCR transfer into T cells specific for persistent viruses may enable these T cells to proliferate both after encountering with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR-transferred T cells after repetitive stimulation via either the introduced antileukemic HA-2-TCR or the endogenous cytomegalovirus (CMV) specific CMV-TCR was preserved. We show that after repetitive stimulation, T cells skew to a population predominantly expressing the triggered TCR. However, HA-2-TCR-transferred CMV-specific T cells with high antileukemic HA-2-TCR expression but low CMV-TCR expression were able to persist and proliferate after repetitive stimulation with pp65. Moreover, HA-2-TCR-transferred CMV-specific T cells remained dual specific after repetitive stimulation and TCR expression could be reverted after additional stimulation via the previously nonstimulated TCR, restoring high-avidity interactions. These data imply persistence of TCR-transferred virus-specific T cells with both antileukemic and antivirus reactivity in vivo.
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- 2009
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5. Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application.
- Author
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Griffioen M, van Egmond HM, Barnby-Porritt H, van der Hoorn MA, Hagedoorn RS, Kester MG, Schwabe N, Willemze R, Falkenburg JH, and Heemskerk MH
- Subjects
- Cells, Cultured, Genetic Vectors genetics, Humans, Minor Histocompatibility Antigens genetics, Minor Histocompatibility Antigens metabolism, Protein Engineering, Minor Histocompatibility Antigens immunology, Receptors, Antigen, T-Cell immunology, Retroviridae genetics, T-Lymphocytes immunology, T-Lymphocytes virology
- Abstract
Background: Donor lymphocyte infusion is an effective form of adoptive immunotherapy for hematologic malignancies after allogeneic stem cell transplantation. Graft-versus-host disease, however, often develops due to recognition of ubiquitously-expressed minor histocompatibility antigens. Transfer of T-cell receptors recognizing hematopoiesis-restricted minor histocompatibility antigens to virus-specific T cells may be a powerful anti-tumor therapy with a low risk of graft-versus-host disease. The purpose of this study was to develop an optimal T-cell receptors-encoding multi-cistronic retroviral vector and an efficient method for generating T-cell receptors-engineered virus-specific T cells., Design and Methods: Retroviral vectors encoding the T-cell receptors for the hematopoiesis-restricted minor histocompatibility antigen HA-2 with and without selection markers were compared for T-cell receptors surface expression and HA-2-specific lysis. In addition, two different methods, i.e. peptide stimulation of CD8(+) cells and Pro5 MHC pentamer-based isolation of antigen-specific T cells, were investigated for their efficiency to generate T-cell receptors-transduced virus-specific T cells., Results: Bi-cistronic vectors without selection markers most efficiently mediated T-cell receptors surface expression and HA-2-specific lysis. Furthermore, both methods were useful for generating gene-modified cells, but the purity of virus-specific T cells was higher after pentamer isolation. Finally, the capacity of gene-modified cells to express the transgenic T-cell receptors at the cell surface markedly differed between virus-specific T cells and was correlated with lysis of relevant target cells., Conclusions: Our data support T-cell receptors gene transfer to pentamer-isolated virus-specific T cells using bi-cistronic retroviral vectors and illustrate the relevance of selection of gene-modified T cells with appropriate transgenic T-cell receptors surface expression for clinical gene therapy.
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- 2008
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6. Multiple myeloma-reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene.
- Author
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van Bergen CA, Kester MG, Jedema I, Heemskerk MH, van Luxemburg-Heijs SA, Kloosterboer FM, Marijt WA, de Ru AH, Schaafsma MR, Willemze R, van Veelen PA, and Falkenburg JH
- Subjects
- Epitope Mapping, Female, Gene Expression Regulation, Graft vs Host Disease immunology, Hematopoietic Stem Cells immunology, Humans, Immunotherapy, Lymphocyte Activation immunology, Lymphocyte Transfusion, Male, Multiple Myeloma therapy, Organ Specificity immunology, Remission Induction, Stem Cell Transplantation, Adenosine Triphosphatases immunology, Antigens, Neoplasm immunology, Epitopes, T-Lymphocyte immunology, Graft vs Tumor Effect immunology, Minor Histocompatibility Antigens immunology, Molecular Chaperones immunology, Multiple Myeloma immunology, Peptides immunology, T-Lymphocytes immunology, Transplantation Chimera immunology
- Abstract
Minor histocompatibility antigens (mHags) play an important role in both graft-versus-tumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infusion. A frequently occurring single nucleotide polymorphism in the human ATP-dependent interferon-responsive (ADIR) gene was found to encode the epitope we designated LB-ADIR-1F. Although gene expression could be found in cells from hematopoietic as well as nonhematopoietic tissues, the patient suffered from only mild acute GVHD despite high percentages of circulating LB-ADIR-1F-specific T cells. Differential recognition of nonhematopoietic cell types and resting hematopoietic cells as compared with activated B cells, T cells, and tumor cells was demonstrated, illustrating variable LB-ADIR-1F expression depending on the cellular activation state. In conclusion, the novel mHag LB-ADIR-1F may be a suitable target for cellular immunotherapy when applied under controlled circumstances.
- Published
- 2007
- Full Text
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7. Up-regulated expression in nonhematopoietic tissues of the BCL2A1-derived minor histocompatibility antigens in response to inflammatory cytokines: relevance for allogeneic immunotherapy of leukemia.
- Author
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Kloosterboer FM, van Luxemburg-Heijs SA, van Soest RA, van Egmond HM, Willemze R, and Falkenburg JH
- Subjects
- Cytokines immunology, Humans, Immunotherapy, Inflammation immunology, Interferon-gamma immunology, Leukemia therapy, Male, Minor Histocompatibility Antigens genetics, Polymorphism, Genetic, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Stromal Cells immunology, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha immunology, Up-Regulation, Graft vs Host Disease immunology, Graft vs Leukemia Effect immunology, Leukemia immunology, Minor Histocompatibility Antigens immunology, Proto-Oncogene Proteins c-bcl-2 immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
T cells directed against hematopoietic-restricted minor histocompatibility antigens (mHags) may mediate graft-versus-leukemia (GVL) reactivity without graft-versus-host disease (GVHD). Recently, the HLA-A24-restricted mHag ACC-1 and the HLA-B44-restricted mHag ACC-2 encoded by separate polymorphisms within the BCL2A1 gene were characterized. Hematopoietic-restricted expression was suggested for these mHags. We demonstrate BCL2-related protein A1 (BCL2A1) mRNA expression in mesenchymal stromal cells (MSCs) that was up-regulated by the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and/or interferon gamma (IFN-gamma). Analysis of cytotoxicity and IFN-gamma production illustrated that ACC-2-specific T cells did not recognize untreated MSCs or IFN-gamma-treated MSCs but showed specific recognition and killing of MSCs treated with TNF-alpha plus IFN-gamma. We hypothesize that under steady-state circumstances BCL2A1-specific T cells may exhibit relative specificity for hematopoietic tissue, but reactivity against nonhematopoietic cells may occur when inflammatory infiltrates are present. Thus, the role of BCL2A1-specific T cells in differential induction of GVL reactivity and GVHD may depend on the presence of inflammatory responses that may occur during GVHD.
- Published
- 2005
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8. Minor histocompatibility antigens as targets of cellular immunotherapy in leukaemia.
- Author
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Falkenburg JH and Willemze R
- Subjects
- Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Humans, T-Lymphocytes immunology, T-Lymphocytes transplantation, Transplantation Immunology, Immunotherapy, Adoptive methods, Leukemia therapy, Minor Histocompatibility Antigens immunology
- Abstract
Allogeneic human-leukocyte-antigen-matched stem cell transplantation is associated with a lower risk of relapse of leukaemia than autologous transplantation due to a T-cell-mediated graft-vs.-leukaemia effect. Replacement of patient haematopoiesis by donor haematopoiesis allows the application of donor-derived specifically targeted cellular immunotherapy for the treatment of leukaemia. Following allogeneic transplantation, donor-derived T cells recognizing minor histocompatibility antigens expressed on haematopoietic cells from the patient may result in eradication of all haematopoietic cells of recipient origin. Since after transplantation, normal haematopoiesis is of donor origin, these T-cell responses may result in establishment of full donor chimerism associated with elimination of the haematological malignancy. By targeting the immune response to minor histocompatibility antigens that are not expressed on non-haematopoietic tissues, graft-vs.-host reactions may be limited. Several methods can be used for in vitro selection of T-cell responses with high specificity for malignant cells, and in vitro manipulation of donor T cells including transfer of antigen-specific T-cell receptors may greatly enhance specificity and efficacy of donor-derived cellular immunotherapy of haematological malignancies.
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- 2004
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9. Minor histocompatibility antigens in human stem cell transplantation.
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Falkenburg JH, van de Corput L, Marijt EW, and Willemze R
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- Graft Rejection etiology, Graft Rejection immunology, Graft vs Host Disease etiology, Graft vs Host Disease immunology, Graft vs Leukemia Effect immunology, Humans, Transplantation, Homologous, Minor Histocompatibility Antigens immunology, Stem Cell Transplantation, Transplantation Immunology
- Abstract
Minor histocompatibility antigens (mHags) play a major role in graft rejection, the induction of detrimental graft-vs-host disease (GVHD), and the development of the beneficial graft-vs-leukemia (GVL) effect after allogeneic stem cell transplantation (SCT). mHags can be defined as amino acid polymorphisms in cellular proteins that can lead to differential presentation of antigenic peptides in HLA molecules and therefore to differential recognition by T cells. The tissue distribution of the mHags and the HLA molecules by which they can be presented play a significant role in the clinical outcome of T-cell responses against these antigens. In part, differential recognition by T cells of mHags specifically expressed in hematopoietic cells, including the malignant cells from the recipient may result in GVL reactivity without concurrent GVHD. Furthermore, T-cell responses against proteins solely expressed in hematopoietic cell lineages from which the malignancy is derived may be appropriate mediators of GVL reactivity without GVHD induction. Characterization of clinical immune responses in patients treated for relapsed leukemia after allogeneic SCT with donor lymphocyte infusion in the absence of GVHD may lead to the characterization of new mHags that can be exploited to generate tumor-specific immune responses. By in vitro generation of T-cell responses against defined mHags, the efficacy and specificity of cellular immunotherapy against hematologic malignancies in the context of allogeneic transplantation may be improved.
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- 2003
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10. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia.
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Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, and Falkenburg JH
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- Bone Marrow Cells cytology, CD8 Antigens biosynthesis, CD8-Positive T-Lymphocytes metabolism, Cell Division, Chromium Radioisotopes, Chromosomes, Human, X, Chromosomes, Human, Y, Female, Fusion Proteins, bcr-abl metabolism, Genes, MHC Class I, Genetic Markers, Humans, Immunotherapy methods, In Situ Hybridization, Fluorescence, Male, Middle Aged, Models, Genetic, Peptides chemistry, Phenotype, Recurrence, Remission Induction, Stem Cell Transplantation, Time Factors, Transplantation, Homologous, Hematopoiesis, Leukemia drug therapy, Leukemia pathology, Minor Histocompatibility Antigens pharmacology, Neoplasm Proteins pharmacology, Oligopeptides pharmacology
- Abstract
Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been shown to be a successful treatment approach. The hematopoiesis-restricted minor histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of the recipient may serve as target antigens for alloreactive donor T cells. Recently we treated three mHAg HA-1- and/or HA-2-positive patients with a relapse of their disease after alloSCT with DLI from their mHAg HA-1- and/or HA-2-negative donors. Using HLA-A2HA-1 and HA-2 peptide tetrameric complexes we showed the emergence of HA-1- and HA-2-specific CD8(+) T cells in the blood of the recipients 5-7 weeks after DLI. The appearance of these tetramer-positive cells was followed immediately by a complete remission of the disease and restoration of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer-positive T cells isolated during the clinical response specifically recognized HA-1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited the growth of leukemic precursor cells in vitro. Thus, HA-1- and HA-2-specific cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate graft-versus-leukemia or myeloma reactivity resulting in a durable remission. This finding implies that in vitro generated HA-1- and HA-2-specific cytotoxic T lymphocytes could be used as adoptive immunotherapy to treat hematological malignancies relapsing after alloSCT.
- Published
- 2003
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11. The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease.
- Author
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Vogt MH, van den Muijsenberg JW, Goulmy E, Spierings E, Kluck P, Kester MG, van Soest RA, Drijfhout JW, Willemze R, and Falkenburg JH
- Subjects
- Amino Acid Sequence, CD4-Positive T-Lymphocytes immunology, DEAD-box RNA Helicases, Epitope Mapping, Epitopes analysis, Epitopes genetics, Epitopes immunology, Female, Genetic Linkage, Hematopoietic Stem Cell Transplantation adverse effects, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Humans, Male, Minor Histocompatibility Antigens genetics, Oligopeptides chemical synthesis, Oligopeptides immunology, Proteins genetics, T-Lymphocytes, Cytotoxic immunology, Graft vs Host Disease immunology, HLA-DQ Antigens immunology, Minor Histocompatibility Antigens immunology, Proteins immunology, Y Chromosome
- Abstract
Graft rejection or graft-versus-host (GVH) disease after HLA-identical stem cell transplantation is the result of recognition of minor histocompatibility antigens (mHags) by immunocompetent T lymphocytes from recipient or donor origin, respectively. Cytolytic T lymphocyte (CTL) clones can be isolated during graft rejection and GVH disease to identify mHags and their corresponding genes. Thus far, all human mHags identified appeared to be HLA class I-restricted. Here, we report the characterization of the first human HLA class II-restricted sex-linked mHag involved in GVH disease. Previously, we isolated an HLA-DQ5-restricted CD4(+) CTL clone from a male patient with chronic myeloid leukemia who developed acute GVH disease grade III-IV after transplantation of HLA genotypically identical female stem cells. Using a panel of female HLA-DQ5(+) EBV cells that we stably transfected with Y chromosome-specific genes, we determined that the HLA class II male-specific mHag (H-Y) was encoded by the Y chromosome-specific gene DBY. The H-Y epitope was localized in the DBY protein using female HLA-DQ5(+) peripheral blood mononuclear cells loaded with DBY protein fragments. The minimal peptide sequence leading to maximal recognition by the specific HLA-DQ5-restricted CTL clone was characterized as the 12-amino acid sequence HIENFSDIDMGE. Although the epitope differed by 3 amino acids from its X-homolog DBX, only 2 polymorphisms were shown to be essential for recognition by the CTL clone.
- Published
- 2002
- Full Text
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