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Bjoern Peters - One of the best experts on this subject based on the ideXlab platform.

  • characterization of magnitude and antigen specificity of hla dp dq and drb3 4 5 restricted denv specific cd4 t cell responses
    Frontiers in Immunology, 2019
    Co-Authors: Alba Grifoni, Eugene Moore, Hannah Voic, John Sidney, Elizabeth J Phillips, Ramesh S Jadi, S Mallal, Aruna D De Silva, Aravinda M De Silva, Bjoern Peters
    Abstract:

    Background: Dengue Virus (DENV) associated disease is a major public health problem. Assessment of HLA class II restricted DENV-specific responses is relevant for immunopathology and definition of correlates of protection. While previous studies characterized responses restricted by the HLA-DRB1 locus, the responses associated with other class II loci have not been characterized to date. Accordingly, we mapped HLA-DP, DQ, and DRB3/4/5 restricted DENV-specific CD4 T cell epitopes in PBMCs derived from the DENV endemic region Sri Lanka. Methods: We studied 12 DP, DQ, and DRB3/4/5 alleles that are commonly expressed and provide worldwide coverage >82% for each of the loci analyzed and >99% when combined. CD4+ T cells purified by negative selection were stimulated with pools of HLA-predicted binders for 2 weeks with autologous APC. Epitope reactive T cells were enumerated using IFNγ ELISPOT assay. This strategy was previously applied to identify DRB1 restricted epitopes. In parallel, membrane expression levels of HLA-DR, DP, and DQ proteins was assessed using flow cytometry. Results: Epitopes were identified for all DP, DQ, and DRB3/4/5 allelic variants albeit with magnitudes significantly lower than the ones previously observed for the DRB1 locus. This was in line with lower membrane expression of HLA-DP and DQ molecules on the PBMCs tested, as compared to HLA-DR. Significant differences between loci were observed in antigen immunodominance. Capsid responses were dominant for DRB1/3/4/5 and DP alleles but negligible for the DQ alleles. NS3 responses were dominant in the case of DRB1/3/4/5 and DQ but absent in the case of DP. NS1 responses were prominent in the case of the DP alleles, but negligible in the case of DR and DQ. In terms of epitope specificity, repertoire was largely overlapping between DRB1 and DRB3/4/5, while DP and DQ loci recognized largely distinct epitope sets. Conclusion: The HLA-DP, DQ, and DRB3/4/5 loci mediate DENV-CD4 specific immune responses of lower magnitude as compared to HLA-DRB1, consistent with their lower levels of expression. The responses are associated with distinct and characteristic patterns of immunodominance, and variable epitope overlap across loci.

Alba Grifoni - One of the best experts on this subject based on the ideXlab platform.

  • characterization of magnitude and antigen specificity of hla dp dq and drb3 4 5 restricted denv specific cd4 t cell responses
    Frontiers in Immunology, 2019
    Co-Authors: Alba Grifoni, Eugene Moore, Hannah Voic, John Sidney, Elizabeth J Phillips, Ramesh S Jadi, S Mallal, Aruna D De Silva, Aravinda M De Silva, Bjoern Peters
    Abstract:

    Background: Dengue Virus (DENV) associated disease is a major public health problem. Assessment of HLA class II restricted DENV-specific responses is relevant for immunopathology and definition of correlates of protection. While previous studies characterized responses restricted by the HLA-DRB1 locus, the responses associated with other class II loci have not been characterized to date. Accordingly, we mapped HLA-DP, DQ, and DRB3/4/5 restricted DENV-specific CD4 T cell epitopes in PBMCs derived from the DENV endemic region Sri Lanka. Methods: We studied 12 DP, DQ, and DRB3/4/5 alleles that are commonly expressed and provide worldwide coverage >82% for each of the loci analyzed and >99% when combined. CD4+ T cells purified by negative selection were stimulated with pools of HLA-predicted binders for 2 weeks with autologous APC. Epitope reactive T cells were enumerated using IFNγ ELISPOT assay. This strategy was previously applied to identify DRB1 restricted epitopes. In parallel, membrane expression levels of HLA-DR, DP, and DQ proteins was assessed using flow cytometry. Results: Epitopes were identified for all DP, DQ, and DRB3/4/5 allelic variants albeit with magnitudes significantly lower than the ones previously observed for the DRB1 locus. This was in line with lower membrane expression of HLA-DP and DQ molecules on the PBMCs tested, as compared to HLA-DR. Significant differences between loci were observed in antigen immunodominance. Capsid responses were dominant for DRB1/3/4/5 and DP alleles but negligible for the DQ alleles. NS3 responses were dominant in the case of DRB1/3/4/5 and DQ but absent in the case of DP. NS1 responses were prominent in the case of the DP alleles, but negligible in the case of DR and DQ. In terms of epitope specificity, repertoire was largely overlapping between DRB1 and DRB3/4/5, while DP and DQ loci recognized largely distinct epitope sets. Conclusion: The HLA-DP, DQ, and DRB3/4/5 loci mediate DENV-CD4 specific immune responses of lower magnitude as compared to HLA-DRB1, consistent with their lower levels of expression. The responses are associated with distinct and characteristic patterns of immunodominance, and variable epitope overlap across loci.

J.h. Frederik Falkenburg - One of the best experts on this subject based on the ideXlab platform.

  • Priming of Allo-HLA-DP-Specific Reactivity from the Naïve T Cell Compartment Is Not Exclusively Mediated by Professional Antigen-Presenting Cells.
    Biology of Blood and Marrow Transplantation, 2020
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Inge Jedema
    Abstract:

    ABSTRACT Allogeneic (allo) stem cell transplantation is applied to patients suffering from hematologic malignancies to replace the diseased hematopoietic system with cells derived from a donor stem cell graft. The majority of 10/10-matched unrelated donors are HLA-DP-mismatched, and this may result in varying degrees of the graft-versus-leukemia (GVL) effect with or without the occurrence of graft-versus-host disease (GVHD). Allo-HLA-reactive T cells are commonly present in the donor T cell repertoire, and thus a very profound alloreactive immune response can be provoked in the HLA-DP-mismatched setting. The magnitude and the diversity of the allo-HLA-DP-specific immune response likely dictates the balance between the occurrence of GVL and/or GVHD after transplantation. To understand the nature of the allo-HLA-DP-specific immune response provoked under different stimulatory conditions, immune responses were induced from both the naive and memory T cell compartments using either HLA-DP-mismatched professional antigen-presenting cells (APCs) (monocyte-derived dendritic cells [allo-DCs]) or HLA-DP-mismatched nonprofessional APCs (skin-derived fibroblasts [allo-fibroblasts]) as stimulator cells. In this study, we observed that allo-HLA-DP-reactive T cells could be provoked from both the naive and memory compartments by both types of APCs. However, the magnitude of the allo-HLA-DP-specific immune response was greater when stimulation was performed with allo-DCs. Moreover, we found that the frequency of allo-HLA-DP-reactive T cells was greater in the naive T cell compartment compared with the memory T cell compartment, but we observed a comparable lineage specificity of these allo-HLA-DP-specific reactivities. Overall, the data from this study illustrate that the presence of professional APCs of recipient origin will mostly dictate the magnitude of the allo-HLA-DP-specific immune response derived from both the naive and memory T cell compartments, but does not exclusively mediate the induction of these immune responses.

  • The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells.
    Haematologica, 2018
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Peter Van Balen, Inge Jedema
    Abstract:

    Stem cell grafts from 10/10 HLA-matched unrelated donors are often mismatched for HLA-DP. In some patients, donor T-cell responses targeting the mismatched HLA-DP allele(s) have been found to induce a specific graft-versus-leukemia effect without coinciding graft-versus-host disease, whereas in other cases significant graft-versus-host disease occurred. Cell-lineage-specific recognition patterns within the allogeneic HLA-DP-specific donor T-cell repertoire could explain the differential clinical effects mediated by donor T cells after HLA-DP-mismatched allogeneic stem cell transplantation. To unravel the composition of the HLA-DP T-cell repertoire, donor T-cell responses were provoked by in vitro stimulation with allogeneic HLA-DP-mismatched monocyte-derived dendritic cells. A strategy including depletion of reactivity against autologous dendritic cells allowed efficient identification and enrichment of allo-reactive T cells upon stimulation with HLA-DP-mismatched dendritic cells. In this study we elucidated that the allogeneic HLA-DP-restricted T-cell repertoire contained T cells with differential cell-lineage-specific recognition profiles. As expected, some of the allogeneic HLA-DP-restricted T cells showed broad recognition of a variety of hematopoietic and non-hematopoietic cell types expressing the targeted mismatched HLA-DP allele. However, a significant proportion of the allogeneic HLA-DP-restricted T cells showed restricted recognition of hematopoietic cells, including primary malignant cells, or even restricted recognition of only myeloid cells, including dendritic cells and primary acute myeloid leukemia samples, but not of other hematopoietic and non-hematopoietic cell types. These data demonstrate that the allogeneic HLA-DP-specific T-cell repertoire contains T cells that show restricted recognition of hematopoietic cells, which may contribute to the specific graft-versus-leukemia effect without coinciding graft-versus-host disease.

  • The Allo-HLA-DP Restricted T Cell Repertoire Contains a Variety of Tissue-Restricted Specificities with Therapeutic Value
    Blood, 2016
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Peter Van Balen, Rick Van De Water, Marian Van De Meent, Inge Jedema
    Abstract:

    T cell-depleted allogeneic stem cell transplantation (alloSCT) is applied in patients with hematological malignancies to reduce the risk of graft versus host disease (GvHD), but the associated increased risk of infections and disease relapse makes scheduled donor-lymphocyte-infusion (DLI) necessary. Since HLA-DP is not taken into account in the matching procedure, stem cell grafts from unrelated donors are often only 10/10 matched, and mismatched for HLA-DP. Under non-inflammatory conditions, expression of HLA-DP is restricted to hematopoietic cells. Therefore, treatment with HLA-DP mismatched donor CD4 T cells can induce a specific graft versus leukemia (GvL) effect. However, in some cases, patients receiving HLA-DP mismatched CD4 T cells suffer from GvHD mediated by a profound allo-HLA-DP specific immune response. Adoptive transfer of in-vitro selected allo-HLA-DP restricted donor T cells directed against antigens specifically expressed on hematopoietic cells may be an elegant strategy to induce a specific GvL effect without coinciding GvHD. To investigate the feasibility of this approach, the allo-HLA-DP restricted T cell repertoire was dissected to unravel potential tissue specificities and to investigate the presence of hematopoiesis-specific CD4+ T cells with therapeutic value within this compartment. To induce allo-HLA-DP directed T cell responses, HLA-DP mismatched (10/10 matched) donor/patient pairs were selected. Donor PBMC were co-cultured with patient mature monocyte-derived dendritic cells (DC) for 14 days. The donor cells were first re-stimulated with autologous DC and depleted of activated auto-reactive CD137+ T cells using magnet cell separation (MACS). The negative fraction was then stimulated with the HLA-DP mismatched patient DC to induce activation of allo-reactive T cells. These allo-reactive CD137+ CD4+ T cells were clonally isolated using flowcytometric cell sorting, and expanded. Allo-HLA-DP restricted recognition of different hematopoietic and non-hematopoietic stimulator cells by the T cell clones was assessed using IFNγ and IL-4 ELISA. The T cells were tested against a large panel of hematopoietic cells (monocytes, DC, EBV-LCL and PHA blasts) of donor and patient origin, leukemic cell samples (AML) and non-hematopoietic cells (IFNγ pretreated, HLA-class-II expressing, skin-derived fibroblasts, and target-HLA-DPB1-transduced HELA, lung, kidney, and colon carcinoma cell lines). After re-stimulation with patient DC, flowcytometry showed frequencies of 0.5-10% of allo-DC activated (CD137+) CD4+ T cells. After cell sorting 1521 T cell clones from 4 different HLA-DP mismatched patient/donor pairs were tested against donor EBV-LCL, donor DC, patient EBV-LCL and patient DC as initial screening for allo-reactivity. 80% of the T cell clones showed allo-reactivity, as defined by recognition of patient, but not donor-derived EBV-LCL and/or DC. 14% of the tested clones showed no reactivity and 6% were auto-reactive. The HLA-DP restriction was analyzed of 400 selected allo-reactive T cell clones, using a panel consisting of donor, patient and 3rd party EBV-LCL or DC, 3rd party fibroblasts and target HLA-DPB1 transduced HELA cells. Of these 400 T cell clones, 65% were confirmed to be HLA-DP restricted. From these allo-HLA-DP restricted T cell clones 80% recognized both hematopoietic and non-hematopoietic cells expressing the target allo-HLA-DPB1. The other 20% of the allo-HLA-DP restricted T cell clones only produced cytokines when stimulated with hematopoietic cells (EBV-LCL and/or DC), and not when stimulated with non-hematopoietic cells (Fibroblasts, HELA, carcinoma cell lines). Moreover, 40% of these T cell clones showing hematopoiesis-restricted recognition only recognized DC, but not EBV-LCL expressing the target HLA-DPB1 allele. These clones also recognized primary AML blasts and proliferating CD34+ progenitor cells, illustrating a myeloid lineage restricted recognition pattern. These results illustrate that reactivity of allo-HLA-DP restricted T cells is not only determined by the expression of the target HLA-DPB1 allele, but is also dictated by cell lineage-specific gene expression causing differential peptide expression in HLA-DPB1. As a result, a significant portion of the allo-HLA-DP specific T cell repertoire harbors a specific GvL recognition pattern with high therapeutic value. Disclosures No relevant conflicts of interest to declare.

  • HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia
    Leukemia, 2008
    Co-Authors: Caroline E. Rutten, S. A. P. Van Luxemburg-heijs, Marieke Griffioen, Erik W.a. Marijt, Inge Jedema, Mirjam H.m. Heemskerk, E.f.m. Posthuma, Roelof Willemze, J.h. Frederik Falkenburg
    Abstract:

    HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia

  • HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia
    Leukemia, 2008
    Co-Authors: Caroline E. Rutten, Marieke Griffioen, Erik W.a. Marijt, Inge Jedema, Mirjam H.m. Heemskerk, E.f.m. Posthuma, Roelof Willemze, S A P Van Luxemburg-heijs, J.h. Frederik Falkenburg
    Abstract:

    Mismatching for human leukocyte antigen (HLA)-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a decreased risk of disease relapse, indicating that HLA-DP may represent a target for graft-versus-leukemia (GVL) reactivity in HLA class II-expressing hematological malignancies. To investigate whether HLA-DP-specific T cells could mediate GVL reactivity following HLA-DPB1-mismatched URD-SCT and donor lymphocyte infusion (DLI), we analyzed the immune response in a patient with leukemic lymphoplasmacytic lymphoma responding to DLI without graft-versus-host disease. The emergence of leukemia-reactive CD4+ T cells during the clinical immune response was demonstrated by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot(ELISPOT)analysis. Following clonal isolation of these leukemia-reactive CD4+ T cells, blocking studies, panel studies and retroviral transduction experiments of both mismatched HLA-DPB1 alleles identified HLA-DPB1(*)0201 and HLA-DPB1(*)0301 as the targets of this immune response. The HLA-DPB1-specific CD4+ T-cell clones were capable of recognizing and lysing several HLA-DP-expressing myeloid and lymphoid hematological malignant cells. Since HLA-DP expression is mainly restricted to hematopoietic cells, HLA-DP may be used as a specific target for immunotherapy following T-cell-depleted URD-SCT. Therefore, in patients with HLA class II-expressing hematological malignancies HLA-DP-mismatched SCT may be preferable over fully matched SCT allowing DLI to induce a GVL effect.

Inge Jedema - One of the best experts on this subject based on the ideXlab platform.

  • Priming of Allo-HLA-DP-Specific Reactivity from the Naïve T Cell Compartment Is Not Exclusively Mediated by Professional Antigen-Presenting Cells.
    Biology of Blood and Marrow Transplantation, 2020
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Inge Jedema
    Abstract:

    ABSTRACT Allogeneic (allo) stem cell transplantation is applied to patients suffering from hematologic malignancies to replace the diseased hematopoietic system with cells derived from a donor stem cell graft. The majority of 10/10-matched unrelated donors are HLA-DP-mismatched, and this may result in varying degrees of the graft-versus-leukemia (GVL) effect with or without the occurrence of graft-versus-host disease (GVHD). Allo-HLA-reactive T cells are commonly present in the donor T cell repertoire, and thus a very profound alloreactive immune response can be provoked in the HLA-DP-mismatched setting. The magnitude and the diversity of the allo-HLA-DP-specific immune response likely dictates the balance between the occurrence of GVL and/or GVHD after transplantation. To understand the nature of the allo-HLA-DP-specific immune response provoked under different stimulatory conditions, immune responses were induced from both the naive and memory T cell compartments using either HLA-DP-mismatched professional antigen-presenting cells (APCs) (monocyte-derived dendritic cells [allo-DCs]) or HLA-DP-mismatched nonprofessional APCs (skin-derived fibroblasts [allo-fibroblasts]) as stimulator cells. In this study, we observed that allo-HLA-DP-reactive T cells could be provoked from both the naive and memory compartments by both types of APCs. However, the magnitude of the allo-HLA-DP-specific immune response was greater when stimulation was performed with allo-DCs. Moreover, we found that the frequency of allo-HLA-DP-reactive T cells was greater in the naive T cell compartment compared with the memory T cell compartment, but we observed a comparable lineage specificity of these allo-HLA-DP-specific reactivities. Overall, the data from this study illustrate that the presence of professional APCs of recipient origin will mostly dictate the magnitude of the allo-HLA-DP-specific immune response derived from both the naive and memory T cell compartments, but does not exclusively mediate the induction of these immune responses.

  • The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells.
    Haematologica, 2018
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Peter Van Balen, Inge Jedema
    Abstract:

    Stem cell grafts from 10/10 HLA-matched unrelated donors are often mismatched for HLA-DP. In some patients, donor T-cell responses targeting the mismatched HLA-DP allele(s) have been found to induce a specific graft-versus-leukemia effect without coinciding graft-versus-host disease, whereas in other cases significant graft-versus-host disease occurred. Cell-lineage-specific recognition patterns within the allogeneic HLA-DP-specific donor T-cell repertoire could explain the differential clinical effects mediated by donor T cells after HLA-DP-mismatched allogeneic stem cell transplantation. To unravel the composition of the HLA-DP T-cell repertoire, donor T-cell responses were provoked by in vitro stimulation with allogeneic HLA-DP-mismatched monocyte-derived dendritic cells. A strategy including depletion of reactivity against autologous dendritic cells allowed efficient identification and enrichment of allo-reactive T cells upon stimulation with HLA-DP-mismatched dendritic cells. In this study we elucidated that the allogeneic HLA-DP-restricted T-cell repertoire contained T cells with differential cell-lineage-specific recognition profiles. As expected, some of the allogeneic HLA-DP-restricted T cells showed broad recognition of a variety of hematopoietic and non-hematopoietic cell types expressing the targeted mismatched HLA-DP allele. However, a significant proportion of the allogeneic HLA-DP-restricted T cells showed restricted recognition of hematopoietic cells, including primary malignant cells, or even restricted recognition of only myeloid cells, including dendritic cells and primary acute myeloid leukemia samples, but not of other hematopoietic and non-hematopoietic cell types. These data demonstrate that the allogeneic HLA-DP-specific T-cell repertoire contains T cells that show restricted recognition of hematopoietic cells, which may contribute to the specific graft-versus-leukemia effect without coinciding graft-versus-host disease.

  • The Allo-HLA-DP Restricted T Cell Repertoire Contains a Variety of Tissue-Restricted Specificities with Therapeutic Value
    Blood, 2016
    Co-Authors: Aicha Laghmouchi, J.h. Frederik Falkenburg, Conny Hoogstraten, Peter Van Balen, Rick Van De Water, Marian Van De Meent, Inge Jedema
    Abstract:

    T cell-depleted allogeneic stem cell transplantation (alloSCT) is applied in patients with hematological malignancies to reduce the risk of graft versus host disease (GvHD), but the associated increased risk of infections and disease relapse makes scheduled donor-lymphocyte-infusion (DLI) necessary. Since HLA-DP is not taken into account in the matching procedure, stem cell grafts from unrelated donors are often only 10/10 matched, and mismatched for HLA-DP. Under non-inflammatory conditions, expression of HLA-DP is restricted to hematopoietic cells. Therefore, treatment with HLA-DP mismatched donor CD4 T cells can induce a specific graft versus leukemia (GvL) effect. However, in some cases, patients receiving HLA-DP mismatched CD4 T cells suffer from GvHD mediated by a profound allo-HLA-DP specific immune response. Adoptive transfer of in-vitro selected allo-HLA-DP restricted donor T cells directed against antigens specifically expressed on hematopoietic cells may be an elegant strategy to induce a specific GvL effect without coinciding GvHD. To investigate the feasibility of this approach, the allo-HLA-DP restricted T cell repertoire was dissected to unravel potential tissue specificities and to investigate the presence of hematopoiesis-specific CD4+ T cells with therapeutic value within this compartment. To induce allo-HLA-DP directed T cell responses, HLA-DP mismatched (10/10 matched) donor/patient pairs were selected. Donor PBMC were co-cultured with patient mature monocyte-derived dendritic cells (DC) for 14 days. The donor cells were first re-stimulated with autologous DC and depleted of activated auto-reactive CD137+ T cells using magnet cell separation (MACS). The negative fraction was then stimulated with the HLA-DP mismatched patient DC to induce activation of allo-reactive T cells. These allo-reactive CD137+ CD4+ T cells were clonally isolated using flowcytometric cell sorting, and expanded. Allo-HLA-DP restricted recognition of different hematopoietic and non-hematopoietic stimulator cells by the T cell clones was assessed using IFNγ and IL-4 ELISA. The T cells were tested against a large panel of hematopoietic cells (monocytes, DC, EBV-LCL and PHA blasts) of donor and patient origin, leukemic cell samples (AML) and non-hematopoietic cells (IFNγ pretreated, HLA-class-II expressing, skin-derived fibroblasts, and target-HLA-DPB1-transduced HELA, lung, kidney, and colon carcinoma cell lines). After re-stimulation with patient DC, flowcytometry showed frequencies of 0.5-10% of allo-DC activated (CD137+) CD4+ T cells. After cell sorting 1521 T cell clones from 4 different HLA-DP mismatched patient/donor pairs were tested against donor EBV-LCL, donor DC, patient EBV-LCL and patient DC as initial screening for allo-reactivity. 80% of the T cell clones showed allo-reactivity, as defined by recognition of patient, but not donor-derived EBV-LCL and/or DC. 14% of the tested clones showed no reactivity and 6% were auto-reactive. The HLA-DP restriction was analyzed of 400 selected allo-reactive T cell clones, using a panel consisting of donor, patient and 3rd party EBV-LCL or DC, 3rd party fibroblasts and target HLA-DPB1 transduced HELA cells. Of these 400 T cell clones, 65% were confirmed to be HLA-DP restricted. From these allo-HLA-DP restricted T cell clones 80% recognized both hematopoietic and non-hematopoietic cells expressing the target allo-HLA-DPB1. The other 20% of the allo-HLA-DP restricted T cell clones only produced cytokines when stimulated with hematopoietic cells (EBV-LCL and/or DC), and not when stimulated with non-hematopoietic cells (Fibroblasts, HELA, carcinoma cell lines). Moreover, 40% of these T cell clones showing hematopoiesis-restricted recognition only recognized DC, but not EBV-LCL expressing the target HLA-DPB1 allele. These clones also recognized primary AML blasts and proliferating CD34+ progenitor cells, illustrating a myeloid lineage restricted recognition pattern. These results illustrate that reactivity of allo-HLA-DP restricted T cells is not only determined by the expression of the target HLA-DPB1 allele, but is also dictated by cell lineage-specific gene expression causing differential peptide expression in HLA-DPB1. As a result, a significant portion of the allo-HLA-DP specific T cell repertoire harbors a specific GvL recognition pattern with high therapeutic value. Disclosures No relevant conflicts of interest to declare.

  • HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia
    Leukemia, 2008
    Co-Authors: Caroline E. Rutten, S. A. P. Van Luxemburg-heijs, Marieke Griffioen, Erik W.a. Marijt, Inge Jedema, Mirjam H.m. Heemskerk, E.f.m. Posthuma, Roelof Willemze, J.h. Frederik Falkenburg
    Abstract:

    HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia

  • HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia
    Leukemia, 2008
    Co-Authors: Caroline E. Rutten, Marieke Griffioen, Erik W.a. Marijt, Inge Jedema, Mirjam H.m. Heemskerk, E.f.m. Posthuma, Roelof Willemze, S A P Van Luxemburg-heijs, J.h. Frederik Falkenburg
    Abstract:

    Mismatching for human leukocyte antigen (HLA)-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a decreased risk of disease relapse, indicating that HLA-DP may represent a target for graft-versus-leukemia (GVL) reactivity in HLA class II-expressing hematological malignancies. To investigate whether HLA-DP-specific T cells could mediate GVL reactivity following HLA-DPB1-mismatched URD-SCT and donor lymphocyte infusion (DLI), we analyzed the immune response in a patient with leukemic lymphoplasmacytic lymphoma responding to DLI without graft-versus-host disease. The emergence of leukemia-reactive CD4+ T cells during the clinical immune response was demonstrated by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot(ELISPOT)analysis. Following clonal isolation of these leukemia-reactive CD4+ T cells, blocking studies, panel studies and retroviral transduction experiments of both mismatched HLA-DPB1 alleles identified HLA-DPB1(*)0201 and HLA-DPB1(*)0301 as the targets of this immune response. The HLA-DPB1-specific CD4+ T-cell clones were capable of recognizing and lysing several HLA-DP-expressing myeloid and lymphoid hematological malignant cells. Since HLA-DP expression is mainly restricted to hematopoietic cells, HLA-DP may be used as a specific target for immunotherapy following T-cell-depleted URD-SCT. Therefore, in patients with HLA class II-expressing hematological malignancies HLA-DP-mismatched SCT may be preferable over fully matched SCT allowing DLI to induce a GVL effect.

Aravinda M De Silva - One of the best experts on this subject based on the ideXlab platform.

  • characterization of magnitude and antigen specificity of hla dp dq and drb3 4 5 restricted denv specific cd4 t cell responses
    Frontiers in Immunology, 2019
    Co-Authors: Alba Grifoni, Eugene Moore, Hannah Voic, John Sidney, Elizabeth J Phillips, Ramesh S Jadi, S Mallal, Aruna D De Silva, Aravinda M De Silva, Bjoern Peters
    Abstract:

    Background: Dengue Virus (DENV) associated disease is a major public health problem. Assessment of HLA class II restricted DENV-specific responses is relevant for immunopathology and definition of correlates of protection. While previous studies characterized responses restricted by the HLA-DRB1 locus, the responses associated with other class II loci have not been characterized to date. Accordingly, we mapped HLA-DP, DQ, and DRB3/4/5 restricted DENV-specific CD4 T cell epitopes in PBMCs derived from the DENV endemic region Sri Lanka. Methods: We studied 12 DP, DQ, and DRB3/4/5 alleles that are commonly expressed and provide worldwide coverage >82% for each of the loci analyzed and >99% when combined. CD4+ T cells purified by negative selection were stimulated with pools of HLA-predicted binders for 2 weeks with autologous APC. Epitope reactive T cells were enumerated using IFNγ ELISPOT assay. This strategy was previously applied to identify DRB1 restricted epitopes. In parallel, membrane expression levels of HLA-DR, DP, and DQ proteins was assessed using flow cytometry. Results: Epitopes were identified for all DP, DQ, and DRB3/4/5 allelic variants albeit with magnitudes significantly lower than the ones previously observed for the DRB1 locus. This was in line with lower membrane expression of HLA-DP and DQ molecules on the PBMCs tested, as compared to HLA-DR. Significant differences between loci were observed in antigen immunodominance. Capsid responses were dominant for DRB1/3/4/5 and DP alleles but negligible for the DQ alleles. NS3 responses were dominant in the case of DRB1/3/4/5 and DQ but absent in the case of DP. NS1 responses were prominent in the case of the DP alleles, but negligible in the case of DR and DQ. In terms of epitope specificity, repertoire was largely overlapping between DRB1 and DRB3/4/5, while DP and DQ loci recognized largely distinct epitope sets. Conclusion: The HLA-DP, DQ, and DRB3/4/5 loci mediate DENV-CD4 specific immune responses of lower magnitude as compared to HLA-DRB1, consistent with their lower levels of expression. The responses are associated with distinct and characteristic patterns of immunodominance, and variable epitope overlap across loci.