title: HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia.
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.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. c.e.rutten@lumc.nl
authors.forename: C E
authors.initials: CE
authors.lastname: Rutten
authors.forename: S A P
authors.initials: SA
authors.lastname: van Luxemburg-Heijs
authors.forename: M
authors.initials: M
authors.lastname: Griffioen
authors.forename: E W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: I
authors.initials: I
authors.lastname: Jedema
authors.forename: M H M
authors.initials: MH
authors.lastname: Heemskerk
authors.forename: E F M
authors.initials: EF
authors.lastname: Posthuma
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: J H F
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D020544:Graft vs Leukemia Effect; D006682:HLA-DP Antigens / Q000276:immunology*; D059868:HLA-DP beta-Chains; D018380:Hematopoietic Stem Cell Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D006650:Histocompatibility Testing; D006801:Humans; D016219:Immunotherapy, Adoptive; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged
chemical_list: D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D000949:Histocompatibility Antigens Class II