title: HLA class II upregulation during viral infection leads to HLA-DP-directed graft-versus-host disease after CD4+ donor lymphocyte infusion.
abstract: CD8+ T cell-depleted (TCD) donor lymphocyte infusion (DLI) after TCD allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with a reduced risk of graft-versus-host disease (GVHD) while preserving conversion to donor hematopoiesis and antitumor immunity, providing a rationale for exploring CD4+ T cell-based immunotherapy for hematologic malignancies. Here, we analyzed the clinical course and specificity of T cell immune responses in 2 patients with acute myeloid leukemia (AML) who converted to full-donor chimerism but developed severe acute GVHD after prophylactic CD4+ DLI after 10/10-HLA-matched, but HLA-DPB1-mismatched TCD-alloSCT. Clonal analysis of activated T cells isolated during GVHD demonstrated allo-reactivity exerted by CD4+ T cells directed against patient-mismatched HLA-DPB1 molecules on hematopoietic cells and skin-derived fibroblasts only when cultured under inflammatory conditions. At the time of CD4+ DLI, both patients contained residual patient-derived T cells, including cytomegalovirus (CMV)-specific T cells as a result of CMV reactivations. Once activated by CMV antigens, these CMV-specific T cells could stimulate HLA-DPB1-specific CD4+ T cells, which in turn could target nonhematopoietic tissues in GVHD. In conclusion, our data demonstrate that GVHD after HLA-DPB1-mismatched CD4+ DLI can be mediated by allo-reactive HLA-DPB1-directed CD4+ T cells and that ongoing viral infections inducing HLA class II expression on nonhematopoietic cells may increase the likelihood of GVHD development. This trial is registered at http://www.controlled-trials.com/ISRCTN51398568/LUMC as #51398568.
authors.affiliation: Department of Hematology, Leiden University Medical Center, The Netherlands;
authors.forename: Sanja
authors.initials: S
authors.lastname: Stevanovic
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: van Bergen
authors.forename: Simone A P
authors.initials: SA
authors.lastname: van Luxemburg-Heijs
authors.forename: Boris
authors.initials: B
authors.lastname: van der Zouwen
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Alwine B
authors.initials: AB
authors.lastname: Kruisselbrink
authors.forename: Marian
authors.initials: M
authors.lastname: van de Meent
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Harskamp
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.forename: Erik W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Constantijn J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000368:Aged; D001782:Blood Donors; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D006682:HLA-DP Antigens / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology* / Q000821:virology
chemical_list: D006680:HLA Antigens; D006682:HLA-DP Antigens