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: Sanja Stevanovic, Cornelis A M van Bergen, Simone A P van Luxemburg-Heijs, Boris van der Zouwen, Ekaterina S Jordanova, Alwine B Kruisselbrink, Marian van de Meent, Jessica C Harskamp, Frans H J Claas, Erik W A Marijt, Jaap Jan Zwaginga, Constantijn J M Halkes, Inge Jedema, Marieke Griffioen, J H Frederik Falkenburg
• Journal: Blood (Blood) Vol. 122 Issue 11 Pg. 1963-73 (Sep 12 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23777765 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA Antigens
• HLA-DP Antigens

Topics

• Aged
• Blood Donors
• CD4-Positive T-Lymphocytes (immunology, transplantation)
• Cells, Cultured
• Cytomegalovirus (immunology)
• Female
• Graft vs Host Disease (immunology)
• HLA Antigens (immunology, metabolism)
• HLA-DP Antigens (immunology)
• Hematologic Neoplasms (immunology, therapy)
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• Immunotherapy, Adoptive (methods)
• Male
• Middle Aged
• Outcome Assessment, Health Care
• Transplantation, Homologous
• Up-Regulation (immunology)
• Virus Diseases (immunology, virology)