title: Mismatched human leukocyte antigen class II-restricted CD8⁺ cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation.
abstract: Partial human leukocyte antigen (HLA)-mismatched hematopoietic stem cell transplantation (HSCT) is often performed when an HLA-matched donor is not available. In these cases, CD8(+) or CD4(+) T cell responses are induced depending on the mismatched HLA class I or II allele(s). Herein, we report on an HLA-DRB1*08:03-restricted CD8(+) CTL clone, named CTL-1H8, isolated from a patient following an HLA-DR-mismatched HSCT from his brother. Lysis of a patient Epstein-Barr virus-transformed B cell line (B-LCL) by CTL-1H8 was inhibited after the addition of blocking antibodies against HLA-DR and CD8, whereas antibodies against pan-HLA class I or CD4 had no effect. The 1H8-CTL clone did not lyse the recipient dermal fibroblasts whose HLA-DRB1*08:03 expression was upregulated after 1 week cytokine treatment. Engraftment of HLA-DRB1*08:03-positive primary leukemic stem cells in non-obese diabetic/severe combined immunodeficient/γc-null (NOG) mice was completely inhibited by the in vitro preincubation of cells with CTL-1H8, suggesting that HLA-DRB1*08:03 is expressed on leukemic stem cells. Finally, analysis of the precursor frequency of CD8(+) CTL specific for recipient antigens in post-HSCT peripheral blood T cells revealed a significant fraction of the total donor CTL responses towards the individual mismatched HLA-DR antigen in two patients. These findings underscore unexpectedly significant CD8 T cell responses in the context of HLA class II.
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirosawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Torikai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Michi
authors.initials: M
authors.lastname: Kamei
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Imahashi
authors.forename: Ayako
authors.initials: A
authors.lastname: Demachi-Okamura
authors.forename: Miyoko
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyamura
authors.forename: Kiyosumi
authors.initials: K
authors.lastname: Shibata
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takahashi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Emi
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akatsuka
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006086:Graft vs Host Disease / Q000209:etiology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D059810:HLA-DR Serological Subtypes; D059811:HLA-DRB1 Chains; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000601:surgery; D014184:Transplantation, Homologous
chemical_list: D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C041559:HLA-DR8 antigen; D059811:HLA-DRB1 Chains