Mismatched human leukocyte antigen class II‐restricted CD8+ cytotoxic T cells may mediate selective graft‐versus‐leukemia effects following allogeneic hematopoietic cell transplantation

• Published in: Cancer science 2011-07, Vol.102 (7), p.1281-1286
• Main Authors: Hirosawa, Tomoya, Torikai, Hiroki, Yanagisawa, Mayumi, Kamei, Michi, Imahashi, Nobuhiko, Demachi‐Okamura, Ayako, Tanimoto, Miyoko, Shiraishi, Keiko, Ito, Mamoru, Miyamura, Koichi, Shibata, Kiyosumi, Kikkawa, Fumitaka, Morishima, Yasuo, Takahashi, Toshitada, Emi, Nobuhiko, Kuzushima, Kiyotaka, Akatsuka, Yoshiki
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Graft vs Host Disease - etiology; Graft vs Leukemia Effect - immunology; Hematopoietic Stem Cell Transplantation - adverse effects; Histocompatibility Testing; HLA-D Antigens - immunology; HLA-DR Antigens - immunology; HLA-DR Serological Subtypes; HLA-DRB1 Chains; Humans; Male; Medical sciences; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - surgery; Transplantation, Homologous; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2011.01949.x

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. (Cancer Sci 2011; 102: 1281–1286)