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

Tomoya Hirosawa, Hiroki Torikai, Mayumi Yanagisawa, Michi Kamei, Nobuhiko Imahashi, Ayako Demachi-Okamura, Miyoko Tanimoto, Keiko Shiraishi, Mamoru Ito, Koichi Miyamura, Kiyosumi Shibata, Fumitaka Kikkawa, Yasuo Morishima, Toshitada Takahashi, Nobuhiko Emi, Kiyotaka Kuzushima, Yoshiki Akatsuka

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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 1week 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.

Original languageEnglish
Pages (from-to)1281-1286
Number of pages6
JournalCancer science
Volume102
Issue number7
DOIs
Publication statusPublished - 01-07-2011

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hirosawa, T., Torikai, H., Yanagisawa, M., Kamei, M., Imahashi, N., Demachi-Okamura, A., Tanimoto, M., Shiraishi, K., Ito, M., Miyamura, K., Shibata, K., Kikkawa, F., Morishima, Y., Takahashi, T., Emi, N., Kuzushima, K., & Akatsuka, Y. (2011). Mismatched human leukocyte antigen class II-restricted CD8+ cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation. Cancer science, 102(7), 1281-1286. https://doi.org/10.1111/j.1349-7006.2011.01949.x