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

Research output: Contribution to journalArticle

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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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Cell Transplantation
HLA Antigens
Leukemia
T-Lymphocytes
Transplants
Hematopoietic Stem Cell Transplantation
Stem Cells
Clone Cells
Tissue Donors
Antigens
Transformed Cell Line
Blocking Antibodies
Human Herpesvirus 4
Siblings
Blood Cells
B-Lymphocytes
Fibroblasts
Alleles
Cytokines

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Mismatched human leukocyte antigen class II-restricted CD8+ cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation. In: Cancer Science. 2011 ; Vol. 102, No. 7. pp. 1281-1286.
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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.",
author = "Tomoya Hirosawa and Hiroki Torikai and Mayumi Yanagisawa and Michi Kamei and Nobuhiko Imahashi and Ayako Demachi-Okamura and Miyoko Tanimoto and Keiko Shiraishi and Mamoru Ito and Koichi Miyamura and Kiyosumi Shibata and Fumitaka Kikkawa and Yasuo Morishima and Toshitada Takahashi and Nobuhiko Emi and Kiyotaka Kuzushima and Yoshiki Akatsuka",
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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, vol. 102, no. 7, pp. 1281-1286. https://doi.org/10.1111/j.1349-7006.2011.01949.x

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

In: Cancer Science, Vol. 102, No. 7, 01.07.2011, p. 1281-1286.

Research output: Contribution to journalArticle

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T1 - Mismatched human leukocyte antigen class II-restricted CD8+ cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation

AU - Hirosawa, Tomoya

AU - Torikai, Hiroki

AU - Yanagisawa, Mayumi

AU - Kamei, Michi

AU - Imahashi, Nobuhiko

AU - Demachi-Okamura, Ayako

AU - Tanimoto, Miyoko

AU - Shiraishi, Keiko

AU - Ito, Mamoru

AU - Miyamura, Koichi

AU - Shibata, Kiyosumi

AU - Kikkawa, Fumitaka

AU - Morishima, Yasuo

AU - Takahashi, Toshitada

AU - Emi, Nobuhiko

AU - Kuzushima, Kiyotaka

AU - Akatsuka, Yoshiki

PY - 2011/7/1

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N2 - 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.

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