Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Yukimi Sakoda, Daigo Hashimoto, Shoji Asakura, Kengo Takeuchi, Mine Harada, Mitsune Tanimoto, Takanori Teshima

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood.We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

Original languageEnglish
Pages (from-to)1756-1764
Number of pages9
JournalBlood
Volume109
Issue number4
DOIs
Publication statusPublished - Feb 15 2007

Fingerprint

T-cells
Graft vs Host Disease
Grafts
T-Lymphocytes
Transplantation (surgical)
Bone
Homologous Transplantation
Bone Marrow Transplantation
Thymectomy
Thymus
Adoptive Transfer
Inbred C3H Mouse
Antigen-Presenting Cells
Major Histocompatibility Complex
Bone Marrow Cells
Thymus Gland
Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Sakoda, Y., Hashimoto, D., Asakura, S., Takeuchi, K., Harada, M., Tanimoto, M., & Teshima, T. (2007). Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood, 109(4), 1756-1764. https://doi.org/10.1182/blood-2006-08-042853

Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. / Sakoda, Yukimi; Hashimoto, Daigo; Asakura, Shoji; Takeuchi, Kengo; Harada, Mine; Tanimoto, Mitsune; Teshima, Takanori.

In: Blood, Vol. 109, No. 4, 15.02.2007, p. 1756-1764.

Research output: Contribution to journalArticle

Sakoda, Y, Hashimoto, D, Asakura, S, Takeuchi, K, Harada, M, Tanimoto, M & Teshima, T 2007, 'Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease', Blood, vol. 109, no. 4, pp. 1756-1764. https://doi.org/10.1182/blood-2006-08-042853
Sakoda Y, Hashimoto D, Asakura S, Takeuchi K, Harada M, Tanimoto M et al. Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood. 2007 Feb 15;109(4):1756-1764. https://doi.org/10.1182/blood-2006-08-042853
Sakoda, Yukimi ; Hashimoto, Daigo ; Asakura, Shoji ; Takeuchi, Kengo ; Harada, Mine ; Tanimoto, Mitsune ; Teshima, Takanori. / Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. In: Blood. 2007 ; Vol. 109, No. 4. pp. 1756-1764.
@article{a682dab4facb4a05bf7ed890c50e77e6,
title = "Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease",
abstract = "Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood.We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.",
author = "Yukimi Sakoda and Daigo Hashimoto and Shoji Asakura and Kengo Takeuchi and Mine Harada and Mitsune Tanimoto and Takanori Teshima",
year = "2007",
month = "2",
day = "15",
doi = "10.1182/blood-2006-08-042853",
language = "English",
volume = "109",
pages = "1756--1764",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

AU - Sakoda, Yukimi

AU - Hashimoto, Daigo

AU - Asakura, Shoji

AU - Takeuchi, Kengo

AU - Harada, Mine

AU - Tanimoto, Mitsune

AU - Teshima, Takanori

PY - 2007/2/15

Y1 - 2007/2/15

N2 - Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood.We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

AB - Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood.We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

UR - http://www.scopus.com/inward/record.url?scp=33846910425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846910425&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-08-042853

DO - 10.1182/blood-2006-08-042853

M3 - Article

VL - 109

SP - 1756

EP - 1764

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -