Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice

Shoji Asakura, Daigo Hashimoto, Shuichiro Takashima, Haruko Sugiyama, Yoshinobu Maeda, Koichi Akashi, Mitsune Tanimoto, Takanori Teshima

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Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.

Original languageEnglish
Pages (from-to)2370-2378
Number of pages9
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
Publication statusPublished - Jul 1 2010

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All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Asakura, S., Hashimoto, D., Takashima, S., Sugiyama, H., Maeda, Y., Akashi, K., ... Teshima, T. (2010). Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice. Journal of Clinical Investigation, 120(7), 2370-2378. https://doi.org/10.1172/JCI39165