Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice
Shoji Asakura, … , Mitsune Tanimoto, Takanori Teshima
Shoji Asakura, … , Mitsune Tanimoto, Takanori Teshima
Published June 7, 2010
Citation Information: J Clin Invest. 2010;120(7):2370-2378. https://doi.org/10.1172/JCI39165.
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Research Article Hematology

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

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.

Authors

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

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Figure 1

Alloantigen expression on host non-hematopoietic cells augments acute GVHD but reduces GVL effects.

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Alloantigen expression on host non-hematopoietic cells augments acute GV...
(A–C) [B6→C3] (diamonds) and [B6→B6] chimeras (triangles) were created by reconstituting lethally irradiated C3 and B6 mice with 5 × 106 TCD BM cells from B6 mice. Four months later, the chimeras were reirradiated and injected with 5 × 106 TCD BM cells alone (open symbols) or with 1 × 106 (black symbols) or 0.1 × 106 (gray symbols) CD8+ T cells from C3 donors (as indicated in parentheses × 106). Survival (A) and clinical GVHD scores (B) after BMT (n = 3–8/group). (C) Leukemia mortality after BMT in chimeras injected with EL4 cells (n = 5–21/group). Data from 3 similar experiments were combined. (D–F) [Db→Ba] (diamonds) and [Db→Db] (triangles) chimeras were reirradiated and injected with TCD BM alone (open symbols) or with 2 × 106 T cells from Ba donors (filled symbols). Survival (D) and clinical GVHD scores (E) after BMT from a representative experiment of 2 similar experiments (n = 4–7/group). (F) Leukemia mortality after BMT in mice injected with P815 cells. Data from 2 similar experiments were combined (n = 6–18/group). (G–I) [Ba→Db] (diamonds) and [Ba→Ba] (triangles) chimeras were similarly transplanted with 5 × 106 TCD BM cells alone (open symbols) or with 2 × 106 T cells from Db donors (filled symbols). Survival (G) and clinical scores (H) after BMT (n = 3–10/group). (I) Leukemia mortality after BMT in chimeras injected with A20 cells (n = 5–10/group). Data from 2 similar experiments were combined. Clinical scores are shown as the mean ± SEM. *P < 0.05 compared with allogeneic controls.