在同种异体造血干细胞移植 (alloSCT) 中，同种异体反应性供体 T 细胞介导移植物抗白血病 (GVL) 效应，但也会攻击非造血组织，导致移植物抗宿主病 (GVHD)。减少同种反应性 T 细胞向 GVHD 靶组织的运输，同时允许它们进入骨髓 (BM) 和脾脏（恶性造血的主要部位），是使用同种反应性 T 细胞作为治疗剂时降低 GVHD 风险的合理策略。在这里，我们发现，在未操作的小鼠和未移植同种异体反应性 T 细胞的小鼠中，效应 T 细胞 (Teff) 进入 BM 和脾脏会受到百日咳毒素敏感 (PTX) 趋化因子受体信号传导的增强。然而，出乎意料的是，在存在 GVH 反应的情况下，趋化因子不再将 T 细胞吸引到 BM 和脾脏中，但对于它们招募到 GVHD 靶组织仍然至关重要。与此一致的是，在同时发生 GVHD 反应的小鼠中，PTX 处理的 Teff 细胞在杀死小鼠 BM 和脾脏中的白血病细胞方面与未处理的 T 细胞一样有效。这些结果提出了一种在 alloSCT 背景下提高同种异体反应性 T 细胞疗法治疗白血病安全性的策略。版权所有 © 2024 美国血液学会。

In allogeneic hematopoietic stem cell transplantation (alloSCT), alloreactive donor T cells mediate the graft-versus-leukemia (GVL) effect but also attack nonhematopoietic tissues causing graft-versus-host disease (GVHD). Reducing alloreactive T cell trafficking to GVHD target tissues while allowing their access to bone marrow (BM) and spleen, major sites of malignant hematopoiesis, is a rational strategy for reducing the GVHD risk when using alloreactive T cells as a therapeutic. Here we show that effector T cell (Teff) entry into BM and spleen in unmanipulated mice and in mice transplanted without alloreactive T cells is augmented by pertussis toxin-sensitive (PTX) chemokine receptor signaling. However, unexpectedly, in the presence of a GVH response, chemokines no longer draw T cells into BM and spleen but remain critical for their recruitment to GVHD target tissues. Consistent with this, PTX-treated Teff cells were as efficacious as untreated T cells in killing leukemia cells in BM and spleen in mice with a concurrent GVHD response. These results suggest a strategy to improve the safety of alloreactive T cell therapeutics in treating leukemias in the context of an alloSCT.Copyright © 2024 American Society of Hematology.