Zhao Kai, Zhu Jieqing, Rosenberger Sarah, Zhou Meng, Shlomchik Warren D
Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
Blood Adv. 2025 Jan 14;9(1):209-221. doi: 10.1182/bloodadvances.2024013291.
In allogeneic hematopoietic stem cell transplantation (allo-SCT), alloreactive donor T cells mediate the graft-versus-leukemia 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 that received transplantation without alloreactive T cells is augmented by pertussis toxin (PTX)-sensitive 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 allo-SCT.
在异基因造血干细胞移植（allo-SCT）中，同种异体反应性供体T细胞介导移植物抗白血病效应，但也会攻击非造血组织，导致移植物抗宿主病（GVHD）。在将同种异体反应性T细胞用作治疗手段时，减少同种异体反应性T细胞向GVHD靶组织的迁移，同时使其能够进入恶性造血的主要部位骨髓（BM）和脾脏，是降低GVHD风险的合理策略。在此，我们表明，在未处理的小鼠以及接受无同种异体反应性T细胞移植的小鼠中，效应T细胞（Teff）进入BM和脾脏的过程会因百日咳毒素（PTX）敏感的趋化因子受体信号传导而增强。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，但对于它们募集到GVHD靶组织仍然至关重要。与此一致的是，在同时存在GVHD反应的小鼠中，经PTX处理的Teff细胞在杀死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。这些结果提示了一种在allo-SCT背景下提高同种异体反应性T细胞治疗白血病安全性的策略。
