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Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease
Bone Marrow Transplantation ( IF 4.5 ) Pub Date : 2020-02-21 , DOI: 10.1038/s41409-020-0830-8
Carlos Cuesta-Mateos 1, 2 , Itxaso Portero-Sainz 1 , Marina García-Peydró 3 , Juan Alcain 3 , Patricia Fuentes 3 , Raquel Juárez-Sánchez 1, 2 , Yaiza Pérez-García 1 , Tamara Mateu-Albero 1 , Paula Díaz-Fernández 1 , Lorena Vega-Piris 4 , Blanca A Sánchez-López 1 , Ana Marcos-Jiménez 1 , Laura Cardeñoso 5 , Valle Gómez-García de Soria 6 , María Luisa Toribio 3 , Cecilia Muñoz-Calleja 1
Affiliation  

Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7)+ T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7+ cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7+ T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naïve and central memory T cells toward CCR7 ligands and depleted target CCR7+ subsets through complement activation. Both mechanisms of action spared CCR7 subsets, including effector memory and effector memory CD45RAT cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7+ T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed.



中文翻译:

评估 CCR7 在急性移植物抗宿主病中的治疗靶向性

移植物抗宿主病(GVHD)是异基因造血干细胞移植后的主要并发症。我们之前揭示了单采术中 CC 基序趋化因子受体 7 (CCR7) + T 细胞的比例与发生 GVHD 的风险之间的相关性。我们想在体内评估低比例 CCR7 +细胞的单采术或用抗人 CCR7 单克隆抗体 (mAb) 治疗是否是预防或治疗临床前异种模型中急性 GVHD 的合适策略。治疗性抗 CCR7 mAb 是预防和治疗环境中最有效的策略,其中抗体显着减少供体 CCR7 的体内淋巴器官浸润+T 细胞,延长寿命并解决临床症状。该抗体中和了幼稚和中央记忆 T 细胞向 CCR7 配体的体外迁移,并通过补体激活耗尽了目标 CCR7 +亚群。两种作用机制都避免了 CCR7 -亚群,包括效应记忆和效应记忆 CD45RA T 细胞,它们可能介导移植物抗白血病效应和抗感染免疫。因此,单采中供体 CCR7 + T 细胞的数量与巨细胞病毒再激活或潜在疾病的复发无关。这些发现为预防和治疗急性 GVHD 提供了一种有希望的新策略,这种情况需要新的特异性、安全和有效的治疗方法。

更新日期:2020-02-21
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