Purpose: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. Experimental Design: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. Results: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. Conclusions: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.

中文翻译：

---

靶向补体替代途径允许移植物抗白血病活性，同时预防移植物抗宿主病。

目的：同种异体造血细胞移植（allo-HCT）在血液系统疾病患者中的应用受到 GVHD 发展的限制。GVHD 和移植物抗白血病 (GVL) 的分离仍然是该领域的一大挑战。我们研究了 GVH 和 GVL 反应中涉及补体级联反应的各个途径的贡献，以确定分离这两个过程的特定目标。实验设计：我们使用了多个临床前小鼠和人对小鼠异种移植模型，这些模型涉及缺乏替代途径 (AP) 或经典途径 (CP)/凝集素途径 (LP) 成分的同种异体 HCT 受体，以剖析每个途径的作用GVHD 发病机制和 GVL 效应。出于翻译目的，我们使用了 AP 特异性补体抑制剂 CR2-fH，它定位于受损的靶器官，允许在炎症部位特异性阻断补体激活。结果：小鼠和 GVHD 患者的肠道有明显的补体沉积。在临床前环境中，AP 的消融而不是 CP/LP 的消融显着改善了 GVHD 的结果。GVHD 进展需要通过宿主造血细胞中的 AP 进行补体激活，特别是树突状细胞 (DC)。受体的 AP 缺乏减少了供体 T 细胞迁移和 Th1/Th2 分化，同时增加了调节性 T 细胞的产生。这是因为 GVHD 靶器官中受体 DC 的激活和刺激活性降低。用 CR2-fH 治疗有效地预防了 GVHD，同时保留了 GVL 活性。结论：这项研究强调了 AP 作为预防异基因 HCT 后 GVHD 和肿瘤复发的新治疗靶点。通过 CR2-fH 靶向 AP 代表了一种有前途的 GVHD 治疗方法。