异基因造血干细胞移植（allo-HSCT）有可能治愈恶性血液疾病和良性疾病，例如血红蛋白病和免疫性疾病。然而，allo-HSCT 与严重的并发症相关。其中最常见且使人衰弱的是移植物抗宿主病（GVHD）。在 GVHD 中，供体来源的 T 细胞对受体产生同种免疫反应。同种免疫反应涉及几个步骤，包括识别受体抗原、次级淋巴器官中 T 细胞的激活和增殖，以及归巢到 GVHD 靶向器官。 T 细胞和内皮细胞上的粘附分子介导 T 细胞归巢至淋巴和非淋巴组织。在这项研究中，我们发现血管性血友病因子（VWF）是一种由活化的内皮细胞分泌的粘附分子，在 GVHD 小鼠模型中发挥着重要作用。我们研究了 VWF 裂解蛋白酶 ADAMTS13 对 GVHD 的影响。我们发现 ADAMTS13 降低了 C57BL6 供体骨髓移植至 BALB/C 受体小鼠后 GVHD 的严重程度。重组 VWF-A2 结构域肽还可降低小鼠的 GVHD。我们发现，ADAMTS13 和重组 VWF-A2 在体外减少了 T 细胞与内皮细胞和 VWF 的结合，并在体内减少了淋巴结、派伊尔集结和 GVHD 靶向器官中的 T 细胞数量。我们确定 LFA-1 (αLβ2) 是 VWF 在 T 细胞上的结合位点。我们的结果表明，通过 ADAMTS13 或 VWF-A2 肽阻断 T 细胞归巢可降低异基因 HSCT 后 GVHD 的严重程度，这是治疗和预防 GVHD 的潜在新方法。© 2024 作者。细胞与分子医学基金会和约翰·威利出版的《细胞与分子医学杂志》

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed that Von Willebrand factor (VWF), an adhesion molecule secreted by activated endothelial cells, plays an important role in mouse models of GVHD. We investigated the effect of the VWF-cleaving protease ADAMTS13 on GVHD. We found that ADAMTS13 reduced the severity of GVHD after bone marrow transplantation from C57BL6 donor to BALB/C recipient mice. A recombinant VWF-A2 domain peptide also reduced GVHD in mice. We showed that ADAMTS13 and recombinant VWF-A2 reduced the binding of T cells to endothelial cells and VWF in vitro, and reduced the number of T cells in lymph nodes, Peyer's patches and GVHD-targeted organs in vivo. We identified LFA-1 (αLβ2) as the binding site of VWF on T cells. Our results showed that blocking T-cell homing by ADAMTS13 or VWF-A2 peptide reduced the severity of the GVHD after allo-HSCT, a potentially novel method for treating and preventing GVHD.© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.