University of Paris, Institut national de la santé et de la recherche médicale, UMRS1148, Paris, France; Department of Pathology, Assistance publique - hôpitaux de Paris, Bichat Hospital, Paris, France.
Department of Reconstructive and Aesthetic Plastic Surgery, Assistance publique - hôpitaux de Paris, Tenon Hospital, Paris, France.
Transplant Proc. 2021 Mar;53(2):746-749. doi: 10.1016/j.transproceed.2021.01.003. Epub 2021 Feb 3.
Antibody-mediated rejection (AMR) is a major cause of graft loss. The development of donor-specific antibodies (DSAs) directed against the allogeneic HLA molecules expressed by the graft also leads to accelerated arteriosclerosis. CD31 is a protein expressed on endothelial and immune cells, ensuring homeostasis at this interface. When strong immune stimulation occurs, the regulatory function of CD31 is lost owing to cleavage of its extracellular portion. P8RI, a synthetic peptide that binds to the ectodomain of CD31, is able to restore the CD31 immunomodulatory function. In this study, we hypothesized that CD31 could represent an attractive molecular target in AMR and investigated whether P8RI could prevent the development of vascular antibody-mediated lesions.
A rat model of orthotopic aortic allograft was used, and P8RI was administered for 28 days. Circulating DSAs were quantified to assess the alloimmune humoral response, and histologic and immunohistochemical analyses of aortic allografts were performed to estimate antibody-mediated lesions in the allograft.
Aorta-allografted rats receiving P8RI developed fewer DSAs than control animals (mean fluorescence intensity 344 vs 741). The density of nuclei in the media (3.4 x 10 vs 2.2 x 10 nuclei/px) and media surface area (2.33 x 10 vs 2.02 x 10 px) were higher in animals treated with P8RI than in control animals.
These data support a therapeutic potential for molecules able to restore the CD31 signaling to fight AMR. P8RI, an agonist synthetic peptide targeting CD31, might prevent DSA production and have a beneficial effect in limiting arterial antibody-mediated lesions. CD31 agonists may become therapeutic tools to prevent and treat solid organ transplant arteriosclerosis.
抗体介导的排斥反应（AMR）是移植物丢失的主要原因。针对移植物表达的同种异体 HLA 分子的供体特异性抗体（DSA）的发展也导致了动脉粥样硬化的加速。CD31 是一种在血管内皮细胞和免疫细胞上表达的蛋白，确保了这个界面的内稳性。当发生强烈的免疫刺激时，CD31 的调节功能会由于其细胞外部分的裂解而丧失。P8RI 是一种与 CD31 的细胞外结构域结合的合成肽，能够恢复 CD31 的免疫调节功能。在本研究中，我们假设 CD31 可能是 AMR 的一个有吸引力的分子靶点，并研究了 P8RI 是否可以预防血管抗体介导的病变的发展。
使用大鼠原位主动脉同种异体移植模型，给予 P8RI 治疗 28 天。通过定量检测循环 DSAs 来评估同种异体体液免疫反应，并对主动脉同种异体移植物进行组织学和免疫组织化学分析，以评估移植物中的抗体介导的病变。
接受 P8RI 治疗的大鼠产生的 DSAs 比对照组动物少（平均荧光强度 344 比 741）。与对照组动物相比，用 P8RI 治疗的动物的中膜核密度（3.4 x 10 比 2.2 x 10 核/px）和中膜表面积（2.33 x 10 比 2.02 x 10 px）更高。
这些数据支持能够恢复 CD31 信号以对抗 AMR 的分子的治疗潜力。P8RI 是一种靶向 CD31 的激动剂合成肽，可能可以预防 DSA 的产生，并对限制动脉抗体介导的病变有有益的影响。CD31 激动剂可能成为预防和治疗实体器官移植后动脉粥样硬化的治疗工具。
