Fu Xiang-Jun, Meng Can, Guo Li, Lin Li-E
Department of Hematology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, NO.19 Xiuhua Road, Xiuying District, Haikou, 570311, Hainan Province, China.
Clin Transl Oncol. 2025 Apr;27(4):1789-1797. doi: 10.1007/s12094-024-03684-1. Epub 2024 Sep 4.
Chronic graft-versus-host disease (cGVHD) is a significant complication following allogenic hematopoietic stem cell transplantation, often necessitating therapeutic interventions such as rituximab (RTX) and cyclosporin A (CsA). This study aims to elucidate the mechanisms by which RTX and CsA jointly address B-cell dysregulation in cGVHD, providing a theoretical foundation and scientific rationale for the treatment and prognostic evaluation of this condition.
A total of 30 cGVHD mouse models were established by subjecting recipient mice to total body irradiation followed by injection of a mixed suspension of bone marrow cells and splenocytes from donor mice. From Day 2 to Day 29 post-model establishment, the mice received subcutaneous administration of RTX and CsA. Throughout the study, body weight, clinical cGVHD scores, and survival rates were monitored. Blood samples were collected via the orbital venous plexus. Serum levels of B-cell activating factor (BAFF) and pro-inflammatory factors were measured using enzyme-linked immunosorbent assay (ELISA), and the ratio of regulatory B cells (Bregs) in the blood sample was assessed via flow cytometry.
Mice with cGVHD exhibited a 14.5% decrease in body weight, elevated clinical scores, and more severe symptoms compared to the control group. Notably, all mice in both the cGVHD and control groups survived until the conclusion of the study. Induction of cGVHD resulted in B-cell dysregulation, evidenced by elevated serum BAFF levels and a decreased proportion of Bregs. However, treatment with RTX combined with CsA ameliorated B-cell dysregulation and significantly reduced serum levels of pro-inflammatory factors in cGVHD mice, with decreases of 39.78% in TNF-α and 37.89% in IL-6.
The combination of RTX and CsA effectively mitigates B-cell dysregulation in cGVHD, thereby reducing the severity and progression of the disease.
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植后的一种严重并发症，常需要进行诸如利妥昔单抗（RTX）和环孢素A（CsA）等治疗干预。本研究旨在阐明RTX和CsA联合解决cGVHD中B细胞失调的机制，为该疾病的治疗和预后评估提供理论基础和科学依据。
通过对受体小鼠进行全身照射，然后注射来自供体小鼠的骨髓细胞和脾细胞混合悬液，共建立30个cGVHD小鼠模型。从模型建立后的第2天至第29天，小鼠接受RTX和CsA的皮下给药。在整个研究过程中，监测体重、临床cGVHD评分和存活率。通过眶静脉丛采集血样。使用酶联免疫吸附测定（ELISA）测量血清中B细胞活化因子（BAFF）和促炎因子的水平，并通过流式细胞术评估血样中调节性B细胞（Bregs）的比例。
与对照组相比，cGVHD小鼠体重下降14.5%，临床评分升高，症状更严重。值得注意的是，cGVHD组和对照组的所有小鼠均存活至研究结束。cGVHD的诱导导致B细胞失调，表现为血清BAFF水平升高和Bregs比例降低。然而，RTX联合CsA治疗改善了cGVHD小鼠的B细胞失调，并显著降低了促炎因子的血清水平，肿瘤坏死因子-α（TNF-α）降低了39.78%，白细胞介素-6（IL-6）降低了37.89%。
RTX和CsA联合可有效减轻cGVHD中的B细胞失调，从而降低疾病的严重程度和进展。
