Mei Heng, Xu Min, Shu Jinhui, Tang Lu, Xie Qinying, Luo Lili, Wei Qiuzhe, Jiang Huiwen, Ming Zhangyin, Hu Yu
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China.
Blood. 2026 Feb 12;147(7):783-799. doi: 10.1182/blood.2025029769.
Only 30% to 50% of patients with immune thrombocytopenia (ITP) exhibit a sustained response upon thrombopoietin receptor agonists (TPO-RA) withdrawal, underscoring the necessity for mechanistic elucidation. We enrolled 49 patients treated with TPO-RA for 4 months and performed a follow-up study for 3 months, classifying them into sustained responders (n = 21), and nonsustained responders (n = 28). Compared with total transforming growth factor β1 (TGF-β1) levels, activated TGF-β1 levels (3854 ± 4380 vs 943 ± 1500 pg/mL; P< .001) were significantly elevated in sustained responders, with integrin αvβ8 regulating TGF-β1 activation and restoring immune tolerance. We established a passive ITP model using platelet factor 4-TGF-β1 conditional knockout (CKO) mice, which exhibited a shorter duration of sustained response than wild-type (WT) mice. CKO mice demonstrated a reduced regulatory T-cell (Treg) population, an increased M1-to-M2 macrophage ratio, and more severe megakaryocyte destruction after anti-CD41 injection. Exogenous administration of αvβ8 (250 ng/kg) effectively activated TGF-β1 and prolonged remission after TPO discontinuation in WT mice. Additionally, CD4+ T cells were transfected with lentiviral small interfering RNA or short hairpin RNA to modulate integrin β8 expression and these were injected into severe combined immunodeficiency mice undergoing an active model of ITP. Results showed that β8 overexpression increased Tregs and reduced megakaryocyte damage. Mechanistically, TPO-RA modulated αvβ8-mediated TGF-β1 activation through the activator protein 1family and Smad family member 2 signaling pathways. Furthermore, D-mannose combined with TPO prolonged the response in ITP mice by upregulating αvβ8 and activating TGF-β1. Overall, the integrin αvβ8-mediated activation of TGF-β1 pathway represents a promising therapeutic target for ITP, with substantial potential for clinical application.
仅有30%至50%的免疫性血小板减少症（ITP）患者在停用血小板生成素受体激动剂（TPO-RA）后表现出持续缓解，这突出了阐明其机制的必要性。我们招募了49例接受TPO-RA治疗4个月的患者，并进行了为期3个月的随访研究，将他们分为持续缓解者（n = 21）和非持续缓解者（n = 28）。与总转化生长因子β1（TGF-β1）水平相比，持续缓解者的活化TGF-β1水平显著升高（3854±4380 vs 943±1500 pg/mL；P<0.001），整合素αvβ8调节TGF-β1的活化并恢复免疫耐受。我们使用血小板因子4-TGF-β1条件性敲除（CKO）小鼠建立了被动ITP模型，该模型的持续缓解持续时间比野生型（WT）小鼠短。CKO小鼠表现出调节性T细胞（Treg）数量减少、M1与M2巨噬细胞比例增加以及抗CD41注射后巨核细胞破坏更严重。在WT小鼠中，外源性给予αvβ8（250 ng/kg）可有效激活TGF-β1并延长停用TPO后的缓解期。此外，用慢病毒小干扰RNA或短发夹RNA转染CD4+T细胞以调节整合素β8的表达，并将其注射到患有活动性ITP模型的严重联合免疫缺陷小鼠中。结果显示，β8过表达增加了Tregs并减少了巨核细胞损伤。从机制上讲，TPO-RA通过激活蛋白1家族和Smad家族成员2信号通路调节αvβ8介导的TGF-β1活化。此外，D-甘露糖与TPO联合使用可通过上调αvβ8和激活TGF-β1来延长ITP小鼠的缓解期。总体而言，整合素αvβ8介导的TGF-β1途径活化代表了ITP一个有前景的治疗靶点，具有很大的临床应用潜力。
