Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany.
Front Immunol. 2021 Oct 11;12:716629. doi: 10.3389/fimmu.2021.716629. eCollection 2021.
Reshaping the immune balance by adoptive transfer of regulatory T-cells (Tregs) has emerged as a promising strategy to combat undesired immune reactions, including in Graft-versus-Host Disease (GvHD), which is the most lethal non-relapse complication of allogeneic hematopoietic stem cell transplantation. Currently however, little is known about the potentially inhibitory effects of conventional immunosuppressive drugs, which are routinely used to treat GvHD, on adoptively transferred Tregs. Here we demonstrate drug-specific effects of the conventional immunosuppressive drugs Cyclosporine A, Mycophenolate mofetil and methylprednisolone on adoptively transferred Tregs in a humanized NOD/SCID/IL2Rgamma-/- GvHD mouse model. The clinical course of GvHD and organ histology, including cellular organ infiltration, showed that co-administration of Cyclosporine A and Tregs is highly beneficial as it enhanced Treg accumulation at inflammatory sites like lung and liver. Similarly, co-administration of Mycophenolate mofetil and Tregs improved clinical signs of GvHD. In contrast, co-administration of methylprednisolone and Tregs resulted in reduced Treg recruitment to inflammatory sites and the fast deterioration of some animals. Consequently, when clinical trials investigating safety and efficacy of adjunctive Treg therapy in GvHD are designed, we suggest co-administering Cyclosporine A, whereas high doses of glucocorticosteroids should be avoided.
通过过继转移调节性 T 细胞（Tregs）来重塑免疫平衡，已成为对抗不良免疫反应的一种有前途的策略，包括移植物抗宿主病（GvHD），这是异基因造血干细胞移植后最致命的非复发并发症。然而，目前对于常规用于治疗 GvHD 的免疫抑制药物对过继转移的 Tregs 的潜在抑制作用知之甚少。在这里，我们在人源化 NOD/SCID/IL2Rγ-/-GvHD 小鼠模型中证明了常规免疫抑制剂环孢素 A、霉酚酸酯和甲泼尼龙对过继转移的 Tregs 的药物特异性作用。GvHD 的临床过程和器官组织学，包括细胞器官浸润，表明环孢素 A 和 Tregs 的联合给药具有高度益处，因为它增强了 Treg 在肺部和肝脏等炎症部位的积累。同样，霉酚酸酯和 Tregs 的联合给药改善了 GvHD 的临床症状。相比之下，甲泼尼龙和 Tregs 的联合给药导致 Treg 向炎症部位的募集减少，并且一些动物的病情迅速恶化。因此，当设计在 GvHD 中进行辅助性 Treg 治疗的安全性和有效性的临床试验时，我们建议联合使用环孢素 A，而应避免使用高剂量的糖皮质激素。
