Medical Research Center of The Affiliated Hospital of Qingdao University, Shandong, China.
Clinical Laboratory of Qilu Hospital, Shandong University, Shandong, China.
Clin Exp Rheumatol. 2023 Jul;41(7):1384-1395. doi: 10.55563/clinexprheumatol/0dck3t. Epub 2022 Oct 29.
Many studies have found that CD38 expression is increased in rheumatoid arthritis (RA), an autoimmune disease in which immune tolerance is dysregulated. Inhibition of CD38 expression or activity can significantly alleviate collagen-induced arthritis (CIA), a well-known animal model used for the study of RA. This study aimed to confirm the therapeutic effect of 78c, a specific inhibitor of CD38, and the role of CD38+ NK cells in immune imbalance in RA.
CIA mice were injected with 78c to observe the therapeutic effect. CD38+ NK cells were extracted from human peripheral blood and treated with 78c. The pretreated NK cells were co-cultured with CD4+ T cells.
We found that 78c significantly suppressed joint inflammation; reduced the levels of B cells, IL-6 and TNF-α; and increased the levels of IL-10, energy metabolism and spontaneous movement in CIA mice. 78c treatment also increased Treg cell numbers and decreased the Th1/Th2 ratio in the CIA model animals. Moreover, the proportion of CD38+ NK cells was increased in the CIA mice and significantly decreased following 78c treatment. Human CD4+ T cells that were co-cultured with 78c-pretreated CD38+ NK cells differentiated into more Treg cells and had lower Th17/Treg and Th1/Th2 ratios than CD4+ T cells co-cultured with CD38+ NK cells without the pretreatment. Transcriptomic analyses demonstrated that 78c changed expression pro les in CD38+ NK cells.
These results suggested that 78c could be used for the treatment of RA and CIA as it alleviates the inhibitory effect of CD38+ NK cells on CD4+ T cell differentiation to Treg cells to restore immune balance.
许多研究发现，CD38 表达在类风湿关节炎（RA）中增加，RA 是一种免疫耐受失调的自身免疫性疾病。抑制 CD38 的表达或活性可以显著缓解胶原诱导关节炎（CIA），CIA 是一种用于研究 RA 的著名动物模型。本研究旨在证实 CD38 特异性抑制剂 78c 的治疗效果以及 CD38+NK 细胞在 RA 免疫失衡中的作用。
用 78c 注射 CIA 小鼠以观察治疗效果。从人外周血中提取 CD38+NK 细胞并用 78c 处理。预处理后的 NK 细胞与 CD4+T 细胞共培养。
我们发现 78c 显著抑制关节炎症；降低 B 细胞、IL-6 和 TNF-α水平；并增加 CIA 小鼠中的 IL-10、能量代谢和自发运动水平。78c 治疗还增加了 CIA 模型动物中的 Treg 细胞数量并降低了 Th1/Th2 比值。此外，CIA 小鼠中 CD38+NK 细胞的比例增加，而经 78c 处理后明显降低。与未经预处理的 CD38+NK 细胞共培养的 CD4+T 细胞分化为更多的 Treg 细胞，并且 Th17/Treg 和 Th1/Th2 比值低于与未经预处理的 CD38+NK 细胞共培养的 CD4+T 细胞。转录组分析表明，78c 改变了 CD38+NK 细胞的表达谱。
这些结果表明，78c 可用于治疗 RA 和 CIA，因为它缓解了 CD38+NK 细胞对 CD4+T 细胞向 Treg 细胞分化的抑制作用，从而恢复了免疫平衡。
