Chiarini Marco, Capra Ruggero, Serana Federico, Bertoli Diego, Sottini Alessandra, Giustini Viviana, Scarpazza Cristina, Rovaris Marco, Torri Clerici Valentina, Ferraro Diana, Galgani Simonetta, Solaro Claudio, Conti Marta Zaffira, Visconti Andrea, Imberti Luisa
Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili, Brescia, Italy.
Centro di Ricerca Emato-oncologica AIL (CREA), ASST Spedali Civili, P.le Spedali Civili 1, 25123, Brescia, Italy.
J Transl Med. 2020 Apr 16;18(1):169. doi: 10.1186/s12967-020-02329-5.
The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility.
In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-β-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells.
Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-β treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-β therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells.
Interferon-β induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-β in multiple sclerosis patients.
干扰素-β治疗多发性硬化症的潜在机制仍未完全明确。在本研究中，我们评估了干扰素-β治疗对复发缓解型多发性硬化症患者中不同调节性T细胞亚群的短期和长期影响，这些患者因对副黏病毒抗性蛋白A诱导敏感而对治疗有生物学反应。
在这项前瞻性纵向研究中，通过流式细胞术同时定量了148例未经治疗的多发性硬化症患者在接受干扰素-β-1a治疗前、治疗6、12、18和24个月后所制备样本中的天然调节性T细胞亚群（初始、中枢记忆和效应记忆）、诱导性调节性T细胞（Tr1）以及体外诱导的调节性T细胞（Tr1样细胞）。对Tr1样细胞中的白细胞介素-10和Tr1相关基因（CD18、CD49b和CD46，以及Cyt-1和Cyt-2 CD46相关异构体）的mRNA进行了定量。
尽管所有调节性T细胞亚群的调节存在个体间的显著差异，但干扰素-β治疗6、12和24个月后，天然调节性T细胞的百分比增加。这种增加的特征是中枢和效应记忆调节性T细胞亚群的扩增。治疗12个月时Tr1的百分比显著升高，并在随后的评估点持续保持高位。在开始干扰素-β治疗前，复发患者的初始调节性T细胞百分比更高，而中枢记忆调节性T细胞和Tr1的百分比更低。此外，仅在病情稳定患者中观察到中枢记忆和Tr1随时间增加。然而，从接受24个月治疗的患者中制备的体外诱导Tr1样细胞与治疗前的Tr1样细胞相比，白细胞介素-10 mRNA的产生量更少。
干扰素-β诱导具有高抑制活性的调节性T细胞亚群扩增，尤其是在临床稳定的患者中。天然和诱导性调节性T细胞亚群的总体同时调节可能解释了干扰素-β对多发性硬化症患者的治疗效果。
