In 't Veld Aliede E, Jansen Manon A A, de Kam Marieke L, Yavuz Yalҫin, Moes Dirk Jan A R, Oudhoff Kathalijne A, van Poelgeest Mariette I E, Burggraaf Jacobus, Moerland Matthijs
Centre for Human Drug Research, 2233 CL Leiden, The Netherlands.
Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Pharmaceutics. 2023 May 31;15(6):1635. doi: 10.3390/pharmaceutics15061635.
Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF's active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-γ production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression.
霉酚酸酯（MMF）是移植后标准免疫抑制治疗的一部分，通常与钙调神经磷酸酶抑制剂（CNI）一起“一刀切”给药。尽管经常监测药物浓度，但仍有一组患者会出现与免疫抑制过度或不足相关的副作用。因此，我们旨在确定反映患者整体免疫状态并可能支持个体化给药的生物标志物。我们之前研究了CNI的免疫生物标志物，并旨在研究这些标志物是否也适用于监测MMF的活性。健康志愿者接受单剂量的MMF或安慰剂，之后测量肌苷-5'-单磷酸脱氢酶（IMPDH）酶活性、T细胞增殖和细胞因子产生，并与三种不同基质（血浆、外周血单核细胞和T细胞）中的霉酚酸（MPA，MMF的活性代谢产物）浓度进行比较。T细胞中的MPA浓度超过外周血单核细胞中的浓度，但所有细胞内浓度均与血浆浓度密切相关。在临床相关的MPA浓度下，白细胞介素-2（IL-2）和干扰素-γ（IFN-γ）的产生受到轻度抑制，而MPA对T细胞增殖有强烈抑制作用。基于这些数据，预计监测接受MMF治疗的移植患者的T细胞增殖可能是避免免疫抑制过度的有效策略。
