Mausberg Anne K, Szepanowski Fabian, Eggert Bianca, Liebig Kai C, Kleinschnitz Christoph, Kieseier Bernd C, Stettner Mark
Department of Neurology, Center for Translational Neuro- and Behavioural Sciences, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
Department of Neurology, University of Duesseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
Immunol Res. 2024 Dec 15;73(1):12. doi: 10.1007/s12026-024-09565-7.
The inhibition of the neonatal Fc receptor (FcRn) is a promising therapeutic pathway in certain autoimmune disorders to reduce the amount of circulating pathogenic IgG autoantibodies by interfering with their recycling system. FcRn antibodies are currently being tested in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This study aimed to investigate the therapeutic potential of an antibody targeting FcRn in the intracellular adhesion molecule 1 (ICAM1)-deficient NOD mouse-a model representative for many aspects of human CIDP. After the onset of clinical signs of neuropathy, ICAM1-deficient NOD mice were assigned to treatment twice per week with anti-FcRn antibody, isotype control antibody (negative control) or intraperitoneal (administered) immunoglobulin (positive control). Disease severity was monitored using disease-specific assessments for ataxia and paresis such as grip strength measurements. Serum immunoglobulin levels and peripheral nerve immune cell infiltration were quantified. Treatment with anti-FcRn antibody did not ameliorate disease progression, as determined by clinical scores and grip strength analysis. Disease progression was reduced in the positive control animals receiving immunoglobulin. Consistent with the clinical results, the composition of infiltrating immune cells was not altered in the peripheral nerve of anti-FcRn antibody-treated mice compared to controls. However, in anti-FcRn antibody-treated mice, significantly lower IgG levels were detectable compared to controls. These findings suggest that targeting the FcRn recycling system does not influence disease progression in the NOD-ICAM1-deficient mouse model of CIDP. Further studies will elucidate whether the reduction of IgG levels was insufficient to deplete pathogenic autoantibodies or whether the major inflammatory driver in the NOD-ICAM1-deficient mouse animal model is mediated by factors other than pathological immunoglobulins.
抑制新生儿Fc受体（FcRn）是某些自身免疫性疾病中一种有前景的治疗途径，可通过干扰其循环系统来减少循环中的致病性IgG自身抗体数量。FcRn抗体目前正在慢性炎症性脱髓鞘性多发性神经根神经病（CIDP）中进行试验。本研究旨在调查一种靶向FcRn的抗体在细胞间黏附分子1（ICAM1）缺陷的NOD小鼠（一种代表人类CIDP诸多方面的模型）中的治疗潜力。在出现神经病临床症状后，将ICAM1缺陷的NOD小鼠每周两次分别用抗FcRn抗体、同型对照抗体（阴性对照）或腹腔内（注射）免疫球蛋白（阳性对照）进行治疗。使用针对共济失调和轻瘫的疾病特异性评估（如握力测量）来监测疾病严重程度。对血清免疫球蛋白水平和外周神经免疫细胞浸润进行定量分析。通过临床评分和握力分析确定，抗FcRn抗体治疗并未改善疾病进展。接受免疫球蛋白治疗的阳性对照动物的疾病进展有所减缓。与临床结果一致，与对照组相比，抗FcRn抗体治疗小鼠的外周神经中浸润免疫细胞的组成没有改变。然而，与对照组相比，在抗FcRn抗体治疗的小鼠中可检测到明显更低的IgG水平。这些发现表明，在CIDP的NOD-ICAM1缺陷小鼠模型中，靶向FcRn循环系统不会影响疾病进展。进一步的研究将阐明IgG水平的降低是否不足以耗尽致病性自身抗体，或者NOD-ICAM1缺陷小鼠动物模型中的主要炎症驱动因素是否由病理性免疫球蛋白以外的因素介导。
