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T-bet⁺CD11c⁺与年龄相关的B细胞在小鼠狼模型中抵抗了针对BLyS和CD20的切除

James J Knox¹, Jean L Scholz¹, Hannah Futeran¹

¹Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Journal of autoimmunity

|March 31, 2025

概括

与年龄相关的B细胞 (ABCs) 在狼小鼠模型中抵抗抗BLyS和抗CD20抗体的枯竭. 这些发现表明,针对自身免疫性疾病中针对ABC的基于抗体的疗法存在局限性.

科学领域:

免疫学免疫学免疫学
这是一种自身免疫力.
B细胞生物学B细胞生物学

背景情况:

B细胞枯竭疗法对自身免疫性疾病具有前景.
这些疗法对致病性T-bet+CD11c+年龄相关B细胞 (ABCs) 的影响尚不清楚.
ABCs与自身免疫性疾病 (如狼) 的病原发生有关.

研究的目的:

为了研究使用单克隆抗体 (mAbs) 对BLyS和CD20的B细胞枯竭的疗效,减少ABC和其他脏B细胞子集.
在两种不同的狼小鼠模型中评估这些策略:NZBxNZWF1和慢性移植对宿主疾病 (cGVHD).

主要方法:

NZBxNZWF1和cGVHD小鼠接受了抗BLyS (10F4),抗CD20 (18B12),组合疗法或疾病发病后的盐水治疗.
包括T-bet+CD11c+ABCs,毛囊 (FO) B细胞和边缘区 (MZ) B细胞在内的B细胞子集,在脏样本中通过流细胞计分析.
进行了剂量范围研究 (0.2 mg或1 mg).

主要成果:

在NZBWF1小鼠中,B细胞枯竭是可变的,并且由于淋巴缺血和治疗耐药性,对FO和MZ B细胞有部分有效.
在NZBWF1小鼠中,T-bet+CD11c+ABC保持不变或增加,并且完全抵抗抗体治疗.
在cGVHD小鼠中,抗BLyS和抗CD20有效地消耗了FOB细胞,对MZB细胞产生了差异性影响.
关键的是,T-bet+CD11c+ABC被单独或组合抗体治疗所影响的最小,无论剂量如何.

结论:

在内居住的T-bet+CD11c+ABC群体表现出对已确立的B细胞废除疗法的显著耐药性,包括抗BLyS和抗CD20.
这些发现凸显了当前抗体介导的B细胞枯竭策略的潜在局限性,用于治疗以ABC积累为特征的自身免疫性疾病.

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