In Vivo Effects of the Anti-Interleukin-6 Receptor Inhibitor Tocilizumab on the B Cell Compartment
In Vivo Effects of the Anti-Interleukin-6 Receptor Inhibitor Tocilizumab on the B Cell Compartment
复制标题
DOI：
10.1002/art.30242
复制
发表时间：
2011-05-01
影响因子：
--
通讯作者：
Tony, Hans-Peter
中科院分区：
文献类型：
--
作者：
Roll, Petra;Muhammad, Khalid;Tony, Hans-Peter
Objective.托珠单抗对白细胞介素-6（IL-6）受体的抑制作用最近被批准用于治疗类风湿性关节炎（RA）。IL-6在体外诱导B细胞分化为抗体形成细胞;然而，IL-6抑制对B细胞区室的体内影响目前尚不清楚。本研究的目的是检查这一功能。16例活动性RA患者在一项开放标签研究中接受托珠单抗治疗（8 mg/kg，每4周一次）。在基线、第12周和第24周进行免疫表型分析。记忆B细胞亚群在托珠单抗治疗期间显著下降。在第24周，转换前记忆B细胞从中位数19.6%下降至12.3%，转换后记忆B细胞从中位数18.6%下降至15.0%（P = 0.04）。同时，CD 19+伊加+和CD 19 +IgG+ B细胞显著减少。IgA表达B细胞的比例从基线时的中位数9.2%降至第12周时的4.3%和第24周时的3.6%（P = 0.01）。IgG+ B细胞从基线时的中位数6.7%下降至第12周时的4.9%（P = 0.007）和第24周时的2.8%（P = 0.01）。血清伊加和IgG水平在24周时显著降低（P < 0.05）。伊加+ B细胞的相对数和绝对数与24周时血清伊加之间有良好的相关性。托珠单抗诱导外周开关前和开关后记忆B细胞频率显著降低。此外，IgG+和伊加+ B细胞数量下降，与血清免疫球蛋白水平降低密切相关。数据表明IL-6阻断影响RA患者的B细胞高反应性。
Objective. Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature.Methods. Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24.Results. Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P = 0.04). In parallel, CD19+IgA+ and CD19+IgG+ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P = 0.01). IgG+ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P = 0.007) and 2.8% at week 24 (P = 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA+ B cells with serum IgA at week 24.Conclusion. Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG+ and IgA+ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.