Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA.
Immune Tolerance Network, Seattle, Washington, USA.
JCI Insight. 2021 Nov 8;6(21):e150074. doi: 10.1172/jci.insight.150074.
BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.
背景
白细胞介素 6 受体 (IL-6R) 信号驱动对 1 型糖尿病发病机制重要的 T 细胞群体的发育。我们评估了单克隆抗体托珠单抗阻断 IL-6R 是否会减缓新诊断的 1 型糖尿病患者残余 β 细胞功能的丧失。
方法
我们在新诊断的 1 型糖尿病患者中进行了一项多中心、随机、安慰剂对照、双盲试验，使用托珠单抗。参与者在诊断后 100 天内进行筛查。符合条件的参与者被随机分为 2:1 接受 7 次每月剂量的托珠单抗或安慰剂。主要结局是在第 52 周时在儿科参与者（6-17 岁）混合餐耐量试验的前 2 小时内收集的 C 肽平均 AUC 从筛查时的变化。
结果
托珠单抗与安慰剂之间在主要结局上没有统计学差异。免疫表型分析显示 T 细胞中 IL-6R 的下游信号转导减少，但 CD4 记忆亚群、Th17 细胞、Tregs 或 CD4+T 效应细胞对 Treg 抑制的抗性没有变化。在治疗期间，一个 DC 亚群减少，但一旦治疗停止，就会恢复到基线。托珠单抗耐受性良好。
结论
托珠单抗降低了 T 细胞 IL-6R 信号，但未调节新诊断的 1 型糖尿病患者的 CD4+T 细胞表型或减缓残余 β 细胞功能的丧失。
试验注册
ClinicalTrials.gov NCT02293837。
资金
美国国立卫生研究院（NIH）国家糖尿病、消化和肾脏疾病研究所（NIDDK）和国家过敏和传染病研究所（NIAID）UM1AI109565、NIH/NCRR 临床和转化科学奖（CTSA）的 UL1TR000004，NIH/NIDDK P30DK036836、NIH/NIDDK U01DK103266、NIH/NIDDK U01DK103266、NIH/NCRR CTSA 的 1UL1TR000064、NIH/NCATS UL1TR001878、UL1TR002537；澳大利亚国家健康与医学研究理事会从业者奖学金（APP1136735）、NIH/NIDDK U01-DK085476、NIH/CTSA UL1-TR002494、印第安纳临床和转化科学研究所奖 UL1TR002529、范德比尔特转化研究所以临床和转化科学奖 UL1TR000445。NIH/NCATS UL1TR003142、NIH/CTSA 计划 UL1-TR002494、退伍军人事务部和 1R01AI132774。
