Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
Diabetes Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
Genes Immun. 2019 Apr;20(4):293-307. doi: 10.1038/s41435-018-0032-1. Epub 2018 Jun 21.
Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab. RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.
使用包括抗 CD3（otelixizumab 和 teplizumab）、抗 CD20（rituximab）、LFA3Ig（alafacept）和 CTLA4Ig（abatacept）在内的药物对 1 型糖尿病（T1D）进行生物治疗，可导致胰岛素 C 肽（内源性胰岛素分泌的替代物）短暂稳定。为了诱导更强的免疫耐受，我们使用系统生物学方法来阐明与临床试验中接受 B 细胞耗竭药物利妥昔单抗治疗的新诊断 T1D 患者的 C 肽稳定相关的机制。该试验的全血样本 RNA 测序（RNA-seq）分析显示，异质性 T 细胞群体短暂增加，这与利妥昔单抗的药效动力学活性降低、对胰岛抗原的增殖反应增加以及 C 肽更快丢失有关。我们的发现说明了利妥昔单抗耗竭 B 细胞所伴随的造血重塑的复杂性，这会影响和预测 T1D 的治疗效果。我们的数据还表明，利妥昔单抗联合针对 CD4+T 细胞的治疗可能对 T1D 患者有益。
