期刊
GENES AND IMMUNITY
卷 20, 期 4, 页码 293-307出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41435-018-0032-1
关键词
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资金
- JDRF [1-PNF-2014-94-Q-R]
- NIH [5UM1AI109565, DP3 DK104465-01, U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282]
- Immune Tolerance Network (ITN)
- Juvenile Diabetes Research Foundation International (JDRF)
- [U01 DK106984]
- [U01 DK106994]
- [U01 DK107013]
- [U01 DK107014]
- [UC4 DK106993]
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.
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