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Genes Immun. 2019 Apr;20(4):293-307. doi: 10.1038/s41435-018-0032-1. Epub 2018 Jun 21.

Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes.

Author information

1
Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA. plinsley@benaroyaresearch.org.
2
Diabetes Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
3
Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
4
Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT, 06520, USA.

Abstract

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.

PMID:
29925930
PMCID:
PMC6477779
DOI:
10.1038/s41435-018-0032-1
[Indexed for MEDLINE]
Free PMC Article

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