Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes.
Carla J GreenbaumCarla J GreenbaumMario RosascoScott PresnellKevan C HeroldMatthew J DufortPublished in: Genes and immunity (2018)
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.
Keyphrases
- diffuse large b cell lymphoma
- type diabetes
- rna seq
- single cell
- chronic lymphocytic leukemia
- hodgkin lymphoma
- clinical trial
- rheumatoid arthritis
- peripheral blood
- glycemic control
- cardiovascular disease
- study protocol
- bone marrow
- emergency department
- electronic health record
- adipose tissue
- cerebral ischemia
- metabolic syndrome
- big data
- randomized controlled trial
- cancer therapy
- nk cells
- deep learning
- drug delivery
- artificial intelligence
- subarachnoid hemorrhage
- data analysis