B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes

JCI Insight. 2019 Feb 21;4(4):e126136. doi: 10.1172/jci.insight.126136.

Abstract

Costimulatory interactions control T cell activation at sites of activated antigen-presenting cells, including B cells. Blockade of the CD28/CD80/CD86 costimulatory axis with CTLA4Ig (abatacept) is widely used to treat certain autoimmune diseases. While transiently effective in subjects with new-onset type 1 diabetes (T1D), abatacept did not induce long-lasting immune tolerance. To elucidate mechanisms limiting immune tolerance in T1D, we performed unbiased analysis of whole blood transcriptomes and targeted measurements of cell subset levels in subjects from a clinical trial of abatacept in new-onset T1D. We showed that individual subjects displayed age-related immune phenotypes ("immunotypes") at baseline, characterized by elevated levels of B cells or neutrophils, that accompanied rapid or slow progression, respectively, in both abatacept- and placebo-treated groups. A more pronounced immunotype was exhibited by a subset of subjects showing poor response (resistance) to abatacept. This resistance immunotype was characterized by a transient increase in activated B cells (one of the cell types that binds abatacept), reprogrammed costimulatory ligand gene expression, and reduced inhibition of anti-insulin antibodies. Our findings identify immunotypes in T1D subjects that are linked to the rate of disease progression, both in placebo- and abatacept-treated subjects. Furthermore, our results suggest therapeutic approaches to restore immune tolerance in T1D.

Keywords: Autoimmunity; B cells; Neutrophils; T cells; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept / pharmacology*
  • Abatacept / therapeutic use
  • Adolescent
  • Age Factors
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B7-1 Antigen / immunology
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / immunology
  • B7-2 Antigen / metabolism
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Child
  • Clinical Trials, Phase II as Topic
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Disease Progression
  • Drug Resistance / genetics
  • Drug Resistance / immunology
  • Female
  • Gene Expression Regulation / genetics*
  • Gene Expression Regulation / immunology
  • Humans
  • Immune Tolerance / drug effects
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Lymphocyte Activation / immunology
  • Male
  • RNA-Seq
  • Randomized Controlled Trials as Topic
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Treatment Outcome
  • Young Adult

Substances

  • B7-1 Antigen
  • B7-2 Antigen
  • CD28 Antigens
  • CD80 protein, human
  • CD86 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunosuppressive Agents
  • Abatacept