Immune Mechanisms and Pathways Targeted in Type 1 Diabetes

Abstract

Purpose of Review

The immunosuppressive agent cyclosporine was first reported to lower daily insulin dose and improve glycemic control in patients with new-onset type 1 diabetes (T1D) in 1984. While renal toxicity limited cyclosporine’s extended use, this observation ignited collaborative efforts to identify immunotherapeutic agents capable of safely preserving β cells in patients with or at risk for T1D.

Recent Findings

Advances in T1D prediction and early diagnosis, together with expanded knowledge of the disease mechanisms, have facilitated trials targeting specific immune cell subsets, autoantigens, and pathways. In addition, clinical responder and non-responder subsets have been defined through the use of metabolic and immunological readouts.

Summary

Herein, we review emerging T1D biomarkers within the context of recent and ongoing T1D immunotherapy trials. We also discuss responder/non-responder analyses in an effort to identify therapeutic mechanisms, define actionable pathways, and guide subject selection, drug dosing, and tailored combination drug therapy for future T1D trials.

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Fig. 1

Abbreviations

T1D:

Type 1 diabetes

nPOD:

Network for Pancreatic Organ donors with Diabetes

AAb:

Autoantibodies

FDR:

First-degree relatives

HLA:

Human leukocyte antigen

OR:

Odds ratios

TCR:

T cell receptor

IAA:

Insulin autoantibody

GADA:

GAD65 autoantibody

GWAS:

Genome wide association study

GRS:

Genetic risk score

RIA:

Radioimmunoassays

IA-2A:

Insulinoma-associated protein 2 autoantibody

ZnT8A:

Zinc transporter 8 autoantibody

ECL:

Electrochemiluminescence

cfDNA:

Cell-free DNA

Teff :

Effector T cell

miRNAs:

MicroRNAs

DRiPs:

Defective ribosomal products

HIPs:

Hybrid insulin peptides

NGS:

Next-generation sequencing

AIRR:

Adaptive immune receptor repertoire

Treg :

Regulatory T cells

GRAS:

Generally regarded as safe

GALT:

Gut-associated lymphoid tissue

ATG:

Anti-thymocyte globulin

GAD:

Alum GAD bound to an aluminum hydroxide adjuvant

MOA:

Mechanisms of action

ACT:

Adoptive cell therapies

GVHD:

Graft-versus-host disease

MSC:

Mesenchymal stem cells

ESCs:

Embryonic stem cells

iPSCs:

Induced pluripotent stem cells

UCB:

Umbilical cord blood

CAR:

Chimeric antigen receptor

CML:

Chronic myelogenous leukemia

IBD:

Inflammatory bowel disease

JIA:

Juvenile idiopathic arthritis

RA:

Rheumatoid arthritis

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Acknowledgments

The authors would like to thank Dr. Mark A. Atkinson for his comments and critical review of the manuscript.

Funding

This effort was supported by grants from the NIH (P01 AI42288 and R01 DK106191 to TMB; F30 DK105788 to BNN), the JDRF (post-doctoral fellowships to LMJ (3-PDF-2018-579-A-N) and DJP (2-PDF-2016-207-A-N)), the Leona M. and Harry B. Helmsley Charitable Trust, and the McJunkin Family Charitable Foundation.

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LMJ, BNN, DJP, ALP, and MJH wrote the manuscript; TMB conceived of and wrote the manuscript.

Corresponding author

Correspondence to Todd M. Brusko.

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Laura M. Jacobsen, Brittney N. Newby, Daniel J. Perry, Amanda L. Posgai, Michael J. Haller, and Todd M. Brusko declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

Laura M. Jacobsen and Brittney N. Newby are co-first authors.

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Jacobsen, L.M., Newby, B.N., Perry, D.J. et al. Immune Mechanisms and Pathways Targeted in Type 1 Diabetes. Curr Diab Rep 18, 90 (2018). https://doi.org/10.1007/s11892-018-1066-5

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Keywords

  • Immune therapy
  • Clinical trial
  • Type 1 diabetes
  • Prevention
  • Treatment
  • Autoimmunity