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Current Diabetes Reports

, 18:90 | Cite as

Immune Mechanisms and Pathways Targeted in Type 1 Diabetes

  • Laura M. Jacobsen
  • Brittney N. Newby
  • Daniel J. Perry
  • Amanda L. Posgai
  • Michael J. Haller
  • Todd M. Brusko
Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of 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.

Keywords

Immune therapy Clinical trial Type 1 diabetes Prevention Treatment Autoimmunity 

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

Notes

Acknowledgments

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

Author Contributions

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

Compliance with Ethical Standards

Conflict of Interest

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.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Laura M. Jacobsen
    • 1
  • Brittney N. Newby
    • 2
  • Daniel J. Perry
    • 2
  • Amanda L. Posgai
    • 2
  • Michael J. Haller
    • 1
  • Todd M. Brusko
    • 2
  1. 1.Department of Pediatrics, College of MedicineUniversity of Florida Diabetes InstituteGainesvilleUSA
  2. 2.Department of Pathology, Immunology and Laboratory Medicine, College of MedicineUniversity of Florida Diabetes InstituteGainesvilleUSA

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