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Diabetologia

pp 1–10 | Cite as

Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis

  • Ana Luisa Perdigoto
  • Paula Preston-Hurlburt
  • Pamela Clark
  • S. Alice Long
  • Peter S. Linsley
  • Kristina M. Harris
  • Steven E. Gitelman
  • Carla J. Greenbaum
  • Peter A. Gottlieb
  • William Hagopian
  • Alyssa Woodwyk
  • James Dziura
  • Kevan C. Herold
  • the Immune Tolerance Network
Article

Abstract

Aims/hypothesis

The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drug-treated responders showed an increased frequency of ‘partially exhausted’ CD8+ T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years.

Methods

Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release.

Results

Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8+ T cells at follow-up.

Conclusions/interpretation

These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to teplizumab.

Trial registration

ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).

Keywords

Anergy Anti-CD3 C-peptide Exhaustion T cells Teplizumab Type 1 diabetes 

Abbreviations

AbATE

Autoimmunity-Blocking Antibody for Tolerance

EOMES

Eomesodermin

FcR

Fc receptor

IA

Insulin autoantibodies

KLRG1

Killer cell lectin-like receptor G1

MIAA

Microinsulin autoantibodies

MMTT

Mixed-meal tolerance test

mAb

Monoclonal antibody

PBMC

Peripheral blood mononuclear cell

PD-1

Programmed cell death protein 1

PHA

Phytohaemagglutinin

qPCR

Quantitative PCR

TIGIT

T cell immunoreceptor with Ig and ITIM domains

Tregs

Regulatory T cells

ZnT8

Zinc transporter 8

Notes

Acknowledgements

The authors express their gratitude to L. Rink and L. Feldman (both from Yale Center for Clinical Investigation, Yale University, USA) for their help in recruitment and evaluation of participants.

Contribution statement

ALP, PPH, PC, SAL, PSL, SEG, CJG, PAG, AW, JD and KCH acquired and analysed data and wrote or revised the manuscript. KMH, JD, AW and WH analysed data and revised the manuscript. All of the authors approved the final version of the manuscript. KCH is the guarantor of this work.

Funding

This study was supported by grant 17-2013-501 from the Juvenile Diabetes Research Foundation and grant DK057846 from the National Institutes of Health. The flow cytometry analysis was sponsored by the Immune Tolerance Network and supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI109565. ALP was supported by grant T32DK007058 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Duality of interest

KCH is a member of the Scientific Advisory Board of Provention Biotech and a Scientific Advisor for Tiziana Life Sciences. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Supplementary material

125_2018_4786_MOESM1_ESM.pdf (212 kb)
ESM (PDF 211 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ana Luisa Perdigoto
    • 1
  • Paula Preston-Hurlburt
    • 2
  • Pamela Clark
    • 2
  • S. Alice Long
    • 3
  • Peter S. Linsley
    • 3
  • Kristina M. Harris
    • 4
  • Steven E. Gitelman
    • 5
  • Carla J. Greenbaum
    • 3
  • Peter A. Gottlieb
    • 6
  • William Hagopian
    • 7
  • Alyssa Woodwyk
    • 8
  • James Dziura
    • 9
  • Kevan C. Herold
    • 2
  • the Immune Tolerance Network
  1. 1.Division of Endocrinology, Department of Internal MedicineYale UniversityNew HavenUSA
  2. 2.Department of ImmunobiologyYale UniversityNew HavenUSA
  3. 3.Benaroya Research Institute at Virginia MasonSeattleUSA
  4. 4.Immune Tolerance Network, Biomarker & Discovery ResearchBethesdaUSA
  5. 5.Division of Pediatric Endocrinology and Diabetes CenterUniversity of California San FranciscoSan FranciscoUSA
  6. 6.Barbara Davis Center for Childhood DiabetesUniversity of Colorado School of MedicineAuroraUSA
  7. 7.Pacific Northwest Research InstituteSeattleUSA
  8. 8.Division of Epidemiology or BiostatisticsWestern Michigan UniversityKalamazooUSA
  9. 9.Department of Emergency MedicineYale UniversityNew HavenUSA

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