Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis
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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.
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.
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.
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.
KeywordsAnergy Anti-CD3 C-peptide Exhaustion T cells Teplizumab Type 1 diabetes
Autoimmunity-Blocking Antibody for Tolerance
Killer cell lectin-like receptor G1
Mixed-meal tolerance test
Peripheral blood mononuclear cell
Programmed cell death protein 1
T cell immunoreceptor with Ig and ITIM domains
Regulatory T cells
Zinc transporter 8
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.
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.
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.
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