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Eur J Immunol. 2016 Jan;46(1):230-41. doi: 10.1002/eji.201545708. Epub 2015 Dec 14.

Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes.

Author information

1
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
2
Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
3
Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
4
Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
5
Immune Tolerance Network, Bethesda, MD, USA.
6
National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.

Abstract

The mechanisms whereby immune therapies affect progression of type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR nonbinding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8(+) central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from two randomized clinical studies of teplizumab in patients with new- and recent-onset T1D. At the conclusion of therapy, clinical responders showed a significant reduction in circulating CD4(+) effector memory T cells. Afterward, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non-CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and nonresponders versus placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T-cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D.

KEYWORDS:

Anti-CD3 mAb ⋅ CD8+ T cells ⋅ Immune therapy ⋅ Tolerance ⋅ Type 1 diabetes

PMID:
26518356
PMCID:
PMC4882099
DOI:
10.1002/eji.201545708
[Indexed for MEDLINE]
Free PMC Article
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