title: Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes.
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.
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.|Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Tooley
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.|Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Nalini
authors.initials: N
authors.lastname: Vudattu
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jinmyung
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Cotsapas
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Devine
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Khadir
authors.initials: K
authors.lastname: Raddassi
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ehlers
authors.affiliation: National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: McNamara
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Sai
authors.initials: S
authors.lastname: Kanaparthi
authors.affiliation: Immune Tolerance Network, Bethesda, MD, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.|Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008297:Male; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D059467:Transcriptome / Q000187:drug effects*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C502540:teplizumab
keywords: Anti-CD3 mAb ⋅ CD8+ T cells ⋅ Immune therapy ⋅ Tolerance ⋅ Type 1 diabetes