Abstract
The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.
Keywords:
Anti-CD3 monoclonal antibody; Immune tolerance; Immunotherapy; T cell inactivation; T lymphocyte; Type 1 diabetes.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Randomized Controlled Trial
MeSH terms
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Adolescent
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Adult
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Antibodies, Monoclonal, Humanized / therapeutic use*
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C-Peptide / agonists
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C-Peptide / genetics
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C-Peptide / immunology
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CD3 Complex / genetics
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CD3 Complex / immunology
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CD57 Antigens / genetics
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CD57 Antigens / immunology
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CD8-Positive T-Lymphocytes / drug effects*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Child
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Diabetes Mellitus, Type 1 / drug therapy*
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / pathology
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Gene Expression
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Humans
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Hypoglycemic Agents / therapeutic use*
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Immune Tolerance / drug effects*
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Immunomodulation
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Immunotherapy / methods
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Interleukin-7 Receptor alpha Subunit / genetics
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Interleukin-7 Receptor alpha Subunit / immunology
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology
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Male
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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T-Lymphocytes, Regulatory / drug effects*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Trans-Activators / genetics
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Trans-Activators / immunology
Substances
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Antibodies, Monoclonal, Humanized
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C-Peptide
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CD3 Complex
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CD57 Antigens
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FOXP3 protein, human
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Forkhead Transcription Factors
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Hypoglycemic Agents
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Interleukin-7 Receptor alpha Subunit
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KLRG1 protein, human
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Lectins, C-Type
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic
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TIGIT protein, human
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Trans-Activators
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teplizumab