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Principal Investigator: Kevan C Herold
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $722,908
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
The overall objective of the work supported by this grant has been to develop therapies to treat, delay, or
prevent Type 1 diabetes (T1D). The work from prior funding cycles has changed the field. The studies have
included clinical and mechanistic investigations that led to the first drug approved by the FDA for delay of T1D
(or any autoimmune disease), and the only drug approved to change the course of T1D since the discovery of
insulin, more than 100 years ago. Our studies have led to the understanding that teplizumab modifies CD8+ T
cells and induces a signal that leads to partial exhaustion, effects of drug treatment on β cells, and patient
features that can affect these responses. However, a number of new questions have emerged which are
essential to address to further advance immune therapy for T1D with teplizumab or other agents. The
phenotypes of CD8+ T cells that identify responses to the drug diminish by 18 months after drug treatment
indicating that there are other factors that account for the long term responses that are seen in some patients.
In addition, not all patients respond but the features of responders and the mechanisms that sustain the clinical
benefits are not well understood. In this continuation proposal we aim to test two hypotheses related to the
mechanisms of teplizumab in clinical responders. We will use unique clinical samples from two successful
clinical trials to address these hypotheses – from the TN10 teplizumab prevention trial (a Phase II trial testing
whether teplizumab would delay the time to diagnosis of Stage 3 clinical T1D in patients at risk with Stage 2
disease) including samples from patients who have shown clinical responses for more than 10 years from a
course of drug, and the PROTECT trial, a Phase III clinical trial of patients with new onset T1D. In the first aim
we will test the hypothesis that teplizumab induces specific changes in autoantigen reactive T cells that results
in its efficacy. We will compare the transcriptome. phenotype (with CITEseq), and epigenome (with ASAP-seq)
of auto and viral antigen specific CD8+ T cells in samples from responders and non-responders from the two
clinical trials including samples from patients whose duration of response is more than 10 years. In the second
aim, we will test the hypothesis that the host environment, which may be shaped by prior infection (with EBV),
commensals (identified by anti-commensal antibodies), age, HLA type, and other factors, determines
responses to teplizumab treatment in responders and non-responders. We will use single cell techniques to
evaluate cells from the patients in the two clinical trials. We will use this information to develop a model that
incorporates the single cell and clinical features to predict clinical responses to teplizumab. These studies will
identify immune mechanisms that can lead to operational tolerance. This information is important for
understanding the pathogenesis of human T1D. I enables us to build on the prior successes by combining
agents that can target pathways that maintain tolerance. In addition, it enables us to identify which patient are
most likely to respond and when they should be treated.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Active Follow-up><Address><Affect><After Care><After-Treatment><Aftercare><Age><Antibodies><Antigens><Autoantigens><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autologous Antigens><Back><Bar Codes><Beta Cell><Brittle Diabetes Mellitus><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CITE sequencing><CITE-seq><CITEseq><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Characteristics><Clinical><Clinical Treatment Moab><Clinical Trials><CoV-2><CoV2><Combined Modality Therapy><DNA><Data><Deoxyribonucleic Acid><Development><Diabetes Mellitus><Diagnosis><Disease><Disease Progression><Disorder><Dorsum><Drug Therapy><Drugs><EB virus><EBV><Environment><Epstein Barr Virus><Exhibits><FDA approved><Frequencies><Funding><Future><Goals><Grant><HHV-4><HHV4><Human><Human Herpesvirus 4><Humulin R><IDDM><Immune><Immune Tolerance><Immune mediated therapy><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Tolerance><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Individual><Infection><Infectious Mononucleosis Virus><Infusion><Infusion procedures><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Investigation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modeling><Modern Man><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Novolin R><OKT3 antigen><Pathogenesis><Pathogenicity><Pathologic Processes><Pathological Processes><Pathway interactions><Patient Selection><Patients><Pharmaceutical Preparations><Pharmacotherapy><Phase><Phase 3 Clinical Trials><Phase III Clinical Trials><Phenotype><Population><Prevention trial><Regular Insulin><Resolution><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Self-Antigens><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Sudden-Onset Diabetes Mellitus><Surface Proteins><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><T3 Antigens><T3 Complex><T3 molecule><T8 Cells><T8 Lymphocytes><Techniques><Testing><Time><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Viral><Viral Antigens><Work><Wuhan coronavirus><active followup><ages><antigen-specific T cells><autoimmune condition><autoimmune disorder><autoimmunity disease><barcode><biobank><biological signal transduction><biorepository><cellular indexing of transcriptomes and epitopes by single cell sequencing><clinical predictors><combination therapy><combined modality treatment><combined treatment><computer based prediction><coronavirus disease 2019 virus><coronavirus disease-19 virus><develop therapy><developmental><diabetes><drug efficacy><drug treatment><drug/agent><early clinical trial><early phase clinical trial><epigenome><exhaustion><experience><follow up><follow-up><followed up><followup><global gene expression><global transcription profile><gut microbes><gut microbial species><hCoV19><immune suppression><immune suppressive activity><immune suppressive function><immune system tolerance><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune unresponsiveness><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunological paralysis><immunological status><immunosuppressive activity><immunosuppressive function><immunosuppressive response><infusions><insulin dependent diabetes><insulin dependent diabetes mellitus onset><insulin dependent type 1><intervention development><intestinal microbes><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><mAbs><machine learning based prediction model><machine learning based predictive model><machine learning prediction><machine learning prediction model><monoclonal Abs><multi-modal therapy><multi-modal treatment><multiomics><multiple omics><nCoV2><panomics><pathway><peripheral blood><phase 2 trial><phase II trial><phase III protocol><post treatment><predictive biomarkers><predictive marker><predictive modeling><predictive molecular biomarker><prevent><preventing><resolutions><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><response><success><therapy development><thymus derived lymphocyte><transcriptome><treatment development><type 1 diabetes onset><type I diabetes><type one diabetes><virus antigen><β-cell><β-cells><βCell>