The many faces of islet antigen‐specific CD8 T cells: clues to clinical outcome in type 1 diabetes

Wiedeman, Alice; Speake, Cate; Long, S. Alice

doi:10.1111/imcb.12437

Cited by 12 publications

(3 citation statements)

References 80 publications

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“…The most robust and clinically relevant reported effect of teplizumab seems to be the expansion of a (partially) exhausted phenotype among total CD8 + T cells, an effect also observed in the AG019/teplizumab combination treatment group of the current study. This exhaustion profile, characterised by the expression of inhibitory receptors (killer cell lectin-like receptor G1 [KLRG1], T cell immunoreceptor with Ig and ITIM domains [TIGIT] and eomesodermin [EOMES]), limited cytokine production and reduced proliferative capacity, results in an effector T cell population with an altered functional response, and is correlated with a better metabolic outcome [ 13 , 26 ] and slower disease progression [ 28 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

Mathieu,

Wiedeman,

Cerosaletti

et al. 2023

Diabetologia

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Aims/hypothesis We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab. Methods Adults (18–42 years) and adolescents (12–17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12–42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively. Results Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy. Conclusions/interpretation Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes. Trial registration ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 Funding This study was funded by Precigen ActoBio Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

Mathieu,

Wiedeman,

Cerosaletti

et al. 2023

Diabetologia

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“…The exact pathogenesis of this disease is not fully understood, but it is known that self-reactive T cells play a crucial role in it (Shao et al, 2020;Mitchell and Michels, 2022;Scherm and Daniel, 2020). Previous studies have identi ed various self-reactive T cells, particularly CD8 + T cells, that are associated with the progression of T1D (Kwong et al, 2021;Wiedeman et al, 2021;Bender et al, 2021). These T cells can recognize and attack Pancreatic islet beta cells, leading to the onset of diabetes (Bulek et al, 2012;Pinkse et al, 2005;Ozturk et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

TRAJ23 Gene Targeting as a Therapeutic Strategy for Type 1 Diabetes: Implications from NOD Mouse Model Studies

Lai,

Luo,

Luo

et al. 2024

Preprint

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Type 1 Diabetes (T1D) is an autoimmune disease characterized by the attack and destruction of Pancreatic islet beta cells by T cells. Understanding the role of T-cell receptor (TCR) in the development of T1D is of paramount importance. This study employs single-cell RNA sequencing (scRNA-seq) to delve into the mechanistic actions and potential therapeutic applications of autoreactive stem cell-like CD8 TCR in T1D. By retrieving T-cell data from non-obese diabetic (NOD) mice via the GEO database, it was revealed that CD8+ T cells are the predominant T-cell subset in the pancreatic tissue of T1D mice, along with the identification of T-cell marker genes closely associated with T1D. Moreover, the gene TRAJ23 exhibits a preference for T1D, and its knockout alleviates T1D symptoms and adverse reactions in NOD mice. Additionally, engineered TCR-T cells demonstrate significant cytotoxicity towards β cells in T1D.

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“…It is characterized by the loss of β cells of islets of Langerhans. 1 The signal peptide of preproinsulin epitopes, which is displayed by human leukocyte antigen (HLA) class I and activates CD8+T-cells, is primarily responsible for β -cell death in T1DM. 2 According to genome-wide association studies (GWAS), human leukocyte antigen genes (HLA genes), in particular HLA class II loci, account for nearly 50% of the genetic susceptibility to T1DM.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms of Endoplasmic reticulum amino peptidase 1 (ERAP1) and Interferon lambda 4 (IFN-λ4) in Egyptian patients with type 1 diabetes mellitus

Nazar¹,

Ghazy²,

Amer³

et al. 2023

EJI

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Different genetic and environmental factors are implicated in type I diabetes (T1DM) pathogenesis. About 50% of the genetic susceptibility for T1DM is related to human leukocyte antigen (HLA) genes. Other non-HLA genes have variable roles in the destruction of pancreatic β cells. A highly variable gene called endoplasmic reticulum associated with antigen processing gene 1(ERAP1) shares in activating autoreactive CD8+ T lymphocytes, peptide trimming, and subsequent pancreatic β cells destruction. Local production of inflammatory cytokines within the cells of islets of Langerhans is linked to T1DM progression. Different viral and autoimmune disorders have been linked to genetic variations in type III interferon (IFNλs). This study aimed to determine genetic polymorphisms of interferon lambda 4 (IFNλ4rs 73555604) and endoplasmic reticulum aminopeptidases 1 (ERAP1 rs26618) in Egyptian patients with T1DM. The study recruited 120 patients with T1DM from Kafrelsheikh University Hospital and 100 normal controls who were age and sex matched with the patients’ group. Single-nucleotide polymorphism (SNP) genotyping of ERAP1(rs26618) and IFN-λ-4(rs73555604) was performed using real-time polymerase chain reaction. Patients with CC genotype were less likely to develop T1DM than those with TC and TT genotypes for both genes. In addition, T allele frequency in comparison to C allele frequency was significantly increased in T1DM patients when compared to control group (p<0.001). There were positive correlations between studied SNPs for both genes, fasting and postprandial blood glucose levels which suggest the association of these genes with T1DM occurrence. We concluded that the studied SNPs of ERAP1gene (rs26618) and IFNλ-4 gene(rs73555604) may be associated with T1DM development. In addition, T alleles for both genes could be considered risk alleles while C alleles would be regarded as a protective allele. Patients with TC and TT genotypes would be at a higher risk for T1DM than those carrying CC genotype.

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The many faces of islet antigen‐specific CD8 T cells: clues to clinical outcome in type 1 diabetes

Cited by 12 publications

References 80 publications

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

TRAJ23 Gene Targeting as a Therapeutic Strategy for Type 1 Diabetes: Implications from NOD Mouse Model Studies

Genetic polymorphisms of Endoplasmic reticulum amino peptidase 1 (ERAP1) and Interferon lambda 4 (IFN-λ4) in Egyptian patients with type 1 diabetes mellitus

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