CTLA4-Ig (abatacept): a promising investigational drug for use in type 1 diabetes

Rachid, Ousama; Osman, Amr; Abdi, Reza; Haik, Yousef

doi:10.1080/13543784.2020.1727885

Cited by 29 publications

(16 citation statements)

References 71 publications

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“…The clinical indication of abatacept is to treat active rheumatoid arthritis, but seminal data are supporting its potential in the treatment of Type 1 diabetes and cardiovascular disease. In TrialNet study for people newly diagnosed, those who took Abatacept showed 59% higher insulin production and prolonged insulin production (57). Moreover, clinical studies in patients with rheumatoid arthritis have shown that Abatacept treatment reduced the risk of Type 1 or Type 2 diabetes, through an anti-inflammatory mechanism preserving β-cell function (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

et al. 2021

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Background: Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in Type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued by treating mice with abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis. Clinical evidence indicated abatacept can slow the decline in beta-cell function.Methods: A cohort of 24 patients (12 with T2D) undergoing hip replacement surgery was enrolled in the study. Flow cytometry and cytokine analyses were performed on BM leftovers from surgery. We next compared the immune profile of db/db and control wt/db mice. In an additional study, db/db mice were randomized to receive abatacept or vehicle for 4 weeks, with endpoints being immune cell profile, indices of insulin sensitivity, and heart performance.Results: Patients with T2D showed increased frequencies of BM CD4+ (2.8-fold, p = 0.001) and CD8+ T cells (1.8-fold, p = 0.01), with the upregulation of the activation marker CD69 and the homing receptor CCR7 in CD4+ (1.64-fold, p = 0.003 and 2.27-fold, p = 0.01, respectively) and CD8+ fractions (1.79-fold, p = 0.05 and 1.69-fold, p = 0.02, respectively). These differences were confirmed in a multivariable regression model. CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T-cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and the levels of proinflammatory cytokines and improved cardiac function but not insulin sensitivity.Conclusions: Results provide proof-of-concept evidence for the activation of BM adaptive immunity in T2D. In mice, treatment with abatacept dampens the activation of adaptive immunity and protects from cardiac damage.

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Section: Discussionmentioning

confidence: 99%

Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

et al. 2021

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“…Insulin ancillary drugs, which improve glycemic control by targeting sodium glucose co-transporters (SGLTs), have also been tested for T1D treatment [ 69 ]. The CTLA4-immunoglobulin fusion protein (Abatacept), which functions by blocking the co-stimulation of T cells, has also yielded positive outcomes as a promising T1D drug [ 70 , 71 ]. Although the results of our analysis do not implicate the SGLTs or PD-L1, they do support the dysregulated T cell-mediated immune response hypothesis, identifying CTLA4 as an potential therapeutic target, as well as additional targets in T cells (ADCY3, LAT, PTEN, and PRKD2), B cells (C1q and TNF related 6 (C1QTNF6)), and APCs (HLA-A, HLA-DQB1, HLA-DRB1, IL27, and SH2B1).…”

Section: Discussionmentioning

confidence: 99%

A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation

et al. 2021

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Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.

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“…Several published clinical trials implemented umbilical cord stem cells [74], immunomodulatory therapies with biological drugs (abatacept, teplizumab, rituximab) or granulocyte-colony-stimulating factor (G-CSF) and combined therapies [75,76]. Immune ablation and autologous hematopoietic stem cell transplantation (AHSCT) is another possible therapeutic strategy to inhibit the immune process in T1D, however this therapy presents significant adverse event risk [77,78].…”

Section: C-peptide and Novel And Future Therapiesmentioning

confidence: 99%

C-peptide and residual β-cell function in pediatric diabetes – state of the art

Jamiołkowska‐Sztabkowska¹,

Głowińska‐Olszewska²,

Bossowski³

2021

pedm

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CTLA4-Ig (abatacept): a promising investigational drug for use in type 1 diabetes

Cited by 29 publications

References 71 publications

Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation

C-peptide and residual β-cell function in pediatric diabetes – state of the art

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