Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

Musthaffa, Yassmin; Hamilton‐Williams, Emma E.; Nel, Hendrik J.; Bergot, Anne‐Sophie; Mehdi, Ahmed M.; Harris, Mark; Thomas, Ranjeny

doi:10.1002/cti2.1315

Cited by 15 publications

(7 citation statements)

References 58 publications

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“…Furthermore, the interferon-γ bias observed in progressors was highest for peptide C13-32 amongst all the peptides tested. These observations together with our previous studies in preclinical individuals, 11,21 and a recent study of at-risk individuals reporting proliferative reactivity to proinsulin C16-C30 which is encompassed in C13-32, 22 highlight a possible key role for C13-32 in type 1 diabetes pathology.…”

Section: Discussionsupporting

confidence: 69%

Evaluating T cell responses prior to the onset of type 1 diabetes

et al. 2022

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Aims In the current study we aimed to evaluat T cell phenotypes and metabolic profiles in high‐risk individuals who progressed to type 1 diabetes compared to those remaining disease free. Methods A Fluorspot assay was used to examine T cell responses to a panel of islet autoantigen peptides in samples obtained 6‐ and 30‐months preceding disease onset and at the same timepoints in non‐progressors. Results We noted a significant increase in the magnitude of the proinflammatory interferon‐γ response to proinsulin and insulin peptides in individuals who progressed to type 1 diabetes. In contrast, in the non‐progressors, we observed an increase in the regulatory IL‐10 response to proinsulin peptides. Furthermore, the T cell responses to the islet peptide panel predisposed towards a proinflammatory interferon‐γ bias in the progressors. Conclusions Collectively, these data suggest that a proinflammatory T cell response is prevalent in high‐risk individuals who progress to type 1 diabetes and can be detected up to 6 months prior to onset of disease. This observation, albeit in a small cohort, can potentially be harnessed in disease staging, particularly in identifying autoantibody‐positive individuals transitioning from stage 2 (dysglycemia present and pre‐symptomatic) to stage 3 (dysglycemia present and symptomatic). The detection of these different T cell phenotypes in progressors and non‐progressors suggests the presence of disease endotypes.

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Section: Discussionsupporting

confidence: 69%

Evaluating T cell responses prior to the onset of type 1 diabetes

et al. 2022

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“…T1D is a T cell–driven autoimmune disease and modulation of effector T cells is considered critically important for a successful therapy to halt the autoimmune attack. While we did not investigate islet-specific T cells, as individuals with long-standing T1D have a low frequency of such cells [ 58 , 59 ], we observed an increase in T cells expressing the immune-regulatory molecule TIGIT. TIGIT is characteristic of exhausted or dysfunctional T cells and was also increased in the successful anti-CD3 and alefacept trials in T1D [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation

et al. 2022

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Background Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status. Results HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention. Conclusion Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D. Trial registration ACTRN12618001391268. Registered 20 August 2018,https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792

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“…The lower number of TCR-β sequences in our new-onset cohort may be indicative of some TCRs being more involved earlier in the disease process, prior to clinical symptoms. Alternatively, there may be more β cell destruction in new-onset individuals compared with those in the preclinical stages of T1D, as evidenced by a recent study demonstrating that proliferation of proinsulin-specific CD4 T cells in children with new-onset T1D correlated to residual β cell function ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Temporal development of T cell receptor repertoires during childhood in health and disease

Mitchell¹,

Baschal²,

McDaniel³

et al. 2022

JCI Insight

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T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next-generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep sequenced the TCR-β chain repertoires from longitudinal peripheral blood DNA samples at 4 time points beginning early in life (median age of 1.4 years) from children who progressed to T1D ( n = 29) and age/sex-matched islet autoantibody-negative controls ( n = 25). From 53 million TCR-β sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independently of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and, separately, those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCR-β sequences were more common and frequent in number as the disease progressed in those who developed T1D compared with genetically at risk nondiabetic children, and this was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCR-β repertoires from a cohort of new-onset T1D patients ( n = 143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.

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Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

Cited by 15 publications

References 58 publications

Evaluating T cell responses prior to the onset of type 1 diabetes

Evaluating T cell responses prior to the onset of type 1 diabetes

Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation

Temporal development of T cell receptor repertoires during childhood in health and disease

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