Islet Autoantibody Standardization Program: interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops

Marzinotto, Ilaria; Pittman, David L.; Williams, Alistair J K; Long, Anna E.; Achenbach, Peter; Schlosser, Michael; Akolkar, Beena; Winter, William E.; Lampasona, Vito

doi:10.1007/s00125-023-05877-9

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…Islet autoantibodies were a primary focus for a majority of the papers identified (100/151, 66%), while others included autoantibody assessments as part of a larger precision analysis or clinical trial follow-up. Notably, less than half (65/151, 43%) reported using autoantibody assays that had been tested in a standardization program such as the islet autoantibody standardization program (IASP) (9). The most frequent autoantibody feature studied was autoantibody type/target protein (137/151, 91%), followed by autoantibody number (97/151, 64%), autoantibody titer (50/151,33%), age at seroconversion (39/151, 26%), rate of seroconversion from single to multiple autoantibodies (32/151, 21%), order of autoantibody appearance after seroconversion (28/151, 18%), novel islet autoantibody/epitope identification (13/151, 9%), and autoantibody affinity (6/151, 4%).…”

Section: Literature Search and Screening Resultsmentioning

confidence: 99%

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Felton

Redondo

Oram

et al. 2023

Preprint

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Background Heterogeneity exists in type 1 diabetes (T1D) development and presentation. Islet autoantibodies form the foundation for T1D diagnostic and staging efforts. We hypothesized that autoantibodies can be used to identify heterogeneity in T1D before, at, and after diagnosis, and in response to disease modifying therapies. at clinically relevant timepoints throughout T1D progression. Methods We performed a systematic review assessing 10 years of original research studies examining relationships between autoantibodies and heterogeneity during disease progression, at the time of diagnosis, after diagnosis, and in response to disease modifying therapies in individuals at risk for T1D or within 1 year of T1D diagnosis. Results 10,067 papers were screened. Out of 151 that met data extraction criteria, 90 studies characterized heterogeneity before clinical diagnosis. Autoantibody type/target was most commonly examined, followed by autoantibody number, titer, order of seroconversion, affinity, and novel islet autoantibodies/epitopes. Recurring themes included positive relationships of autoantibody number and specific types and titers with disease progression, differing clinical phenotypes based on the order of autoantibody seroconversion, and interactions with age and genetics. Overall, reporting of autoantibody assay performance was commonly included; however, only 43% (65/151) included information about autoantibody assay standardization efforts. Populations studied were almost exclusively of European ancestry. Conclusions Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before clinical diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly when considered in relation to age and genetic risk, could offer more precise stratification. Increased participation in autoantibody standardization efforts is a critical step to improving future applicability of autoantibody-based precision medicine in T1D.

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Section: Literature Search and Screening Resultsmentioning

confidence: 99%

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Felton

Redondo

Oram

et al. 2023

Preprint

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“…Harmonization to international criteria would facilitate cross-study comparisons and improve reproducibility, a critical challenge with functional immune markers. The T1D field has been strengthened by an international standardization program for autoantibody measurement that underpinned the development of type 1 diabetes staging criteria 111 . An important consideration is that if novel mechanistic markers (immune, metabolic, or other) can be used to predict treatment response, then similar scrutiny and standardization of these markers will be needed.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response

Felton

Griffin

Oram

et al. 2023

Preprint

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Background Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention. Methods To understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results We identified 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss in individuals at disease onset. Seventeen agents tested, mostly immunotherapies, showed benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employed precision analyses to assess features linked to treatment response. Age, measures of beta cell function and immune phenotypes were most frequently tested. However, analyses were typically not prespecified, with inconsistent methods reporting, and tended to report positive findings. Conclusions While the quality of prevention and intervention trials was overall high, low quality of precision analyses made it difficult to draw meaningful conclusions that inform clinical practice. Thus, prespecified precision analyses should be incorporated into the design of future studies and reported in full to facilitate precision medicine approaches to T1D prevention.

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“…Tests for diabetes-related autoantibodies glutamic acid decarboxylase 65 (GAD65), microinsulin aAb assay (mIAA), islet-antigen 2 (IA-2), or zinc transporter 8 (ZnT8) were assessed using procedures outlined previously in the Diabetes Antibody Standardization Program ( 45 , 46 ). MMTT-stimulated tests were performed as previously described ( 47 ) at screening and weeks 26, 52, and 104 for 4 hours and weeks 13 and 78 for 2 hours.…”

Section: Methodsmentioning

confidence: 99%

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

Bender,

Wiedeman,

et al. 2024

Sci. Transl. Med.

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CD4 + CD25 hi CD127 lo/− FOXP3 + regulatory T cells (T regs ) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T regs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T regs (expT regs ) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 10 6 cells/kilogram) or low-dose (1 × 10 6 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT regs and peripheral blood samples from participants. The single doses of expT regs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo ( P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpT regs were highly activated and suppressive in vitro. A transient increase of activated memory T regs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT regs . However, the in vitro fold expansion of expT regs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of T reg dose. These results suggest that a single dose of polyclonal expT regs does not alter progression in T1D; instead, T reg quality may be an important factor.

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Islet Autoantibody Standardization Program: interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops

Cited by 10 publications

References 40 publications

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

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