ORCID Profile
0000-0002-0281-1240
Current Organisation
Benaroya Research Institute
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Publisher: Springer Science and Business Media LLC
Date: 10-2023
Publisher: American Diabetes Association
Date: 20-03-2019
DOI: 10.2337/DB18-1081
Abstract: Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used s les from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell–mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis late features that arose at or near T1D diagnosis and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2023
Publisher: American Society for Clinical Investigation
Date: 02-2021
DOI: 10.1172/JCI143648
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2023
DOI: 10.1101/2023.04.18.23288756
Abstract: 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. 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 in iduals at risk for T1D or within 1 year of T1D diagnosis. 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. 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. We performed a systematic review to ascertain whether islet autoantibodies, biomarkers of autoimmunity against insulin-producing cells, could aid in stratifying in iduals with different clinical presentations of type 1 diabetes. We found existing evidence most strongly supporting the application of these biomarkers to the period before clinical diagnosis, when certain autoantibody features (number, type) and the age when they develop, can provide important information for patients and care providers on what to expect for future type 1 diabetes progression.
Publisher: American Diabetes Association
Date: 09-04-2019
DOI: 10.2337/DB19-0057
Abstract: A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P & 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
Publisher: Wiley
Date: 25-09-2021
DOI: 10.1111/EEN.12949
Abstract: It is often necessary to assess the density of honey bee colonies in an environment. In theory, a random s le of males obtained at a mating lek (Drone Congregation Area) can be used to infer the number of queens that contributed sons to the s le, and thereby estimate colony density based on the area from which drones are drawn to a DCA. Because of its utility and efficiency, the technique is being increasingly used. However, the accuracy of the method has never been evaluated, and there are no recommendations for s le size. Here, we infer the genotypes of 322 mother queens from the genotypes of 2329 drones caught at a single DCA using the program COLONY. We then use this realistic pool of queen genotypes to generate multiple simulated data sets of drone genotypes, varying the number of queens and sons that each queen contributed to the s le. We find that the technique provides an accurate estimate ( % error) of the total number of families present in a drone s le, provided that queens contribute at least six drones to the s le on average. This threshold can be reduced when colony density is low. Non‐s ling error only becomes significant when queens contribute fewer than three sons on average across simulated s les. We conclude that the technique is robust and can be used with confidence provided that the s le size is adequate.
Publisher: American Diabetes Association
Date: 15-03-2023
DOI: 10.2337/DC22-2200
Abstract: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in in iduals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept lacebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702 95% CI 0.452, 1.09 P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P & 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P & 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk in iduals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Publisher: Wiley
Date: 23-12-2019
DOI: 10.1111/EEN.12715
Publisher: American Society for Clinical Investigation
Date: 08-11-2021
No related grants have been discovered for Sarah Alice Long.