المؤلفون: Herold, Kevan C., Delong, Thomas, Perdigoto, Ana Luisa, Biru, Noah, Brusko, Todd M., Walker, Lucy S. K.

المصدر: Nature Reviews Immunology; 20240101, Issue: Preprints p1-17, 17p

مستخلص: Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.

المؤلفون: So, Michelle, Speake, Cate, Steck, Andrea K, Lundgren, Markus, Colman, Peter G, Palmer, Jerry P, Herold, Kevan C, Greenbaum, Carla J

المصدر: Endocrine Reviews; October 2021, Vol. 42 Issue: 5 p584-604, 21p

مستخلص: Islet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk individuals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number; it has been robustly shown that nearly all multiple-autoantibody-positive individuals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression among multiple-autoantibody-positive individuals is highly heterogenous. Accurate prediction of the most rapidly progressing individuals is crucial for efficient and informative clinical trials and for identification of candidates most likely to benefit from disease modification. This is increasingly relevant with the recent success in delaying clinical disease in presymptomatic subjects using immunotherapy, and as the field moves toward population-based screening. There have been many studies investigating islet autoantibody characteristics for their predictive potential, beyond a simple categorical count. Predictive features that have emerged include molecular specifics, such as epitope targets and affinity; longitudinal patterns, such as changes in titer and autoantibody reversion; and sequence-dependent risk profiles specific to the autoantibody and the subject’s age. These insights are the outworking of decades of prospective cohort studies and international assay standardization efforts and will contribute to the granularity needed for more sensitive and specific preclinical staging. The aim of this review is to identify the dynamic and nuanced manifestations of autoantibodies in type 1 diabetes, and to highlight how these autoantibody features have the potential to improve study design of trials aiming to predict and prevent disease.Graphical Abstract

المؤلفون: Burkhardt, Daniel B., Stanley, Jay S., Tong, Alexander, Perdigoto, Ana Luisa, Gigante, Scott A., Herold, Kevan C., Wolf, Guy, Giraldez, Antonio J., van Dijk, David, Krishnaswamy, Smita

المصدر: Nature Biotechnology; May 2021, Vol. 39 Issue: 5 p619-629, 11p

مستخلص: Current methods for comparing single-cell RNA sequencing datasets collected in multiple conditions focus on discrete regions of the transcriptional state space, such as clusters of cells. Here we quantify the effects of perturbations at the single-cell level using a continuous measure of the effect of a perturbation across the transcriptomic space. We describe this space as a manifold and develop a relative likelihood estimate of observing each cell in each of the experimental conditions using graph signal processing. This likelihood estimate can be used to identify cell populations specifically affected by a perturbation. We also develop vertex frequency clustering to extract populations of affected cells at the level of granularity that matches the perturbation response. The accuracy of our algorithm at identifying clusters of cells that are enriched or depleted in each condition is, on average, 57% higher than the next-best-performing algorithm tested. Gene signatures derived from these clusters are more accurate than those of six alternative algorithms in ground truth comparisons.

المؤلفون: Speake, Cate, Ylescupidez, Alyssa, Neiman, Daniel, Shemer, Ruth, Glaser, Benjamin, Tersey, Sarah A, Usmani-Brown, Sahar, Clark, Pamela, Wilhelm, Joshua J, Bellin, Melena D, Herold, Kevan C, Mirmira, Raghavendra G, Dor, Yuval, Evans-Molina, Carmella

المصدر: The Journal of Clinical Endocrinology & Metabolism; March 2020, Vol. 105 Issue: 3 p781-791, 11p

المؤلفون: Wang, Hongjun, Gou, Wenyu, Strange, Charlie, Wang, Jingjing, Nietert, Paul J., Cloud, Colleen, Owzarski, Stefanie, Shuford, Betsy, Duke, Tara, Luttrell, Louis, Lesher, Aaron, Papas, Klearchos K., Herold, Kevan C., Clark, Pamela, Usmani-Brown, Sahar, Kitzmann, Jennifer, Crosson, Craig, Adams, David B., Morgan, Katherine A.

المصدر: Cell Transplantation; December 2019, Vol. 28 Issue: Supplement 1 p25S-36S, 12p

مستخلص: Stresses encountered during human islet isolation lead to unavoidable β-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, β-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less β-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.

المؤلفون: Dayan, Colin M, Korah, Maria, Tatovic, Danijela, Bundy, Brian N, Herold, Kevan C

المصدر: The Lancet; October 2019, Vol. 394 Issue: 10205 p1286-1296, 11p

مستخلص: Over several decades, studies have described the progression of autoimmune diabetes, from the first appearance of autoantibodies until, and after, the diagnosis of clinical disease with hyperglycaemia and insulin dependence. Despite the improved management of type 1 diabetes with exogenous insulin, most patients do not meet clinical glycaemic goals, and diabetes remains an important medical problem that affects children and adults. Clinical and preclinical studies have suggested strategies to prevent the diagnosis of type 1 diabetes in people at risk, but the outcomes of previous clinical trials have not met their primary endpoints of disease prevention or delay. The results from the TN-10 teplizumab prevention trial show that the diagnosis of type 1 diabetes can be delayed by treatment with a FcR non-binding monoclonal antibody to CD3 in people at high risk for disease. This Series paper discusses how this clinical achievement raises new questions about for whom, and when, immunological strategies might be developed to prevent type 1 diabetes, and how to achieve this goal.

المؤلفون: Xie, Quin Yuhui, Oh, Sean, Wong, Anthony, Yau, Christopher, Herold, Kevan C., Danska, Jayne S.

المصدر: Science Translational Medicine; October 2023, Vol. 15 Issue: 719

مستخلص: Immune-targeted therapies have efficacy for treatment of autoinflammatory diseases. For example, treatment with the T cell–specific anti-CD3 antibody teplizumab delayed disease onset in participants at high risk for type 1 diabetes (T1D) in the TrialNet 10 (TN-10) trial. However, heterogeneity in therapeutic responses in TN-10 and other immunotherapy trials identifies gaps in understanding disease progression and treatment responses. The intestinal microbiome is a potential source of biomarkers associated with future T1D diagnosis and responses to immunotherapy. We previously reported that antibody responses to gut commensal bacteria were associated with T1D diagnosis, suggesting that certain antimicrobial immune responses may help predict disease onset. Here, we investigated anticommensal antibody (ACAb) responses against a panel of taxonomically diverse intestinal bacteria species in sera from TN-10 participants before and after teplizumab or placebo treatment. We identified IgG2 responses to three species that were associated with time to T1D diagnosis and with teplizumab treatment responses that delayed disease onset. These antibody responses link human intestinal bacteria with T1D progression, adding predictive value to known T1D risk factors. ACAb analysis provides a new approach to elucidate heterogeneity in responses to immunotherapy and identify individuals who may benefit from teplizumab, recently approved by the U.S. Food and Drug Administration for delaying T1D onset.

المؤلفون: Perdigoto, Ana Luisa, Quandt, Zoe, Anderson, Mark, Herold, Kevan C

المصدر: The Lancet Diabetes & Endocrinology; June 2019, Vol. 7 Issue: 6 p421-423, 3p

المؤلفون: Herold, Kevan C., Majzoub, Joseph A., Melmed, Shlomo, Pendergrass, Merri, Schlumberger, Martin

المصدر: Nature Reviews Endocrinology; November 2015, Vol. 11 Issue: 11 p672-680, 9p

مستخلص: Here, five of our Advisory Board Members look back at the past decade of endocrinology research, highlighting key advances and identifying roadblocks. They also discuss where effort and money should be invested now and speculate on where progress might be made in the coming decade.

المؤلفون: Reed, James C., Herold, Kevan C.

المصدر: Nature Reviews Endocrinology; May 2015, Vol. 11 Issue: 5 p308-314, 7p

مستخلص: Successful studies in the nonobese diabetic (NOD) mouse model often do not translate to positive outcomes in human studies. This Perspectives outlines the genetic and immunologic differences that might contribute to these differential outcomes and suggests how the NOD mouse model could be adapted to improve its utility.