Browsing by Author "Griffin, Kurt J."

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    Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
    (American Society for Clinical Investigation, 2015-08-03) Rigby, Mark R.; Harris, Kristina M.; Pinckney, Ashley; DiMeglio, Linda A.; Rendell, Marc S.; Felner, Eric I.; Dostou, Jean M.; Gitelman, Stephen E.; Griffin, Kurt J.; Tsalikian, Eva; Gottlieb, Peter A.; Greenbaum, Carla J.; Sherry, Nicole A.; Moore, Wayne V.; Monzavi, Roshanak; Willi, Steven M.; Raskin, Philip; Keyes-Elstein, Lynette; Long, S. Alice; Kanaparthi, Sai; Lim, Noha; Phippard, Deborah; Soppe, Carol L.; Fitzgibbon, Margret L.; McNamara, James; Nepom, Gerald T.; Ehlers, Mario R.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT00965458. FUNDING: NIH and Astellas.
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    Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes
    (Springer, 2024-09) Phillip, Moshe; Achenbach, Peter; Addala, Ananta; Albanese-O'Neill, Anastasia; Battelino, Tadej; Bell, Kirstine J.; Besser, Rachel E. J.; Bonifacio, Ezio; Colhoun, Helen M.; Couper, Jennifer J.; Craig, Maria E.; Danne, Thomas; de Beaufort, Carine; Dovc, Klemen; Driscoll, Kimberly A.; Dutta, Sanjoy; Ebekozien, Osagie; Elding Larsson, Helena; Feiten, Daniel J.; Frohnert, Brigitte I.; Gabbay, Robert A.; Gallagher, Mary P.; Greenbaum, Carla J.; Griffin, Kurt J.; Hagopian, William; Haller, Michael J.; Hendrieckx, Christel; Hendriks, Emile; Holt, Richard I. G.; Hughes, Lucille; Ismail, Heba M.; Jacobsen, Laura M.; Johnson, Suzanne B.; Kolb, Leslie E.; Kordonouri, Olga; Lange, Karin; Lash, Robert W.; Lernmark, Åke; Libman, Ingrid; Lundgren, Markus; Maahs, David M.; Marcovecchio, M. Loredana; Mathieu, Chantal; Miller, Kellee M.; O'Donnell, Holly K.; Oron, Tal; Patil, Shivajirao P.; Pop-Busui, Rodica; Rewers, Marian J.; Rich, Stephen S.; Schatz, Desmond A.; Schulman-Rosenbaum, Rifka; Simmons, Kimber M.; Sims, Emily K.; Skyler, Jay S.; Smith, Laura B.; Speake, Cate; Steck, Andrea K.; Thomas, Nicholas P. B.; Tonyushkina, Ksenia N.; Veijola, Riitta; Wentworth, John M.; Wherrett, Diane K.; Wood, Jamie R.; Ziegler, Anette-Gabriele; DiMeglio, Linda A.; Pediatrics, School of Medicine
    Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.
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    Correction to: Consensus guidance for monitoring individuals with islet autoantibody‑positive pre‑stage 3 type 1 diabetes
    (Springer, 2024) Phillip, Moshe; Achenbach, Peter; Addala, Ananta; Albanese-O'Neill, Anastasia; Battelino, Tadej; Bell, Kirstine J.; Besser, Rachel E. J.; Bonifacio, Ezio; Colhoun, Helen M.; Couper, Jennifer J.; Craig, Maria E.; Danne, Thomas; de Beaufort, Carine; Dovc, Klemen; Driscoll, Kimberly A.; Dutta, Sanjoy; Ebekozien, Osagie; Elding Larsson, Helena; Feiten, Daniel J.; Frohnert, Brigitte I.; Gabbay, Robert A.; Gallagher, Mary P.; Greenbaum, Carla J.; Griffin, Kurt J.; Hagopian, William; Haller, Michael J.; Hendrieckx, Christel; Hendriks, Emile; Holt, Richard I. G.; Hughes, Lucille; Ismail, Heba M.; Jacobsen, Laura M.; Johnson, Suzanne B.; Kolb, Leslie E.; Kordonouri, Olga; Lange, Karin; Lash, Robert W.; Lernmark, Åke; Libman, Ingrid; Lundgren, Markus; Maahs, David M.; Marcovecchio, M. Loredana; Mathieu, Chantal; Miller, Kellee M.; O'Donnell, Holly K.; Oron, Tal; Patil, Shivajirao P.; Pop-Busui, Rodica; Rewers, Marian J.; Rich, Stephen S.; Schatz, Desmond A.; Schulman-Rosenbaum, Rifka; Simmons, Kimber M.; Sims, Emily K.; Skyler, Jay S.; Smith, Laura B.; Speake, Cate; Steck, Andrea K.; Thomas, Nicholas P. B.; Tonyushkina, Ksenia N.; Veijola, Riitta; Wentworth, John M.; Wherrett, Diane K.; Wood, Jamie R.; Ziegler, Anette-Gabriele; DiMeglio, Linda A.; Pediatrics, School of Medicine
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    Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review
    (Springer Nature, 2023-10-05) Felton, Jamie L.; Griffin, Kurt J.; Oram, Richard A.; Speake, Cate; Long, S. Alice; Onengut-Gumuscu, Suna; Rich, Stephen S.; Monaco, Gabriela S. F.; Evans-Molina, Carmella; DiMeglio, Linda A.; Ismail, Heba M.; Steck, Andrea K.; Dabelea, Dana; Johnson, Randi K.; Urazbayeva, Marzhan; Gitelman, Stephen; Wentworth, John M.; Redondo, Maria J.; Sims, Emily K.; Pediatrics, School of Medicine
    Background: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. Methods: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. Conclusions: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.
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    IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes
    (American Society for Clinical Investigation, 2021) Greenbaum, Carla J.; Serti, Elisavet; Lambert, Katharina; Weiner, Lia J.; Kanaparthi, Sai; Lord, Sandra; Gitelman, Stephen E.; Wilson, Darrell M.; Gaglia, Jason L.; Griffin, Kurt J.; Russell, William E.; Raskin, Philip; Moran, Antoinette; Willi, Steven M.; Tsalikian, Eva; DiMeglio, Linda A.; Herold, Kevan C.; Moore, Wayne V.; Goland, Robin; Harris, Mark; Craig, Maria E.; Schatz, Desmond A.; Baidal, David A.; Rodriguez, Henry; Utzschneider, Kristina M.; Nel, Hendrik J.; Soppe, Carol L.; Boyle, Karen D.; Cerosaletti, Karen; Keyes-Elstein, Lynette; Long, S. Alice; Thomas, Ranjeny; McNamara, James G.; Buckner, Jane H.; Sanda, Srinath; ITN058AI EXTEND Study Team; Pediatrics, School of Medicine
    Background: IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods: We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results: There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion: Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.
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    Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review
    (Springer Nature, 2024-04-06) Felton, Jamie L.; Redondo, Maria J.; Oram, Richard A.; Speake, Cate; Long, S. Alice; Onengut-Gumuscu, Suna; Rich, Stephen S.; Monaco, Gabriela S. F.; Harris-Kawano, Arianna; Perez, Dianna; Saeed, Zeb; Hoag, Benjamin; Jain, Rashmi; Evans-Molina, Carmella; DiMeglio, Linda A.; Ismail, Heba M.; Dabelea, Dana; Johnson, Randi K.; Urazbayeva, Marzhan; Wentworth, John M.; Griffin, Kurt J.; Sims, Emily K.; ADA/EASD PMDI; Pediatrics, School of Medicine
    Background: Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. Methods: We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. Results: Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. Conclusions: Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.
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    Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective
    (American Diabetes Association, 2022) Sims, Emily K.; Besser, Rachel E. J.; Dayan, Colin; Rasmussen, Cristy Geno; Greenbaum, Carla; Griffin, Kurt J.; Hagopian, William; Knip, Mikael; Long, Anna E.; Martin, Frank; Mathieu, Chantal; Rewers, Marian; Steck, Andrea K.; Wentworth, John M.; Rich, Stephen S.; Kordonouri, Olga; Ziegler, Anette-Gabriele; Herold, Kevan C.; NIDDK Type 1 Diabetes TrialNet Study Group; Pediatrics, School of Medicine
    Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established.