Browsing by Author "Keyes-Elstein, Lynette"

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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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    Correlation Among Hypoglycemia, Glycemic Variability, and C-Peptide Preservation After Alefacept Therapy in Patients with Type 1 Diabetes Mellitus: Analysis of Data from the Immune Tolerance Network T1DAL Trial
    (Elsevier, 2016-06) Pinckney, Ashley; Rigby, Mark R.; Keyes-Elstein, Lynette; Soppe, Carol L.; Nepom, Gerald T.; Ehlers, Mario R.; Pediatrics, School of Medicine
    PURPOSE: In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation. METHODS: We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c]). FINDINGS: Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P < 0.001), highest readings (p < 0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p < 0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p < 0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p < 0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups. IMPLICATIONS: Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression.
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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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    Targeting effector memory T cells with alefacept in new onset type 1 diabetes: 12 month results from the T1DAL study
    (Elsevier, 2013-12) Rigby, Mark R; DiMeglio, Linda A; Rendell, Marc S; Felner, Eric I; Dostou, Jean M; Gitelman, Stephen E; Patel, Chetanbabu M; Griffin, Kurt J; Tsalikian, Eva; Gottlieb, Peter A; Greenbaum, Carla J; Sherry, Nicole A; Moore, Wayne V; Monzavi, Roshanak; Willi, Steven M; Raskin, Philip; Moran, Antoinette; Russell, William E; Pinckney, Ashley; Keyes-Elstein, Lynette; Howell, Michael; Aggarwal, Sudeepta; Lim, Noha; Phippard, Deborah; Nepom, Gerald T; McNamara, James; Ehlers, Mario R; Department of Pediatrics, IU School of Medicine
    Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D. Methods The T1DAL study is a phase II, double-blind, placebo-controlled trial that randomised T1D patients 12-35 years old within 100 days of diagnosis, 33 to alefacept (two 12-week courses of 15 mg IM per week, separated by a 12-week pause) and 16 to placebo, at 14 US sites. The primary endpoint was the change from baseline in mean 2-hour C-peptide area under the curve (AUC) at 12 months. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings The mean 2-hour C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110 nmol/L) in the alefacept group and decreased by 0.115 nmol/L (95% CI -0.278 to 0.047) in the placebo group, which was not significant (p=0.065). However, key secondary endpoints were met: the mean 4-hour C-peptide AUC was significantly higher (p=0.019), and daily insulin use and the rate of hypoglycemic events were significantly lower (p=0.02 and p<0.001, respectively) at 12 months in the alefacept vs. placebo groups. Safety and tolerability were comparable between groups. There was targeted depletion of Tems and Tcms, with sparing of naïve and regulatory T cells (Tregs). Interpretation At 12 months, alefacept preserved the 4-hour C-peptide AUC, lowered insulin use, and reduced hypoglycemic events, suggesting a signal of efficacy. Depletion of memory T cells with sparing of Tregs may be a useful strategy to preserve beta cell function in new-onset T1D.