Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline

Orban, Tihamer; Beam, Craig A.; Xu, Ping; Moore, Keith; Jiang, Qi; Deng, Jun; Müller, Sarah; Gottlieb, Peter A.; Spain, Lisa M.; Peakman, Mark

doi:10.2337/db14-0047

Cited by 84 publications

(78 citation statements)

References 20 publications

(30 reference statements)

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“…It is unknown whether the response to alefacept in T1D was dictated by quantitative or qualitative differences in lymphocytic infiltrates in the islets, but it may be worth exploring the use of larger doses of alefacept or treatment for longer periods in future trials to overcome a theoretical tissue resistance. In contrast to our results with alefacept, a recent report showed that preservation of C-peptide in new-onset T1D subjects treated with abatacept correlated with a reduction in the proportion of CD4 + Tcm in the peripheral blood collected at the preceding study visit (37).…”

Section: Discussioncontrasting

confidence: 56%

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Rigby

Harris²,

Pinckney³

et al. 2015

Journal of Clinical Investigation

247

210

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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 betweengroup 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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Section: Discussioncontrasting

confidence: 56%

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Rigby

Harris²,

Pinckney³

et al. 2015

Journal of Clinical Investigation

247

210

View full text Add to dashboard Cite

show abstract

“…The effect on CD4 Teff is less dramatic, although in the AbATE clinical trial – an intervention study conducted by the ITN in recent-onset T1D subjects—a significant decrease in Teff was observed at the completion of the study in subjects with a favorable clinical response [93]. A similar type of modest immune modulation was seen with CTLA4-Ig therapy in a comparable trial conducted by TrialNet, although in this analysis the reduction in Teff was limited to the central memory compartment, and it appeared to precede clinical response [94]. …”

Section: Targeting Teff With T1d Immunotherapymentioning

confidence: 94%

Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes

Buckner

Nepom

2016

Journal of Autoimmunity

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Autoreactive lymphocytes display a programmed set of characteristic effector functions and phenotypic markers that, in combination with antigen-specific profiling, provide a detailed picture of the adaptive immune response in Type 1 diabetes (T1D). The CD4+ T cell effector compartment (referred to as “Teff” in this article) has been extensively analyzed, particularly because the HLA genes most strongly associated with T1D are MHC class II alleles that form restriction elements for CD4+ T cell recognition. This “guilt by association” can now be revisited in terms of specific immune mechanisms and specific forms of T cell recognition that are displayed by Teff found in subjects with T1D. In this review, we describe properties of Teff that correlate with T1D, and discuss several characteristics that advance our understanding of disease persistence and progression. Focusing on functional disease-associated immunological pathways within these Teff suggests a rationale for next-generation clinical trials with targeted interventions. Indeed, immune modulation therapies in T1D that do not address these properties of Teff are unlikely to achieve durable clinical response.

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“…Analysis of peripheral T-cell subsets by flow cytometry revealed a modest but significant increase in naive CD4 T cells and a decrease in central memory CD4 T cells, which seemed to correlate with C-peptide preservation 36. Of some concern was a parallel and significant decrease in Tregs,36 which may have contributed to the observation that C-peptide responses began to decline soon after treatment began, albeit at an initially slower rate than in controls 35.…”

Section: Targets For Immune Interventionmentioning

confidence: 97%

Immune interventions to preserve β cell function in type 1 diabetes

Ehlers

2016

J Investig Med

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Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic beta cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual beta cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. Over the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off-therapy in the majority of treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T cell-directed therapies, including therapies that lead to partial depletion or modulation of effector T (Teff) cells and preservation or augmentation of regulatory T (Treg) cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: a Teff-depleting or modulating drug, a cytokine-based tolerogenic (Treg-promoting) agent, and an antigen-specific component. The long-term goal is to reestablish immunologic tolerance to beta cells, thereby preserving residual beta cells early after diagnosis or enabling restoration of beta cell mass from autologous stem cells or induced neogenesis in patients with established T1D.

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Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline

Cited by 84 publications

References 20 publications

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes

Immune interventions to preserve β cell function in type 1 diabetes

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