Herold KC, Gitelman S, Greenbaum C, et al. Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years

Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
Clinical Immunology (Impact Factor: 3.67). 06/2009; 132(2):166-73. DOI: 10.1016/j.clim.2009.04.007
Source: PubMed


Anti-CD3 mAbs may prolong beta cell function up to 2 years in patients with new onset Type 1 diabetes (T1DM). A randomized open label trial of anti-CD3 mAb, Teplizumab, in T1DM was stopped after 10 subjects because of increased adverse events than in a previous trial related with higher dosing of drug. Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not increased. There was a trend for reduced loss of C-peptide over 2 years with drug treatment (p=0.1), and insulin use was lower (p<0.001). In 4 drug-treated subjects followed up to 60 months, C-peptide responses were maintained. We conclude that increased doses of Teplizumab are associated with greater adverse events without improved efficacy. The drug may marginate rather than deplete T cells. C-peptide levels may remain detectable up to 5 years after treatment.

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Available from: Jeffrey Bluestone, Dec 26, 2013
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    • "Two independent clinical trials using either Teplizumab (United States) or Otelixizumab (Europe) led to the sustained preservation of insulin production. In NOD mice, anti-CD3 therapy permanently reversed diabetes and in humans C-peptide levels were sustained from 1 to 5 years, demonstrating long term protection could be obtained (Herold et al., 2002, 2009; Keymeulen et al., 2005). "
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    ABSTRACT: There is increasing evidence that dysregulated immune responses play key roles in the pathogenesis and complications of type 1 but also type 2 diabetes. Indeed, chronic inflammation and autoimmunity, which are salient features of type 1 diabetes, are now believed to actively contribute to the pathogenesis of type 2 diabetes. The accumulation of activated innate and adaptive immune cells in various metabolic tissues results in the release of inflammatory mediators, which promote insulin resistance and β-cell damage. Moreover, these dysregulated immune responses can also mutually influence the prevalence of both type 1 and 2 diabetes. In this review article, we discuss the central role of immune responses in the patho-physiology and complications of type 1 and 2 diabetes, and provide evidence that regulation of these responses, particularly through the action of regulatory T cells, may be a possible therapeutic avenue for the treatment of these disease and their respective complications.
    Frontiers in Endocrinology 06/2013; 4:76. DOI:10.3389/fendo.2013.00076
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    • "The measurements that are used actually measure β-cell function: they do not gauge the pathologic process and can be affected by metabolic factors such as ambient glucose levels. Moreover, newer immune therapies, such as FcR nonbinding anti-CD3 (teplizumab) and anti-CD20 monoclonal antibodies (rituximab) or CTLA4Ig (abatacept), have been shown to decrease the rate of decline in β-cell function, but owing to the lack of a more direct measure of β-cell destruction, their effects on the primary cause of the disease have not been assessed (3–8). As suggested by our previous studies, immune modulatory agents may cause functional recovery of degranulated β-cells even without eliminating β-cell killing (9). "
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    ABSTRACT: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of β-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death.
    Diabetes 02/2013; 62(5). DOI:10.2337/db12-1207 · 8.10 Impact Factor
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    • "Most T-cell-targeting strategies have utilized nonspecific or blanket therapies, such as Thymoglobulin or anti- CD3 monoclonal antibodies, that target all T cells. Therefore, these treatments may also prevent protective immunity by the adaptive immune system, resulting in susceptibility to new infections, viral reactivation, or increased risk of cancer [12] [13]. Thus, researchers have pursued various means of exclusively modulating the autoreactive T cells with antigen, which can be delivered covalently linked to tolerizing cells, within viral vectors, or as whole proteins or soluble peptide fragments [14] [15]. "
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    Clinical and Developmental Immunology 05/2012; 2012:380289. DOI:10.1155/2012/380289 · 2.93 Impact Factor
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