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Review Diabetes Updates on Immune Therapies in Type 1 Diabetes Bimota Nambam 1 and Michael J Haller 2 1. Division of Endocrinology, Louisiana State University, Shreveport, US ; 2, Division of Endocrinology, University of Florida, Gainesville, US M ultiple clinical trials investigating the efficacy and safety of immunotherapeutic interventions in new onset type 1 diabetes (T1D) have failed to yield long term clinical benefit. Lack of efficacy has frequently been attributed to an incomplete understanding of the pathways involved in T1D and the use of single immunotherapeutic agents. Recent mechanistic studies have improved our knowledge of the complex etiopathogenesis of T1D. This in turn has provided the framework for new and ongoing clinical trials in new onset T1D patients and at-risk subjects. Focus has also shifted towards the potential benefits of synergistic combinatorial approaches, both in terms of efficacy and the potential for reduced side effects. These efforts seek to develop intervention strategies that will preserve β -cell function, and ultimately prevent and reverse clinical disease. Keywords T1D, immunotherapy, antibody, combination therapy, cytokine, Treg, tolerance Disclosure: Bimota Nambam and Michael J Haller have nothing to disclose in relation to this article. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 23 May 2016 Accepted: 28 June 2016 Citation: European Endocrinology, 2016;12(2):89–95 Corresponding Author: Michael J Haller, Professor and Chief, Pediatric Endocrinology University of Florida, Gainesville, US. E: hallemj@peds.ufl.edu Despite the introduction of newer and faster acting insulin analogues along with advances in glucose monitoring and insulin delivery technology, the majority of patients with type 1 diabetes (T1D) fail to achieve target glycemic control. There still remains a high burden of long term end- organ complications of T1D. Consequently, researchers continue to search for treatment modalities that not only preserve residual β-cell function, but also halt disease progression or even reverse the disease. An improved understanding of the complex immunological pathogenesis of T1D over the past decade has aided the identification of immunotherapeutics aimed at preserving residual β-cell function in high risk, and new onset T1D patients. However, previous intervention studies have not yielded adequate long term clinical benefit, a limitation many have suggested, results from our reliance on monotherapeutic approaches. Additionally, the task of employing safe and effective combination approaches has been challenging due to issues surrounding equipoise and an incomplete understanding of T1D etiopathogenesis. Herein, we provide a review of recently targeted pathways, drugs selected to augment those pathways, their respective clinical trials, relevant outcomes, and future directions. Anti-CD3 antibodies T-cells have been shown to have play an important role in the pathogenesis of T1D with autoreactive T effector cells (Teffs) bringing about islet cell destruction and suppressive T regulatory cells (Tregs) ameliorating autoimmunity. Hence, T-cells have been targeted in various immune interventions studies with the aim of preventing or delaying immune mediated destruction of β-cells. CD3, a transmembrane protein, acts as a co-receptor for the T-cell receptor (TCR), and is involved in activation and differentiation of naïve T-cells into pathogenic Teffs. Though not clearly understood, monoclonal antibodies against CD3 prevent activation and promote depletion of T-cells, with Teffs being more sensitive to the effects of anti-CD3 antibodies compared to Tregs. This leads to depletion of Teffs, restores the Teff/Treg ratio, and thus, promotes self- tolerance. 1 Experimental studies in non-obese diabetic (NOD) mice have also shown that short term anti-CD3 antibody treatment can induce remission from disease. 2,3 Otelixizumab is a humanised monoclonal antibody against CD3 with a mutation in the γFc portion, rendering it incapable of binding to the Fc receptor. The Fc mutation inhibits T-cell crosslinking, mitogenicity, and cytokine release. The Belgian Diabetes Registry conducted a randomised, placebo controlled, phase II study, where otelixizumab (48–64 mg) was administered over 6 days to new onset, T1D patients (12–39 yrs, T1D duration <4 weeks and positive for Epstein Barr virus [EBV] IgG). At 6, 12, and 18 months of follow up, subjects in the treatment group had a significantly higher stimulated C-peptide compared to placebo. 4 At 36 months, those <27 years old in the treatment group continued to have higher C-peptide levels (80% higher) than in the placebo group of the same age range. 5 Despite no significant differences in glycated haemoglobin (HbA 1c ) levels throughout the study, daily dose of insulin in the treatment group at all time points were significantly lower compared to placebo. However, one notable concern was the reactivation of EBV in more than 75% of the treatment group, though polymerase chain TOU CH MED ICA L MEDIA 89