Interleukin-1 Antagonism: A Sturdy Companion for Immune Tolerance Induction in Type 1 Diabetes?

  1. Thomas Mandrup-Poulsen
  1. Immuno-endocrinology Laboratory, Section for Endocrinological Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  1. Corresponding author: Thomas Mandrup-Poulsen, tmpo{at}sund.ku.dk.

Intervention trials testing immunomodulatory monotherapies in type 1 diabetes have generally been disappointing (1). Possible explanations include suboptimal pharmacokinetics/dynamics or inappropriate dosing/timing of the interventions and heterogeneity of study populations. However, considering that β-cell destruction in type 1 diabetes involves complex cooperation between the innate and adaptive immune systems (2), evolutionarily designed to provide foolproof protection of the host with redundant backup systems against environmental threats, we have been naïve in our belief that monotherapies would cure type 1 diabetes.

Although combination therapy for type 1 diabetes may increase efficacy and safety, clinical testing of drug combinations is a daunting enterprise. How do we decide on rational and safe combinations, doses, timing, and in which patients? How do we obtain regulatory approval, funding, and sufficient statistical power with the limited number of available patients? Is there solid preclinical evidence favoring a certain combination?

Animal models of type 1 diabetes have been rightly mocked for unjustified promise for prevention (3,4). However, few animal studies have shown reversal of overt diabetes (5), and therefore it is worth paying attention to these studies because of their relevance to the treatment not of at-risk patients, but of patients with disease of recent onset. In this issue, Pagni et al. (6) report one of these rare studies using transgenic mice with β-cell−specific expression of lymphocytic choriomeningitis virus in which diabetes is …

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