Biomarkers for immune intervention trials in type 1 diabetes

Abstract

After many efforts to improve and standardize assays for detecting immune biomarkers in type 1 diabetes (T1D), methods to identify and monitor such correlates of insulitis are coming of age. The ultimate goal is to use these correlates to predict disease progression before onset and regression following therapeutic intervention, which would allow performing smaller and shorter pilot clinical trials with earlier endpoints than those offered by preserved β-cell function or improved glycemic control. Here, too, progress has been made. With the emerging insight that T1D represents a heterogeneous disease, the next challenge is to define patient subpopulations that qualify for personalized medicine or that should be enrolled for immune intervention, to maximize clinical benefit and decrease collateral damage by ineffective or even adverse immune therapeutics. This review discusses the current state of the art, setting the stage for future efforts to monitor disease heterogeneity, progression and therapeutic intervention in T1D.

Introduction

Type 1 diabetes (T1D) represents a prototypic tissue-specific autoimmune disease [1]. Indeed, progress in unraveling the immune components involved in the pathogenesis of T1D has been spectacular and often more rewarding than for other autoimmune diseases. Several islet antigens (Ags) have been identified with compelling associations with the β-cell destruction process, including (pre)proinsulin [(pre)PI], glutamic acid decarboxylase (GAD)65, insulinoma-associated protein 2 (IA-2), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and zinc transporter (ZnT)8 [2], [3], [4]. Additional candidate target molecules expressed by β cells have been revealed and studied, such as chromogranin A, (prepro) islet amyloid polypeptide (ppIAPP), peripherin and an ill-defined 38 kDa protein in insulin secretory granules, but their role in association with clinical T1D remains unclear or controversial [5]. The immunology of diabetes community has been blessed with this large series of T-cell and/or autoantibody (autoAb) targets that can be employed in monitoring the islet autoreactivity of T1D [6]. Islet autoAbs against many of these Ags have proven particularly useful for T1D prediction, but less so for following disease activity and progression after T1D onset or during therapeutic intervention (so called “immune staging”) [7]. This notion is putting a substantial burden on the options to monitor changes in disease activity. It implies that we may have to resort to using cellular autoimmunity to this end, with all the challenges involved in terms of technologies and targets.

New access to the pancreatic lesions of T1D patients through the establishment of an international consortium collecting, distributing and characterizing tissues of diabetic donors (www.jdrfnpod.org) has led spectacular new insights into the immune processes involved in the selective destruction of insulin-producing β cells in pancreatic islets [8]. Seminal recent lessons learned through these studies include additional proofs of the autoimmune nature of T1D, the demonstration of islet-specific CD8⁺ T cells in destructive insulitic lesions, the unexpectedly low frequencies of islet-infiltrating CD4⁺ T cells, the apparent lack of CD4⁺CD25⁺FoxP3⁺ T regulatory cells (Tregs) in insulitis, the profound difference in immunopathology between men and mice, an overwhelming heterogeneity in the pathologic lesions and patient population, and the demonstration of focal disease activity much akin to what observed in other tissue-specific autoimmune diseases such as vitiligo [9]. Collectively, these insights have set the stage for new therapeutic strategies that may also prove effective in protecting β cells long after T1D clinical onset. Many of these strategies are currently assessed for clinical efficacy to prevent, stop of reverse disease. Some recent-onset T1D patients have already achieved a lasting remission from insulin dependency for up to seven years, showing proof of principle that T1D may be cured, at least in some patients and at least for a number of years [10]. Yet, there is an urgent need for definition of endpoints and biomarkers of immunological and clinical efficacy to guide therapeutic interventions in T1D. The immune system holds important clues to provide immune correlates of safety and clinical efficacy, both for selecting the appropriate patients for a given therapy and to monitor whether the intervention can preserve β-cell function.