It appeared clearly from these models that the abnormal metabolic control, as assessed by hyperglycaemia and glycosuria, the hallmarks of T1D clinical diagnosis, was preceded by a long phase defined as ‘prediabetes’ during which the β cell autoantigen-specific inflammatory response developed silently, yet progressively. Thus, in NOD mice

progressive infiltration of the islets of Langerhans by mononuclear cells, also termed insulitis, evolves in two distinct phases [1]. Insulitis appears by 3–4 weeks of age and up to 8–10 weeks is confined to the periphery of the islets (peri-insulitis) without any sign of active destruction of insulin-secreting β cells. As disease progresses, by 10–14 selleckchem weeks of age the infiltrating cells invade the islets quite abruptly, i.e. aggressive insulitis, and

rapid β cell destruction occurs causing overt hyperglycaemia. The orchestrated mechanisms leading to β cell destruction all represent potential targets for therapeutic intervention. These mechanisms involve a central triad constituted by β cells, autoantigen-presenting cells and T lymphocytes. Autoantigen-presenting cells are heterogeneous and include dendritic cells (DCs), selleck products macrophages and B lymphocytes. The observation that B cell-deficient NOD mice are disease free indicates that disease development is B cell-dependent [2]. In addition to their antigen-presenting role, macrophages and DCs are also key inflammatory effector cells. T lymphocytes involved in T1D are functionally heterogeneous, comprising pathogenic T cells and specialized subsets of regulatory T cells. β cell destruction involves

pathogenic T cells, as demonstrated by the capacity of ‘diabetogenic’ CD4+ and CD8+ lymphocytes from the spleen of diabetic NOD mice to transfer disease into syngeneic immune-compromised recipients [NOD neonates, irradiated adult NOD mice, NOD severe combined immunodeficiency (SCID) mice][3]. In parallel, there is evidence to show that CHIR 99021 disease progression is controlled by T cell-mediated immune regulatory circuits involving distinct subsets of regulatory T cells [4,5]. It is also important to stress that β cells must not be viewed simply as ‘passive’ targets that are killed immediately by the immune-mediated insult. In a first step they ‘suffer’ from the inflammatory environment created by the insulitis that, in a partially reversible fashion, inhibits their capacity to secrete insulin but also provides all the premises for establishing ‘cross-talk’ between the β cell and the immune cells and cytokines from the environment [6]. It is only in a second step that the β cell is eventually destroyed through apoptosis. During recent years the epidemiology of T1D has become alarming.