Modified from 6, 7
Modified from 6, 7. Anti-IL-1 therapy has been successful in systemic autoimmune conditions that include rheumatoid arthritis, systemic juvenile idiopathic arthritis, and the rare autoinflammatory syndromes such as Familial Mediterranean Fever 7. some residual insulin ( 0.2nM C-peptide after mixed meal tolerance stimulation). Antagonism of IL-1 was achieved by the use of anti-IL-1 monoclonal antibody, Canakinumab, as well as by anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra). The only significant adverse events in the treatment groups compared with the placebo, were injection site reactions in the anakinra group. Of importance, neutropenia occurred in both the cankinumab and placebo groups, but in the canakinumab-treated patients, further doses were not associated with subsequent neutropenia. The multifactorial nature of T1D presents several targets and pathways to consider for immunotherapy. It is generally accepted that T cells, together with an inflammatory environment in the pancreatic islets, play a key role in death of insulin-producing cells in T1D. Nevertheless, there is Lumefantrine a strong environmental component, which suggests that the innate immune system may also play a significant role, especially in the early phases of disease. The long time course, that may span years, leading to development of the islet autoimmune response with loss of insulin production, potentially provides many opportunities for intervention, if we could predict and safely target the pathogenic players. Once clinical diabetes manifests, the islet autoimmune response with both effector and memory T cells targeting multiple autoantigens is highly developed, making it much more difficult to tackle single components of the disease process. Why focus on IL-1? IL-1 is a major early inflammatory, widely produced cytokine that has major effects in causing inflammation in response to tissue stress (Figure 1). It is produced by many cell types including macrophages. In addition, islet cells produce IL-1, in response to hyperglycemia in vitro 2. Pancreatic islet cells express IL-1 receptors and signaling through the IL-1 receptor1 (IL-1R1)(Figure 1), together with interferon- and TNF-, not only inhibits insulin secretion but also induces apoptosis 3. IL-1 also interfaces with the adaptive immune system, providing a signal for amplification of CD4 T helper cell responses, and for differentiation of IL-17 producing T cells 4. Furthermore, the inflammatory microenvironment in the pancreatic islets, fuelled by both the immune effectors, as well as by high glucose which is toxic to the beta cell, contributes to damage to beta cells that are highly sensitive to such insults 5. Thus, both theoretical and experimental evidence of a role for IL-1 in islet cell inflammation provided a strong scientific rationale 6 for the studies reported by Moran and colleagues 1. Open in a separate window Figure 1 IL-1 secretion and action on islet cellsIL-1 is secreted after the IL-1 precursor is cleaved by caspase 1, produced from the NALP3 inflammasome complex of proteins after activation by tissue stress. IL-1 binds to IL-1 receptor 1 (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP), inducing wide-ranging inflammatory effects. The naturally occurring IL-1 antagonist (IL-1Ra) is produced and secreted from cells expressing IL-1, with a circulating concentration of 100C300ng/ml. It binds to IL-1 receptor, but does not induce signaling and antagonizes the effect of IL-1 by competition for binding to the receptor. In islets, IL-1 signals via a number of pathways, Lumefantrine ultimately leading to apoptosis. Adapted from 6, 7. Anti-IL-1 therapy has been successful in systemic autoimmune conditions that include rheumatoid arthritis, systemic juvenile idiopathic arthritis, and the rare autoinflammatory syndromes such as Familial Mediterranean Fever 7. This Lumefantrine success, together with a preclinical rationale 6, may have given hope that this treatment would be an alternative route to halting what has been an inevitable decline in beta cell function. Unfortunately, this was not to be. T1D is a very different organ-specific autoimmune disorder to the systemic autoimmune conditions, with a strong T cell contribution. IL-1, produced by macrophages and possibly islet cells themselves, is likely to be only one Rabbit Polyclonal to MPHOSPH9 of several pathogenic components. Immunotherapy has.