Safely targeting autoimmunity in type 1 diabetes: the MonoPepT1De trial

Abstract

urrent treatment of type 1 diabetes (T1D) centres on exogenous insulin to replace the deficit due to autoimmune destruction of β-cells. Despite considerable advances in insulin therapy and delivery, patients still have the daily concern of glucose excursions which lead to the serious complications of hyperglycaemia, risks of hypoglycaemia and the significant psychological impact of the disease. Immunotherapy for diabetes aims to target the disease at its core, halting autoimmune destruction of β-cells and removing dependence on exogenous insulin. Early studies in the 1980s provided proof of principle that immunosuppression with agents such as cyclo sporine, 1 azathioprine and prednisolone 2 could lead to remission of β-cell destruction and metabolic improvements, at least in the short term. More recent studies show varying degrees of success in prolonging β-cell function by targeting different aspects of the autoimmune response via drugs such as anti-CD3 3,4 and anti-CD20 5 monoclonal antibodies and CTLA-4 fusion protein. 6 Yet this type of immunosuppression/immune modulation remains generalised and continues to raise concerns over side effects of non-specific targeting of the immune system. Ideal timing for immunotherapy is at or preferably before clinical onset, the point at which there is greatest scope for β-cell salvage. Such early treatment targets a young age group leading to greater concerns over the potential impact of long-term risks such as toxicity, viral reactivation and malignancy, especially as current insulin treatment is relatively simple and safe. Antigen-specific immunotherapy (ASI) offers a safer targeted approach to modulating the autoimmune process towards a tolerogenic response instead of global suppression. The aim is to re-establish tolerance by administration of an autoantigen, which can be in the form of a whole protein or as peptide immunotherapy (PIT), using short peptides derived from key β-cell autoantigens. The use of ASI has been successfully pioneered in clinical allergy 7‐10 with interest fuelling research across autoimmune and inflammatory diseases (Figure 1). Use of peptides has potential benefits over whole antigen administration such as ease of use, enabling a pure highly concentrated epitope to be delivered at lower cost than whole antigen without the risk of complications of biological activity. 11 In PIT, natural pro