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The prospect of vaccination to prevent type 1 diabetes
L.C. Harrison, M.C. Honeyman, C.E. Steele, N.L. Stone, in collaboration with E. Sarugeri, E. Bonifacio, Department of Internal Medicine, Istituto Scientifico San Raffaele, Milan, Italy; J.J. Couper, Department of Endocrinology, Women’s and Children’s Hospital, Adelaide, Australia; P.G. Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville
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Autoimmune diseases result from a breakdown of immune tolerance to self-antigens. Type 1 diabetes (T1D) is an autoimmune disease in which the body’s immune cells react against and destroy the insulin-producing beta cells in the islets of the pancreas. Individuals with underlying islet inflammation, in the pre-clinical phase of T1D, can be identified by blood testing for antibodies to beta-cell self-antigens. Proinsulin is the only self-antigen in T1D that is specific for beta cells and there is strong evidence that it plays a key role in driving autoimmune beta-cell destruction (reviewed in 1). The application of self-antigens as tools to induce protective immunity, free from the toxic effects of conventional non-specific immunosuppression, is the 'Holy Grail' of autoimmune disease therapy (2). In animal models, ‘negative’ vaccination against self-antigens to induce disease-specific immune tolerance can be achieved by administering antigen via a ‘tolerogenic’ route, e.g. via the mucosal immune system, as well as in several other ways. In the non-obese diabetic (NOD) mouse, a model of T1D, we previously found that insulin administered to the naso-respiratory mucosa induced regulatory T cells that protected against diabetes, and was associated with reduced T-cell and increased antibody responses to insulin (3). On this basis, we carried out a randomised controlled, crossover pilot trial of intranasal insulin, the intranasal insulin trial I (INIT I) (4), in 38 young T1D relatives (median age 10.8 yr) with antibodies to beta-cell antigens and a 5-year risk of T1D of 26-50%. We aimed to determine if weekly treatment for 6 months with intranasal insulin was safe and induced changes in surrogate immune markers consistent with protective ‘mucosal tolerance’. Intranasal insulin was safe and associated with an increase in antibody and a decrease in T-cell responses to insulin (Figure 1), as seen in NOD mice. Twelve participants developed diabetes after a median of 1.1 years, but these had negligible beta-cell function at entry. In the remaining 26, there was no decrease overall in beta-cell function after 4 years follow-up. The projected 5-year median diabetes incidence was 15.2%, against a predicted ~ 40%. These promising results have lead to INIT II, a large, multicentre trial funded by the Diabetes Vaccine Development Centre (NHMRC and JDRF) to determine if this vaccination strategy prevents progression to T1D.
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Figure 1: Antibody and T-cell responses to insulin in individual participants The monthly rate of change of either insulin antibody (upper panel) or the T-cell response to denatured insulin (lower panel) was determined from serial measurements in each participant in the insulin (I) /placebo (P) and P/I arms. Dotted lines link each subject in the two treatment periods
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Narendran P, Mannering SI, Harrison LC (2003). Proinsulin – a pathogenic autoantigen in type 1 diabetes. Autoimmun Rev 2:204-210.
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Harrison LC, Hafler DA (2000). Antigen-specific therapy for autoimmune disease. Curr Opin Immunol 12:704-711.
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Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K (1996). Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167-2174.
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Harrison LC, Honeyman MC, Steele CE, Stone NL, Sarugeri E, Bonifacio E, Couper JJ, Colman PG (2004). Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes Diabetes Care 27:2348-2355.
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