Clinical Potential of Antigen-Specific Therapies in Type 1 Diabetes

Abstract

■ AbstractIn type 1 diabetes (T1D), pancreatic beta-cells are attacked and destroyed by the immune system, which leads to a loss of endogenous insulin secretion. The desirable outcome of therapeutic intervention in autoimmune diseases is the restoration of immune tolerance to prevent organ damage. Past trials with immune suppressive drugs highlight the fact that T1D is in principle a curable condition. However, the barrier in T1D therapy in terms of drug safety is set particularly high because of the predominantly young population and the good prognosis associated with modern exogenous insulin therapy. Thus, there is a general consensus that chronic immune suppression is associated with unacceptable longterm safety risks. On the other hand, immune-modulatory biologicals have recently failed to confer significant protection in phase 3 clinical trials. However, the concept of antigen-specific tolerization may offer a unique strategy to safely induce long-term protection against T1D. In this review, we analyze the potential reasons for the failure of the different tolerization therapies, and describe how the concept of antigen-specific toleraization may overcome the obstacles associated with clinical therapy in T1D.

Metabolic syndrome – Removing roadblocks to therapy: Antigenic immunotherapies

“…The approach has been tested in the clinic in a series of autoimmune conditions, so far with disappointing outcomes [3,30] . Of note, most trials, including some in T1D, have treated diagnosed individuals.…”

“…In the face of that scenario, it was postulated that the reverse mechanism could be the path to restoring balance, i.e. by presenting the antigen in such a way that T cells are ‘re-educated’ and start ‘seeing’ the tissue antigen as self again [3] . One such pathway is through administration of antigen via the oral route, a mechanism termed oral tolerance [4] .…”

Safety and efficacy of autoantigen‐specific therapy with 2 doses of alum‐formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial

“…Since those children are considered healthy and that the process may last many years, the safety profile of the therapy is important. Autoantigenspecific therapies are considered safe27 without severe side effects or intervening with the child's ability to respond to infections, attend daycare, and build up the immune defense, and thereby may be the therapies of choice. Like oral insulin, used as autoantigenspecific therapy in primary9 and secondary5,6 prevention, we now demonstrate that GAD-Alum has a good safety profile in young prediabetic children.The inability to prove any effect on metabolic variables or delay of type 1 diabetes, although treated children had a marked rise in GADA, may have several explanations.…”