Targeting innate immunity for treatment of type 1 diabetes.

Abstract

Type 1 diabetes (T1D) is an auto immune disease perpetuated by intricate inter­ actions between innate and adaptive immune responses, which collaborate to cause destruction of insulin producing islet β cells. Antigen­specific CD8 and CD4 T cells ultimately destroy pancreatic islet β cells; however, clinical trials directed at dominant T­cell epitopes in T1D (e.g., glu­ tamic acid decarboxylase or insulin) have failed to reverse disease [1]. This does not necessarily mean that antigen­specific ther­ apies will not work, but highlights the need to uncover new therapeutic approaches and/ or combination therapies. Why have T­cell directed therapies failed? There may be fun­ damental innate immune defects that estab­ lish and maintain persistent auto reactive T­cell responses. These innate immune defects have been highlighted both in the mouse model of T1D, nonobese diabetic (NOD) mice, as well as in T1D patients reviewed elsewhere [2]. It is thus possible that correcting or ‘re­tuning’ the innate immune response will have beneficial effects in controlling autoreactive adaptive immune responses. The role of innate immunity in T1D may explain the rapidly rising incidence of T1D since the mid­20th century [3,4]. The ‘hygiene hypothesis’ explains the rising inci­ dence of T1D, as well as other autoimmune diseases, by positing that the lack of innate immune stimulation early in life primes the adaptive immune system toward auto­ immunity. The NOD mouse model sup­ ports this hypothesis, since mice housed in colonies with a greater bacterial burden have lower incidence of T1D compared with mice housed in ‘clean’ cages [5]. This suggests that innate immune stimulation may be beneficial in the prevention of T1D. There is indeed a large literature on effi­ cacy of therapeutic agents which stimulate or modulate the innate immune system to prevent T1D in NOD mice. However, although predictive biomarkers for T1D are being investigated, preventative therapeutics are currently inutile until an accurate marker is found. The unsolved clinical problem remains reversal of new onset disease. New onset T1D presents with elevated blood glucose levels, polyuria, failed glucose toler­ ance test and weight loss; these symptoms all arise after destruction of pancreatic islet β cells have already progressed. These clini­ cal features are present in the NOD mouse model and our lab (and others) has changed our focus from T1D prevention to reversal, which is a much more difficult task. Some adaptive immune modulatory agents have reversed T1D and induced hypertrophy of islet β cells in the NOD mouse model [6], but with limited effect in humans (gener­ Targeting innate immunity for treatment of Type 1 diabetes