Diabetes Care. 2009 October
Realizing immune-based interventions for human type 1 diabetes will be necessary, even if an unlimited source of new islets can be obtained from stem cells or other sources, because autoimmune memory cells will have to be controlled to avoid continued loss of β-cells over time. The key issue that must be tackled is achieving a tolerable balance between immunosuppression and the associated side-effects and long-term tolerance. In our opinion, the likelihood that monotherapies with systemically acting immunomodulators will achieve this is low because, even in the best case scenario, side effects will emerge after 20–30 years, as has been seen with immunosuppressive regimens in transplantation ( 84 ). Therefore, adaptive Tregs that recognize β-cell antigens, proliferate in the pancreatic lymph nodes ( 85 , 86 ), and can, at least in multiple animal models, mediate islet-specific immunosuppression should be induced in conjunction with systemic immunomodulatory therapies, for example by immunization with GAD65, (pro)insulin, (pro)insulin peptides, or DNA vaccines. To optimize dosing regimens, in silico modeling approaches could be used together with animal experimentation and reliable biomarkers that can predict successful induction of adaptive Tregs following aAg immunization must be established.