(A) Due to several combined defects, autoreactive T cells in NOD mice escape negative selection in the thymus and become activated in the pancreatic lymph nodes. The resulting effector T cells are kept under control for a limited period (resulting in peri-insulitis) until regulation (likely to involve Treg’s) is no longer sufficient, and overt T1DM develops. (B) In irradiated NOD mice reconstituted with HSCs expressing a protective form of MHC class II, autoreactive T cells are efficiently deleted in the thymus and absolutely no insulitis is observed. (C) Antigen-specific Treg’s from the islet infiltrate may be isolated and expanded ex vivo. When reintroduced, these cells prove to be efficient suppressors and may do so both in the pancreatic lymph nodes and in the pancreatic lesions. (D) DCs (or antigen-specific T cells) may be isolated and modified ex vivo to express: (a) immunoregulatory proteins that induce tolerance, apoptosis, or immune deviation of autoreactive T cells; and (b) appropriate receptors to enhance their trafficking into the sites of inflammation. Alternatively, inhibitory cytokines that have been engineered to become activated only under inflammatory conditions can be injected. These two strategies favor local versus systemic action of inhibitory products.