Immunotherapy for autoimmune diabetes

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Type I diabetes (TID) or insulin-dependent diabetes mellitus (IDDM) is an immunemediated disease in which the beta ([beta]) cells of the pancreatic islets of Langerhans are destroyed as a consequence of inflammatory reactions triggered by activation of T cells specific for [beta]-cell associated antigens. Numerous approaches have been tested in the non obese diabetic (NOD) mouse, a commonly studied animal model of TID, to treat disease but very few have made it to clinical settings because of two main reasons. Firstly, most of these therapies are non-antigen specific and target all the T cells, thereby inducing a state of generalized immunosuppression. Secondly, the majority of interventions are preventive. As many TID patients are identified only at diabetes onset, agents that can reverse disease at late stages are urgently required. Two approaches have been developed to meet the above mentioned requisites for treatment of TID. In the first study, glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2), representing a late stage diabetic epitope, was genetically incorporated into an Ig molecule to magnify tolerance and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the pre-insulitis phase but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration as well as [beta]-cell division and restored normoglycemia when given to hyperglycemic mice at the pre-diabetic stage. This was dependent on the induction of splenic IFN? that inhibited IL-17 production. In fact, neutralization of IFN[lowercase gamma] led to a significant increase in the frequency of Th17 cells and the treatment became non-protective. Thus, treatment with Ig-GAD2 induces IFN[lowercase gamma] that reverses TID and restores normoglycemia in an antigen-specific manner most likely by localized bystander suppression of pathogenic IL-17-producing cells. In the second study, a tolerogenic population of NOD dendritic cells (DC) was identified that upon being loaded with diabetic antigens could mediate protection from disease in an antigenspecific manner. In fact, treatment with the CD8[alpha][superscript -]CD4[superscript -] CD11c[superscript +] DC subset reduced destructive infiltration within the islets, induced antigen-specific IFN[lowercase gamma] and IL-10 producing T regulatory type 1 (Tr1) T cells and expanded CD4[superscript -] CD25[superscript +] Foxp3[superscript hi] regulatory T (Treg) cells in the spleen. The protective function was due to the ability of DCs to traffic efficiently to the non-inflammatory organ spleen but not to the inflammatory organs pancreatic lymph nodes and pancreas. Thus, the CD8[alpha]CD4[superscript -] CD11c[superscript +] DC subset induces regulatory T cells in spleen that likely interfere with the influx of diabetogenic effector T cells to the pancreas and/or the pathogenic function of effector cells, thereby reducing destructive islet infiltration and mediating protection from disease.