Therapeutic Targeting of B Cells and T Cells in Autoimmune Diabetes

Schematic summary of the biological mechanisms observed after parenteral CD20 and oral CD3 antibody administration. Parenteral CD20 administration leads to massive depletion of B cells expressing the surface antigen. The consequences of this depletion are a deprivation of autoantigen-presenting B cells and an inhibition of autoantigen spreading. Another described consequence is the induction of regulatory B cells (8). After oral delivery, CD3 antibody reaches the intestine and reported data show uptake in the intestinal mucosa and Peyer patches (20). Local stimulation of adaptive/induced Tregs that express distinct phenotypes, depending on the model, is observed. In the report by Hu et al. (13), the cells were CD4⁺FoxP3⁻ IL-10–producing, thereby closely resembling Tr1 cells. In the work by Weiner and colleagues (20–22). in the experimental allergic encephalomyelitis model, in the collagen-induced arthritis model, and in the streptozotocin-induced diabetes model, the cells were CD4⁺FoxP3⁻TGF-β/LAP⁺TGF-β–dependent. In further studies it will be important to elucidate the pattern of migration of these induced Tregs; does the pattern go from Peyer patches to mesenteric lymph nodes and then to pancreatic lymph nodes or to the bloodstream? It also will be important to define the relationship between these “polyclonal” Tregs induced in the intestine and CD4⁺FoxP3⁺ Tregs, which probably include antigen-specific Tregs, present in the target tissue and that have a suppressive function that appears upregulated by the combined treatment (13).