Using dendritic cells to present beta cell antigens in vivo for manipulation of diabetes pathogenesis

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

In order to find conditions in which DC-targeted insulin peptide can alter diabetes pathogenesis, we are using chimeric antibodies that can target several peptides derived from pancreatic beta cell self-antigens to DCIR2+ DCs. DCIR2+ DCs were chosen because of our previously published data showing this subset is more tolerogenic than DEC205+ DCs in NOD mice. We can follow antigen specific T cells, both effectors and regulatory cells using staining of MHC class II I-Ag7 tetramers with the appropriate self peptide for identifying beta cell-specific CD4 T cells in vivo. We are now testing how giving both antigen and IL-2 alters antigen-specific effector T cells and Foxp3+ Tregs in NOD mice. Low-dose IL-2 has been shown to selectively enhance Tregs, but antigen-specific cells have not been clearly followed. Although we do find that this combined treatment increases antigen-specific Tregs, because the autoreactive effector T cells can also express high CD25, these pathogenic cells are also expanded. In sites of endogenous antigen exposure, this effect on both auto-antigen specific Treg and Teff was observed even without addition of DC-targeted antigen. Because of current clinical trials using IL-2 to treat autoimmunity, these results are timely, and suggest that peripheral expansion of Foxp3+ Tregs may not be a good biomarker for disease treatment.