with potential in clinical immunosuppression Creation of tolerogenic human DC via intracellular CTLA4: a novel strategy

Abstract: Activation of T lymphocytes requires the recognition of peptide-MHC complexes and co-stimulatory signals provided by antigen presenting cells (APCs). It has been shown that T cell activation without co-stimulation can lead to anergy. In this study, we developed a novel strategy to inhibit expression of B7 molecules (CD80/86) by transfecting APCs with a gene construct encoding a modified CTLA4 molecule (CTLA4-KDEL) that is targeted to the endoplasmic reticulum (ER). APCs expressing this construct failed to express CD80/86 on their surface, were unable to stimulate allogeneic and peptide-specific T cell responses and induced antigen specific anergy of the responding T cells. Cells expressing CTLA4-KDEL do not upregulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-Ig. This gene-based strategy to knockout surface receptors is an attractive alternative to using immature dendritic cellsfor preventing transplant rejection and treating of autoimmune diseases.From bloodjournal.hematologylibrary.org by guest on May 28, 2012. For personal use only.