Dual Mechanisms for Antigen-Specific Peripheral Tolerance Induction as a Therapy for Experimental Autoimmune EncephalomyelitisPublic Deposited
MHC class II-restricted T cell responses are a common driving force of autoimmune disease. Numerous therapeutic strategies target CD4+ T cells hoping to attenuate autoimmune responses and restore self-tolerance. We have previously reported that i.v. treatment with antigen-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SP) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SP coupled with peptide can directly present peptide:MHC class II complexes to target CD4+ T cells in the absence of costimulation to induce anergy. However, Ag-SP coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SP and target CD4+ T cells. We thus investigated whether MHC class II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during EAE. Using MHC-deficient, allogeneic and/or syngeneic donor Ag-SP, we demonstrate that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. We also found that ECDI treatment induces apoptosis of the donor cells promoting uptake and re-processing of donor cell peptides by APCs resulting in the apparent MHC class II-independent induction of tolerance. Syngeneic donor cells were more efficient at inducing tolerance suggesting that Ag-SP induce functional tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and treatment of EAE. This cross-tolerance is likely due to a splenic APC population as tolerance is inhibited in mice that have undergone splenectomy surgery. Depletion studies suggest that plasmacytoid dendritic cells play an important role in tolerance induction, likely contributing to the indirect cross-tolerance mechanism of Ag-SP tolerance. This recent data along with the use of red blood cells as ECDI-Ag-coupled cells to induce tolerance lend support to the potential clinical efficacy of Ag-SP as a therapy for MS and other autoimmune diseases. Taken together, the induction of Ag-SP appears to work by several distinct synergistic mechanisms; the induction of anergy due to defective co-stimulation from direct or indirect interaction of host T cells with donor Ag-SP; the activation or induction of regulatory T cells through indirect tolerance.
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