Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis.

Abstract

Clinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4⁺ T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides. EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP_139-151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG_35-55 (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4⁺, CD4⁺CD25^- and CD4⁺CD25⁺ T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed. This experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFβ, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3⁺ regulatory T cells (T_reg cells) in vivo. We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific T_reg cells. These findings have overcome the drawbacks of long and repeated depletion of CD4⁺ T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FUND: This research was supported by the Intramural Research Program of the NIH, NIDCR.