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

BACKGROUND

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.

METHODS

EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP (pPLP) and myelin-oligodendrocyte glycoprotein MOG (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, CD4CD25 and CD4CD25 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.

FINDINGS

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 cells) in vivo.

INTERPRETATION

We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific T 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.