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

Shimpei Kasagi, Dandan Wang, Pin Zhang, Peter Zanvit, Hua Chen, Dunfang Zhang, Jia Li, Li Che, Takashi Maruyama, Hiroko Nakatsukasa, Ruiqing Wu, Wenwen Jin, Lingyun Sun, Wan Jun Chen

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4 Citations (Scopus)

Abstract

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 PLP139–151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG35–55 (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. 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 (Treg cells) in vivo. Interpretation: We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific Treg 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.

Original languageEnglish
Pages (from-to)50-59
Number of pages10
JournalEBioMedicine
Volume44
DOIs
Publication statusPublished - 2019 Jun

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kasagi, S., Wang, D., Zhang, P., Zanvit, P., Chen, H., Zhang, D., Li, J., Che, L., Maruyama, T., Nakatsukasa, H., Wu, R., Jin, W., Sun, L., & Chen, W. J. (2019). Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis. EBioMedicine, 44, 50-59. https://doi.org/10.1016/j.ebiom.2019.05.005