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

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.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

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

doi

10.1016/j.ebiom.2019.05.005

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

50-59

issn

2352-3964

pii

S2352-3964(19)30306-8

journal_volume

pub_type

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