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

Research output: Contribution to journalArticle

2 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 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. 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 reg cells) in vivo. Interpretation: 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.

Original languageFrench
JournalEBioMedicine
DOIs
Publication statusPublished - 2019 Jan 1
Externally publishedYes

Fingerprint

T-cells
Autoimmune Experimental Encephalomyelitis
T-Lymphocytes
Peptides
Regulatory T-Lymphocytes
Inbred C57BL Mouse
Immunotherapy
Therapeutics
Multiple Sclerosis
Antibodies
Anti-Idiotypic Antibodies
National Institute of Dental and Craniofacial Research (U.S.)
Myelin-Oligodendrocyte Glycoprotein
Immunization
Proteolipids
Immune Tolerance
Histology
Macrophages
Autoantigens
Therapeutic Uses

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis. / Kasagi, Shimpei; Wang, Dandan; Zhang, Pin; Zanvit, Peter; Chen, Hua; Zhang, Dunfang; Li, Jia; Che, Li; Maruyama, Takashi; Nakatsukasa, Hiroko; Wu, Ruiqing; Jin, Wenwen; Sun, Lingyun; Chen, Wan Jun.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Kasagi, Shimpei ; Wang, Dandan ; Zhang, Pin ; Zanvit, Peter ; Chen, Hua ; Zhang, Dunfang ; Li, Jia ; Che, Li ; Maruyama, Takashi ; Nakatsukasa, Hiroko ; Wu, Ruiqing ; Jin, Wenwen ; Sun, Lingyun ; Chen, Wan Jun. / Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis. In: EBioMedicine. 2019.
@article{0ee22f76d73b4953a8106e2278efca75,
title = "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 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. 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 reg cells) in vivo. Interpretation: 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.",
author = "Shimpei Kasagi and Dandan Wang and Pin Zhang and Peter Zanvit and Hua Chen and Dunfang Zhang and Jia Li and Li Che and Takashi Maruyama and Hiroko Nakatsukasa and Ruiqing Wu and Wenwen Jin and Lingyun Sun and Chen, {Wan Jun}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ebiom.2019.05.005",
language = "French",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis

AU - Kasagi, Shimpei

AU - Wang, Dandan

AU - Zhang, Pin

AU - Zanvit, Peter

AU - Chen, Hua

AU - Zhang, Dunfang

AU - Li, Jia

AU - Che, Li

AU - Maruyama, Takashi

AU - Nakatsukasa, Hiroko

AU - Wu, Ruiqing

AU - Jin, Wenwen

AU - Sun, Lingyun

AU - Chen, Wan Jun

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 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. 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 reg cells) in vivo. Interpretation: 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.

AB - 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 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. 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 reg cells) in vivo. Interpretation: 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.

UR - http://www.scopus.com/inward/record.url?scp=85065515826&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065515826&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.05.005

DO - 10.1016/j.ebiom.2019.05.005

M3 - Article

C2 - 31097410

AN - SCOPUS:85065515826

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -