In vivo administration of plasmid DNA encoding recombinant immunotoxin DT390-IP-10 attenuates experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune demyelinating disease. The expression of chemokine receptor CXCR3 on activated T cells is crucial to direct the migration of effector cells into the inflammatory sites and initiate EAE. In this study we tested the effect of a novel recombinant immunotoxin targeting CXCR3(+) cells for EAE prevention. The immunotoxin construct DT390-IP-10-SRalpha consisted of interferon gamma-inducible protein 10 (IP-10), a ligand of CXCR3, as the targeting moiety, and a truncated diphtheria toxin (DT390) as the toxic moiety. In vitro transfection of DT390-IP-10-SRalpha into NIH3T3 cells resulted in expression of DT390-IP-10 which proved highly toxic to activated T cells. To evaluate the effect of DT390-IP-10-SRalpha on EAE prevention in vivo, cationic liposome-embedded DT390-IP-10-SRalpha was injected into the muscle of hind limbs of C57BL/6 mice immunized by myelin basic protein (MBP). DT390-IP-10-SRalpha-treated mice showed a delayed onset of EAE and milder symptoms compared to the mice treated with empty control plasmid or PBS alone. Immunohistochemical staining detected significantly reduced infiltrating CXCR3(+) cells in the inflammatory lesions of CNS from immunotoxin treated mice as compared to the controls. This study suggests that targeting CXCR3(+) T cells with recombinant immunotoxin could be achieved in vivo to delay and ameliorate murine EAE.
Chen
Wenjie
W
West China School of Preclinical and Forensic Medicine, Sichuan University, Number 17, Section , Renmin Nan Road, Chengdu, Sichuan 610041, People's Republic of China.
Li
Hong
H
Jia
Yi
Y
Lv
Meili
M
Li
Mingyuan
M
Feng
Ping
P
Hu
Huaizhong
H
Zhang
Lin
L
D000818:Animals; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D000922:Immunotoxins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D000922:Immunotoxins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D004247:DNA