Plasmid DNA encoding IFN-gamma-inducible protein 10 redirects antigen-specific T cell polarization and suppresses experimental autoimmune encephalomyelitis.
IFN-gamma-inducible protein 10 (IP-10) is a CXC chemokine that stimulates the directional migration of activated T cells, particularly Th1 cells. We demonstrate in this work that during activation this chemokine drives naive CD4(+) T cells into Th1 polarization. Administration of plasmid DNA encoding self IP-10 was found capable of breaking down immunological tolerance to IP-10, resulting in the generation of self-specific immunity to the gene product of the vaccine. Despite the CpG motif that drives T cells into Th1, the vaccine redirected the polarization of myelin basic protein-specific T cells into Th2 and conferred the vaccinated recipients a high state of resistance against experimental autoimmune encephalomyelitis, a T cell-mediated autoimmune disease of the CNS. The vaccine also suppressed full-blown ongoing disease in a mouse model of multiple sclerosis. Self-specific Ab to IP-10 developed in protected animals could inhibit leukocyte migration, alter the in vitro Th1/Th2 balance of autoimmune T cells, and adoptively transfer disease suppression. This demonstrates not only the pivotal role of a chemokine in T cell polarization and function but also its potential implications for plasmid DNA gene therapy.
Wildbaum
Gizi
G
Department of Immunology and Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Netzer
Nir
N
Karin
Nathan
N
D000818:Animals; D000917:Antibody Formation; D002460:Cell Line; D016764:Cell Polarity; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics* / Q000276:immunology; D018899:CpG Islands / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy; D010957:Plasmids; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D019444:Vaccines, DNA / Q000276:immunology*
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D019444:Vaccines, DNA