Targeting the function of IFN-gamma-inducible protein 10 suppresses ongoing adjuvant arthritis.
IFN-gamma-inducible protein 10 (IP-10) is a CXC chemokine that is thought to manifest a proinflammatory role because it stimulates the directional migration of activated T cells, particularly Th1 cells. It is an open question whether this chemokine is also directly involved in T cell polarization. We show here that during the course of adjuvant-induced arthritis the immune system mounts a notable Ab titer against self-IP-10. Upon the administration of naked DNA encoding IP-10, this titer rapidly accelerates to provide protective immunity. Self-specific Ab to IP-10 developed in protected animals, as well as neutralizing Ab to IP-10 that we have generated in rabbits, could inhibit leukocyte migration, alter the in vivo and in vitro Th1/Th2 balance toward low IFN-gamma, low TNF-alpha, high IL-4-producing T cells, and adoptively transfer disease suppression. This not only demonstrates the pivotal role of this chemokine in T cell polarization during experimentally induced arthritis but also suggests a practical way to interfere in the regulation of disease to provide protective immunity. From the basic science perspective, this study challenges the paradigm of in vivo redundancy. After all, we did not neutralize the activity of other chemokines that bind CXCR3 (i.e., macrophage-induced gene and IFN-inducible T cell alpha chemoattractant) and yet significantly blocked not only adjuvant-induced arthritis but also the in vivo competence to mount delayed-type hypersensitivity.
Department of Immunology, Bruce Rappaport Faculty of Medicine, Haifa, Israel.
Izhar
I
Salomon
Nir
N
Netzer
Gizi
G
Wildbaum
Sagie
S
Schif-Zuck
Gila
G
Maor
Nathan
N
Karin
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D019264:Adoptive Transfer; D000818:Animals; D000918:Antibody Specificity / Q000235:genetics; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis / Q000627:therapeutic use; D002464:Cell Migration Inhibition; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use; D007113:Immunity, Innate / Q000235:genetics; D016233:Immunotherapy, Active / Q000379:methods*; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D019444:Vaccines, DNA; D007371:Interferon-gamma