IFN-Inducible Protein 10/CXC Chemokine Ligand 10-Independent Induction of Experimental Autoimmune Encephalomyelitis

• Published in: The Journal of immunology (1950) 2004-01, Vol.172 (1), p.550-559
• Main Authors: Klein, Robyn S, Izikson, Leonid, Means, Terry, Gibson, Hilary D, Lin, Eugene, Sobel, Raymond A, Weiner, Howard L, Luster, Andrew D
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Brain - immunology; Brain - pathology; Cell Movement - immunology; Chemokine CXCL10; Chemokine CXCL11; Chemokine CXCL9; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - biosynthesis; Chemokines, CXC - deficiency; Chemokines, CXC - genetics; Chemokines, CXC - immunology; Chemokines, CXC - physiology; CXCL10 protein; Down-Regulation - genetics; Down-Regulation - immunology; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Epitopes, T-Lymphocyte - immunology; Female; Genetic Predisposition to Disease; Intercellular Signaling Peptides and Proteins - genetics; Interferon-gamma - physiology; IP10 protein; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphocyte Subsets - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; myelin oligodendrocyte glycoprotein; RNA, Messenger - biosynthesis; Severity of Illness Index; Spinal Cord - immunology; Spinal Cord - pathology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta1; Up-Regulation - genetics; Up-Regulation - immunology; Vaccination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.1.550

In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), autoaggressive T cells traffic into the CNS and induce disease. Infiltration of these pathogenic T cells into the CNS has been correlated with the expression of the chemokine IFN-inducible protein (IP)10/CXC chemokine ligand (CXCL)10, a chemoattractant for activated T cells, and its receptor CXCR3, in the CNS of both MS patients and mice with EAE. In the present study, we report that targeted deletion of IP-10 did not diminish the expression, severity, or histopathology of EAE induced by active immunization with 100 micro g of myelin oligodendrocyte glycoprotein peptide (MOG)p35-55. However, we found that IP-10-deficient mice had a lower threshold for expression of disease compared with wild-type littermates. EAE induced by immunization with 5 micro g of MOGp35-55 resulted in more severe disease characterized by a greater number of CNS lesions and infiltrating mononuclear cells in IP-10-deficient mice compared with wild-type controls. IP-10-deficient mice immunized with MOGp35-55 demonstrated increased levels of IFN-inducible T cell alpha-chemokine/CXCL11 mRNA in the CNS and decreased levels of monokine induced by IFN-gamma/CXCL9 mRNA in draining lymph nodes, suggesting differential compensation for loss of IP-10 in lymphoid vs parenchymal tissue compartments. EAE in IP-10-deficient mice induced by low-dose immunization was associated with enhanced Ag-specific Th1 responses in the draining lymph node, which corresponded with diminished lymph node TGF-beta1 expression. Our data demonstrated that IP-10 was not required for the trafficking of pathogenic T cells into the CNS in EAE but played an unexpected role in determining the threshold of disease susceptibility in the periphery.