Targeting the Function of IFN-γ-Inducible Protein 10 Suppresses Ongoing Adjuvant Arthritis

Abstract

IFN-γ-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-γ, low TNF-α, 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 α chemoattractant) and yet significantly blocked not only adjuvant-induced arthritis but also the in vivo competence to mount delayed-type hypersensitivity.

A Fusion Protein Encoding the Second Extracellular Domain of CCR5 Arrests Chemokine-Induced Cosignaling and Effectively Suppresses Ongoing Experimental Autoimmune Encephalomyelitis

“…For example, the CXCR3 ligand CXCL10 polarizes CD4 + T cells into effector Th1 (15,16), whereas CXCL12 skews T cell polarization into IL-10-producing Ag-specific regulatory T cells (17). Another example for the variety of biological properties of chemokines is their role in the activation of adhesion receptors, an essential step allowing rapid influx of leukocytes to target organs (18,19).…”

Human dendritic cells respond to Porphyromonas gingivalis LPS by promoting a Th2 effector response in vitro

“…IL-12 p70 is instrumental in committing T cells to Th1-lineage differentiation [26]. IFN-+ -inducible protein 10 (IP-10) is a CXC chemokine that, in addition to directing the migration of Th1 cells preferentially, also directly drives naive T cells into the Th1 lineage [27]. To establish whether human MDDC can be cytokine-polarized by different LPS moieties, MDDC were pulsed with P. gingivalis or E. coli LPS at a range of concentrations, and supernatants were analyzed ( Fig.…”

Chemokine production during hypersensitivity pneumonitis

“…The CXC chemokines IP-10, Mig, and I-TAC are induced by IFN-+ , and attract activated T cells and NK cells bearing the chemokine receptor CXCR3 [18][19][20]. These chemokines have been found to be associated with several Th1 diseases such as rheumatoid arthritis, sarcoidosis, and inflammatory bowel disease [21][22][23]. The CC chemokines eotaxin, MCP-1, MCP-3, and MCP-4 have been found to be associated with Th2 diseases such as asthma and allergies, although the strongest correlation appears to be with eotaxin [24][25][26].…”