Neutralization of IFN-inducible protein 10/CXCL10 exacerbates experimental autoimmune encephalomyelitis

Abstract

We examined the effect of a monoclonal antibody (mAb) against interferon (IFN)‐inducible protein 10 (IP‐10)/CXCL10 on the development of experimental autoimmune encephalomyelitis (EAE) in ratsinduced by injecting xenogeneic brain homogenates into footpads. Treatment with neutralizing mAb against CXCL10 exacerbated EAE with increased infiltrating CD4+ cells in the central nervous system. Furthermore, the exacerbation by the mAb treatment was accompanied by less enlarged draining popliteal lymph nodes (LN) in parallel with cell number compared with those of EAE rats treatedwith control mAb, whereas other lymphoid organs such as the spleen and thymus were not significantly different between rats treated with anti‐CXCL10 and the control mAb. Induction of gene expression of CXCL9/Mig and CXCL10 and their receptor CXCR3 was confirmed in the draining LN in EAE rats. Induction of the third CXCR3 ligand, CXCL11/I‐TAC was not seen in the draining LN, whereas all three CXCR3 ligands and CXCR3 itself were markedly detected in the spinal cords following the development of EAE. These findings suggest that CXCL10 produced in the LN plays a specific inhibitory role in the development of Th1‐mediated diseases such as EAE by holding sensitized and activated Th1s expressing CXCR3 in the draining LN.

Among CXCR3 Chemokines, IFN-γ-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN-γ (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease

“…The presence of transgenic RIP-GP sequences was determined by performing standard PCR with genomic DNA obtained from mouse tails as described (12). Generation of GFP ϫ TCR(GP [33][34][35][36][37][38][39][40][41] ) double transgenic mice has been described (17). Briefly, C57BL/6-TgN(ACTbEGFP)1Osb mice (GFP mice; The Jackson Laboratory, Bar Harbor, ME) that express GFP under the control of the ␤-actin promoter (18) were crossed with B6;D2-TgN(TcRLCMV)327Sdz mice that express a D b (GP [33][34][35][36][37][38][39][40][41] )-specific TCR (19).…”

Islet-Specific Expression of CXCL10 Causes Spontaneous Islet Infiltration and Accelerates Diabetes Development

“…3 ), and CXCL11 (IFN-inducible T cell ␣ chemoattractant) play an important role in autoimmune disease (1)(2)(3). CXCR3 chemokine ligands are mainly expressed by keratinocytes, macrophages, fibroblasts, and endothelial cells upon stimulation with IFN-␥ or TNF-␣ (4, 5), but are also generated by activated T cell hybridomas, normal T cells, and thymocytes (6).…”

CXCL10 DNA Vaccination Prevents Spontaneous Diabetes through Enhanced β Cell Proliferation in NOD Mice

“…In the NOD mouse, replacement of an Idd gene, except the MHC region, does not suppress spontaneous insulitis completely; therefore, multiple background genes might be involved in the progression of insulitis in the NOD mouse (39,40). Although differences in the dose, timing, or route of intervention can lead to different outcomes in the development of diabetes in NOD mice (30), our results at least suggest that pCAGGS-CXCL10 treatment did not aggravate the immunological response against ␤ cells in spontaneous diabetes as well as in a CY-induced diabetes model in NOD mice (15) and that "CXCL10 neutralization therapy" can be used to prevent autoimmune diabetes irrespective of the timing of intervention.…”

“…Three ligands for CXCR3, CXCL10/ IFN-␥ inducible protein 10 kDa, CXCL9/monokine induced by IFN-␥, and CXCL11/IFN-inducible T cell ␣ chemoattractant, have been identified (9 -13). Among these three chemokines, CXCL10 is associated with the pathogenesis of various Th1-dominant diseases (14) such as experimental autoimmune encephalomyelitis (15)(16)(17), rheumatoid arthritis (18,19), and infectious diseases (12,20).…”