Chemokine receptors and their ligands play an important role in mediating leukocyte trafficking [1,2]. Chemokines are proteins of approximately 10 kD that are secreted at the site of inflammation and bind to specific G-protein coupled receptors (GPCRs) expressed on the surface of T cells and other leukocytes [3]. The secreted chemokines form a concentration gradient by binding to glycosaminoglycans on the surface of cells adjacent to the inflamed tissue, including the endothelial cells that line the blood vessels. As T cells approach the site of inflammation, they slow down in a process that is mediated by selectins. This allows the chemokine receptors expressed on the surface of T cells to come in contact with their ligands on the surface of the vascular endothelial cells. Chemokine receptor activation triggers integrin-mediated arrest of T cells on the surface of the endothelial wall and their extravasation guided by the chemokine gradient. CXCR3 is a chemokine receptor primarily expressed on activated CD4+ and CD8+ T cells with a Th1 phenotype [4], although it is also expressed on B cells [5], natural killer (NK) cells [6], malignant T cells [7] and astrocytes [8]. The ligands for CXCR3, Mig (CXCL9), IP-10 (CXCL10), and ITAC (CXCL11), are induced primarily by IFN- γ and are produced by macrophages as well as other cell types in inflamed tissue [9-15]. Disease tissue samples taken from patients suffering from a variety of autoimmune diseases show that CXCR3 is expressed at high levels on infiltrating T cells. At the same time, the ligands for CXCR3 are upregulated in these disease tissue samples. In inflammatory bowel disease patients, there is an increased number of CXCR3+ cells that are found in the lamina propria and submucosa of colon tissue [16], as well as an increase in the numbers of IP-10 secreting cells [17]. In rheumatoid arthritis (RA) patients, researchers have reported that as many as 97% of the infiltrating cells in synovial fluid express CXCR3 [4] and protein levels of IP-10 and Mig are elevated as much as 50 to 100 fold relative to normal individuals [18]. In psoriasis patients, IP-10 [19] and Mig [20] levels are increased in psoriatic plaques and CXCR3 expressing cells infiltrate into the dermis and basal layer of the epidermis of psoriatic lesions [21]. In multiple sclerosis (MS) patients, 80-86% of CD4+ T cells and 92-97% of CD8+ T cells in cerebrospinal fluid have been reported to express CXCR3 [22-24]. Also, CXCR3-expressing T cells and the ligands Mig and IP-10 are found in brain lesions of MS patients [24-26]. In addition, elevated levels of Mig and IP-10, were found in the CSF of MS patients experiencing acute attacks [22,23]. Moreover, in an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), mice treated with a neutralizing antibody to IP-10 show decreased signs of disease severity [27]. However, conflicting results were observed with the IP-10 knock-out mice in an active immunization model of EAE [28], as well as with rats treated with a neutralizing antibody to IP-10 [29]. In patients undergoing transplant rejection, increased levels of the CXCR3 ligands and a large number of infiltrating T cells that express CXCR3 are found in biopsies from organs undergoing rejection [30-38]. Furthermore, cardiac allograft experiments with CXCR3 knock-out mice show increased allograft tolerance when compared to similar experiments performed with wild-type mice [39]. Likewise, transplant experiments with antibodies to the CXCR3 ligands, Mig and IP-10, enhance allograft survival [40,41]. The significance of the role that CXCR3 mediated cellular recruitment plays in transplant has now been demonstrated in a broad variety of in vivo models, including cardiac, lung, small bowel and islet transplant models [39,42-44]. Moreover, cardiac allografts taken from mice lacking IP-10 show prolonged allograft survival time in wild-type mice [40]. No enhancement in allograft survival time is observed when a cardiac allograft from a wild-type mice is transplanted into an IP-10-deficient mice, indicating the importance that the CXCR3 ligand plays in promoting allograft rejection. It is thought that blockade of CXCR3 will prevent inflammatory cells from reaching sites of inflammation and thus should alleviate the disease. In this article we will provide a literature overview regarding potential therapeutic applications for a CXCR3 antagonist and examine the recent reports of CXCR3 antagonism, including blockade of the CXCR3 receptor by antibodies, peptides, and small molecules. © 2005 Elsevier Inc. All rights reserved.
