| Chemokines and chemokine receptors are important regulators of leukocyte trafficking and immune response. Accordingly, intensive chemokine signalling has been observed in many inflammatory diseases. The chemokine system is highly specialised and could be a promising drug target candidate for these diseases. It is well established that chemokines and their receptors are also expressed in various diseases of the central nervous system (CNS), that range from multiple sclerosis and stroke to HIV encephalopathy. Thus inhibition of chemokine signalling in mice significantly reduces or even completely inhibits the clinical signs of EAE, an experimental model for MS. New MS therapies based on inhibition of chemokine signalling are therefore currently envisaged. CXCL9 (Mig), CXCL10 (IP10) and CXCL11 (I-TAC) are chemokines that are prominently expressed in tissues affected by MS. These three chemokines activated the chemokine receptor CXCR3 that is present in both intrinsic glia as well as in infiltrating cells. Currently, little is known about the function of these chemokines in the pathology of EAE and MS. Since they attract CXCR3-expressing Th1 cells it is suggested that these chemokines regulate the infiltration of the MS brain by Th1 cells. Because this infiltration is a crucial event in the pathology of MS, various groups have suggested that interference with CXCR3 signalling would inhibit Th1 cell infiltration and thereby would be beneficial for the disease. This assumption has not been proven yet. Recently, we have found expression of CXCR3 in glial cells (microglia and astrocytes). It is therefore proposed that CXCR3, in addition to attracting Th1 cells to the brain, might be an important receptor in local neuroimmune signalling. Thus, CXCR3 is involved in the regulation of glial activity, a process that is of crucial importance in local inflammation observed in tissues affected by MS and EAE. In order to elucidate the function of CXCR3 in EAE, thereby looking at Th1 cell infiltration and glial activity, we intend to compare EAE in wild type and CXCR3 deficient mice. |
