This research will be done primarily in Poland as an extension of NIH grant # 1 R01 NS 32151 """"""""Chemokines in CNS inflammation."""""""" Leukocyte infiltration into the central nervous system (CNS) is a key event in many neuroimmunologic diseases. The recruitment of lymphocytes and macrophages into the brain is likely the result of chemokine (chemoattractant cytokine) expression in the CNS. In the parent grant we analyze how specific pairs of chemokines and their receptors govern recruitment of inflammatory cells to the CNS during animal model of multiple sclerosis (MS) - experimental autoimmune encephalomyelitis (EAE). In this proposal, we would like to extend those studies and analyze the role of chemokines and chemokine receptors in a newly described focal model of MS-like CNS lesions induced by intracerebral injection of bacillus Calmette-Guerin (BCG). This model is an example of brain delayed type hypersensitivity (DTH) reaction and is characterized by the presence of a single mononuclear inflammatory focus in brain striatum. Unlike EAE brain, the DTH model is induced by non-CNS antigen (BCG) and allows observation of bystander damage to the brain triggered by inflammatory reaction. Similar types of CNS damage is postulated for MS pathogenesis. This research will concentrate on the following three Specific Aims: 1) Development and characterization of the murine model of brain DTH reaction. Initially, murine model of brain DTH reaction will be described. Originally this model was described in rats a few years ago. Mouse DTH model will enable us to use several murine reagents not available for rats and use genetically modified animals in the future. 2) Analysis of chemokines and chemokine receptor expression in brain DTH model. Once the histopathology of a new model is described, we will address the potential role of chemokines in its development. Expression of chemokines and chemokine receptors in the brain during development of DTH lesion will be analyzed. This project will be concluded with Aim 3) Prevention and treatment of brain DTH model with chemokine inhibitors. Some chemokines and their receptors are most likely upregulated in the brain during BCG-induced model of neuroinflammation. This observation may lead to modulation of this pathology with anti-chemokine strategy. Upregulated chemokines will also be targeted in Aim 3. Research proposed here will complement ongoing studies by the parent grant without overlap. Results of those studies may suggest new therapeutic strategies for neuroinflammatory disorders.
| Ubogu, Eroboghene E; Cossoy, Michael B; Ransohoff, Richard M (2006) The expression and function of chemokines involved in CNS inflammation. Trends Pharmacol Sci 27:48-55 |
| Engelhardt, Britta; Ransohoff, Richard M (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485-95 |
| Glabinski, Andrzej R; Bielecki, Bartosz; Kawczak, Julie A et al. (2004) Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression. Autoimmunity 37:465-71 |
| Glabinski, Andrzej R; Bielecki, Bartosz; Kolodziejski, Pawel et al. (2003) TNF-alpha microinjection upregulates chemokines and chemokine receptors in the central nervous system without inducing leukocyte infiltration. J Interferon Cytokine Res 23:457-66 |
