Experimental models of autoimmune disease have been used to dissect the mechanisms of disease pathogenesis in the corresponding human diseases. This chapter will deal with experimental autoimmune encephalomyelitis (EAE) as a model for human multiple sclerosis (MS) and experimental autoimmune diabetes (EAD) in the NOD mouse as a model for human diabetes. In the case of these tissue-specific autoimmune diseases, the autoreactive lymphocytes originate in lymph nodes and must migrate to either the central nervous system (CNS) in the case of EAE or the pancreas in the case of EAD. The accepted paradigm of leukocyte migration from blood into tissue involves a number of molecular events including selectin binding, chemokine binding, integrin binding and activation, and extravasation [1, 2]. Therefore, chemokines have a central role in the pathogenesis of tissue-specific autoimmune diseases. The approaches that have been used to study the role of chemokines in animal models of autoimmune disease included assessing tissue-specific temporal chemokine expression patterns, assessing corresponding chemokine receptor expression patterns on the tissue-infiltrating leukocytes, using neutralizing anti-chemokine therapy, employing chemokine and/or chemokine receptor knockout mice in the various disease models, and making transgenic mice that overexpress certain chemokines in specific tissues. This has resulted in the identification of subsets of the chemokine and chemokine receptor families that play a role in disease pathogenesis. This chapter will review the role of chemokines and their receptors in EAE and EAD as examples of tissue-specific autoimmune diseases.
KeywordsExperimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis Chemokine Receptor Expression Chemokine mRNA Experimental Autoimmune Encephalomyelitis Development
Unable to display preview. Download preview PDF.
- 6.Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ (1998) Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1. J Neuroimmunol 92: 98–108PubMedCrossRefGoogle Scholar
- 13.Fife BT, Kennedy KJ, Paniagua MC, Lukacs NW, Kunkel SL, Luster AD, Karpus WJ (2001) CXCL10 (IFN-gamma-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol 166: 7617–7624PubMedGoogle Scholar
- 17.Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM (2001) Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 193: 713–726PubMedCrossRefGoogle Scholar
- 28.Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM (1997) Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med 185: 1959–1968PubMedCrossRefGoogle Scholar
- 41.Christen U, McGavern DB, Luster AD, Von Herrath MG, Oldstone MB (2003) Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. J Immunol 171: 6838–6845PubMedGoogle Scholar
- 45.Grewal IS, Rutledge BJ, Fiorillo JA, Gu L, Gladue RP, Flavell RA, Rollins BJ (1997) Transgenic monocyte chemoattractant protein-1 (MCP-1) in pancreatic islets produces monocyte-rich insulitis without diabetes. Abrogation by a second transgene expressing systemic MCP-1. J Immunol 159: 401–408PubMedGoogle Scholar
- 46.Morimoto J, Yoneyama H, Shimada A, Shigihara T, Yamada S, Oikawa Y, Matsushima K, Saruta T, Narumi S (2004) CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis. J Immunol 173: 7017–7024PubMedGoogle Scholar