Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein Sandra Columba-Cabezas a , Marilena Griguoli a , Barbara Rosicarelli a , Roberta Magliozzi a , Francesco Ria b , Barbara Serafini a , Francesca Aloisi a, ⁎ a Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy b Institute of General Pathology, Catholic University, Rome, Italy Received 28 February 2006; received in revised form 16 May 2006; accepted 9 June 2006 Abstract We have recently shown that de novo formation of lymphoid structures resembling B-cell follicles occurs in the inflamed central nervous system (CNS) meninges in a subset of patients with secondary progressive multiple sclerosis and in SJL mice with relapsing–remitting experimental autoimmune encephalomyelitis (EAE). Because lymphotoxin (LT) α 1 β 2 is essential for lymphoid tissue organization, we used real-time PCR to examine LTβ and LTβ receptor (LTβR) gene expression in the CNS of SJL mice immunized with PLP 139–151 peptide. Moreover, we used the decoy receptor LTβR-immunoglobulin fusion protein to block the interaction of lymphotoxin (LT) α 1 β 2 with the LTβ receptor (LTβR) in mice with established EAE and evaluate the effect of systemic and local treatments with the fusion protein on disease progression, CNS lymphocytic infiltration and formation of meningeal B-cell follicles. The present findings indicate that both LTβ and LTβR are upregulated at EAE onset and during subsequent relapses and that systemic and local blockade of the LT pathway with LTβR-Ig results in protracted and transient inhibition of EAE clinical signs, respectively. LTβR-Ig treatment also reduces T- and B-cell infiltration and prevents the induction of the chemokines CXCL10 and CXCL13 and the formation of organized ectopic follicles in the EAE-affected CNS. Targeting of molecules involved in lymphoid organogenesis could represent a valid strategy to inhibit CNS inflammation and formation of ectopic follicles, which may play a role in maintaining an abnormal, intrathecal humoral immune response in CNS autoimmune disease. © 2006 Elsevier B.V. All rights reserved. Keywords: Central nervous system; Experimental autoimmune encephalomyelitis; Lymphoid neogenesis; Germinal centres; Lymphotoxin 1. Introduction Lymphotoxin (LT) α 1 β 2 , a membrane heterotrimer belonging to the tumor necrosis factor (TNF) family, binds to the LTβ receptor (LTβR) and plays a key role in the development and maintenance of the lymphoid microenvir- onment (Fu et al., 1995; Gonzales et al., 1998; Ngo et al., 1999). In the adult immune system, LTα 1 β 2 is expressed on the surface of B and T cells (Browning et al., 1997; Gommerman and Browning, 2003) and its binding to the LTβR on reticular stromal cells induces expression of lymphoid chemokines, like CCL19, CCL21 and CXCL13, that regulate the homeostatic trafficking of lymphocytes in lymphoid organs and their compartmentalization in B-cell areas (follicles) and interfollicular T-cell areas (Ngo et al., 1999; Ansel and Cyster, 2001; Cupedo and Mebius, 2003). Signalling through the LTβR is also required for the differentiation and function of high endothelial venules (Browning et al., 2005) and of follicular dendritic cells (FDCs) (Fu et al., 1995; Gonzales et al., 1998; Endres et al., 1999; Tumanov et al., 2002), which provide the micro- environment for the colonisation of primary follicles and the Journal of Neuroimmunology 179 (2006) 76 – 86 www.elsevier.com/locate/jneuroim ⁎ Corresponding author. Tel.: +39 0649902087; fax: +39 064957821. E-mail address: fos4@iss.it (F. Aloisi). 0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2006.06.015