Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein

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) α1β2 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) α1β2 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.