Immunopathogenesis of Multiple Sclerosis

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Multiple sclerosis is an immunopathological, presumably autoimmune, disease that is clearly influenced by environmental and genetic factors. The development of therapeutic strategies for MS has followed the evolution of pathogenetic concepts (Hemmer et al. 2006; Sospedra and Martin 2005; Hafler 2004), and current models of MS immunopathogenesis offer numerous molecular targets for mAb therapy (Fig. 13.1).

Autoimmune T- and B-cell responses to CNS antigens are believed to drive the pathogenesis of MS (Hohlfeld 1997) (Fig. 13.1). The immunopathological cascade is probably orchestrated by autoreactive, presumably myelin-reactive, T cells. Several different types of T cells (including CD4+ helper, suppressor, and inflammatory T cells, as well as CD8+ effector and regulatory T cells) seem to contribute to this complex scenario. Once the autoreactive T cells have traversed the blood-brain barrier, they are thought to be locally reactivated by (auto-) antigens displayed on the surface of non-professional antigen-presenting cells, including microglia, monocytes, dendritic cells and B cells (Kawakami et al. 2005). The re-activated T cells then secrete an array of proinflammatory mediators and cytokines, which either directly mediate myelin injury, or act indirectly by stimulating other immune cells, thus initiating a cascade of proinflammatory damage. Based on this concept, several therapeutic targets can be envisaged. For example, the deletion or inhibition of effector and helper T cells would be a rational therapeutic objective. Also, myelin-reactive antibodies and B cells, which contribute to the pathogenesis, could be targeted. Immune cell migration, as well as cytokine and chemokine networks, may be considered as additional therapeutic targets (Fig. 13.1).

Cell Therapies Multiple Sclerosis

Fig. 13.1. Possible targets of therapeutic mAbs in MS. According to the current scheme of MS pathogenesis, pre-existing autoreactive T cells are activated outside the CNS. After local reactivation, they secrete cytokines, which stimulate microglia and astrocytes, recruit additional inflammatory cells, and stimulate antibody production by plasma cells. Anti-myelin antibodies, activated macrophages/microglia, and cytotoxic T cells all cooperate to inflict myelin and axon damage. Possible therapeutic targets include (1) depletion or inhibition ofT cells; (2) depletion or inhibition of B cells; (3) interference with the molecular mechanisms of T-cell activation; (4) inhibition of lymphocyte migration; and (5) inhibition of soluble mediators, such as cytokines and che-mokines

Fig. 13.1. Possible targets of therapeutic mAbs in MS. According to the current scheme of MS pathogenesis, pre-existing autoreactive T cells are activated outside the CNS. After local reactivation, they secrete cytokines, which stimulate microglia and astrocytes, recruit additional inflammatory cells, and stimulate antibody production by plasma cells. Anti-myelin antibodies, activated macrophages/microglia, and cytotoxic T cells all cooperate to inflict myelin and axon damage. Possible therapeutic targets include (1) depletion or inhibition ofT cells; (2) depletion or inhibition of B cells; (3) interference with the molecular mechanisms of T-cell activation; (4) inhibition of lymphocyte migration; and (5) inhibition of soluble mediators, such as cytokines and che-mokines

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