Immunopathology and Infectious Diseases Fn 14-TRAIL , a Chimeric Intercellular Signal Exchanger , Attenuates Experimental Autoimmune Encephalomyelitis

Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectively prevented chronic, nonremitting, paralytic disease in myelin oligodendrocyte glycoprotein-challenged C57BL/6 mice. Disease suppression in this model was reflected by decreases in the clinical score, disease incidence, nervous tissue inflammation, and Th1, Th2, and Th17 cytokine responses. Significantly, the therapeutic efficacy of Fn14-TRAIL could not be recapitulated simply by administering its component parts (Fn14 and TRAIL) as soluble agents, either alone or in combination. Its functional pleiotropism was manifest in its additional ability to attenuate the enhanced permeability of the blood-brain barrier that typically accompanies autoimmune encephalomyelitis. (Am J Pathol 2009, 174:460–474; DOI: 10.2353/ajpath.2009.080462) Despite a steadily expanding set of treatment options for multiple sclerosis (MS), there remains a pressing need for more effective therapeutic agents to address this debilitating autoimmune disorder of the central nervous system (CNS). Although the precise etiology of MS is unknown, key features of its pathogenesis and clinical evolution are emerging. Among various immune cellular effectors that have been implicated, pathogenic T cells loom large as pivotal drivers of the disease. As a consequence, various therapeutic paths are converging on T effectors as targets, with complementary goals of blocking their activation and re-activation, eliminating them from the larger T-cell reservoir, and interfering with their transit to sites of pathogenesis within the CNS. A complex interplay of positive and negative intercellular signals regulates activation and maintenance of Tcell effector functions. Proteins of the tumor necrosis factor (TNF) superfamily figure prominently in this matrix of signals, bridging various cells of the immune system, as well as to cells of other organ systems. In so doing, TNF superfamily members contribute to both tissue homeostasis and pathogenesis via effects on cell survival and death, cellular differentiation, and inflammation. From the standpoint of autoimmune pathogenesis, two especially interesting members of the TNF superfamily are the cell surface ligands TWEAK (TNF-related weak inducer of apoptosis) and TRAIL (TNF-related apoptosis-inducing ligand). TWEAK, a TNF superfamily ligand, and its counter-receptor Fn14 (fibroblast growth factor-inducible 14-kDa protein) are expressed in a range of immune and nonimmune cell types. TWEAK, which is expressed on cells such as macrophages, dendritic cells, NK cells, endothelial cells, microglial cells, and astrocytes, stimulates proliferation of astrocytes