Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Abstract

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

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

“…As a counterproof, it has been shown that GITR-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after SCI (Nocentini et al, 2008). In the same line, Razmara et al (2009) showed that Fn14-TRAIL, a chimeric intercellular signal exchanger, attenuates experimental autoimmune encephalomyelitis inflammatory hallmarks. In this study, it is shown that neutralization of TRAIL by in vivo treatment with TRAIL-neutralizing antibody results in diminished expression of GITR and its ligand.…”

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…This response could be designed to counteract the detrimental effects to the pathological elevation of kynurenine metabolites. This is supported by the observation of toxic levels of QUIN and 3-HK that are reached in the spinal cord but not the brain in EAE animals with concomitant increased activity and expression of KMO (67,117,118).…”

“…Similar to QUIN, the plasma, brain, and spinal cord levels of 3-HK are elevated in EAE rats (118). There is evidence that 3-HK is a neurotoxic metabolite and it, therefore, may have an important role in the neurodegeneration of MS (173).…”

“…For example, the proteoglycan decorin is strongly upregulated in CNS injury (116). In other tissues, decorin has been shown to bind TGFβ and inhibit its function (117), while decorin binding to IFNγ or TNFα promotes their signaling capacity (118). Alterations in these particular cytokines could change leukocyte motility by modulating responses to chemokines and altering matrix metalloproteinase activity (119).…”

“…In the EAE mouse model, the activity of KMO is significantly increased in spinal cords and this correlates with an increase in QUIN and 3-HK to neurotoxic levels. Administration of the KMO inhibitor Ro 61-8048 reduced the rise in levels of both QUIN and 3-HK, increased neuroprotective KYNA production and significantly alleviated disease progression (118). A number of immunomodulatory drugs such as leflunomide (the active metabolite is Teriflunomide) and Laquinimod, are structurally analogous to KYN and KYNA, respectively, and exhibit immunosuppressive properties by promoting a TH2 profile through a shift in cytokine balance and inhibiting activated T cells.…”