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 interce… Show more
“…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.…”
Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly on the extent of damage in which proapoptotic cytokines have a crucial function. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the function of the proapoptotic cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Immunostaining for TRAIL and its receptor DR5 was found in the white and gray matter of the perilesional area, as also confirmed by western blotting experiments. Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-a, IL-1b, and MPO), and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax, and Bcl-2 expression). As glucocorticoid-induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with upregulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR À/À ) in comparison with wild-type mice suggesting that TRAIL-and GITRL-activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.
“…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.…”
Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly on the extent of damage in which proapoptotic cytokines have a crucial function. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the function of the proapoptotic cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Immunostaining for TRAIL and its receptor DR5 was found in the white and gray matter of the perilesional area, as also confirmed by western blotting experiments. Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-a, IL-1b, and MPO), and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax, and Bcl-2 expression). As glucocorticoid-induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with upregulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR À/À ) in comparison with wild-type mice suggesting that TRAIL-and GITRL-activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.
“…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).…”
Section: Kp and Immune Modulation In The Pathomechanism Of Mssupporting
confidence: 53%
“…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).…”
Section: -Hydroxykynureninementioning
confidence: 94%
“…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).…”
Section: Unique Lanscape Of the Cnsmentioning
confidence: 99%
“…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.…”
Section: Modulation Of the Kp As A Therapeutic Strategy In Msmentioning
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