Critical role of preproenkephalin in experimental autoimmune encephalomyelitis

Weir, Catherine; McNeill, Andrea; Hook, Sarah; Harvie, Marina; Flamme, Anne Camille La; Gros, Graham Le; Bäckström, B. Thomas

doi:10.1016/j.jneuroim.2006.06.021

Cited by 15 publications

(9 citation statements)

References 30 publications

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“…Furthermore, it is known that the peptidases that break down enkephalins, and specifically neprilysin, are activated in patients with MS (Ziaber et al, 1999(Ziaber et al, , 2000. Whether the dysregulation of the OGF-OGFr axis involves increased enkephalinase activity (Gironi et al, 2000;Jankovic, 1991;Weir et al, 2006), as well as decreased processing of the precursor proenkephalin is unknown.…”

Section: Discussionmentioning

confidence: 99%

Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

Hammer

Zagon

McLaughlin

2015

Brain Research Bulletin

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Section: Discussionmentioning

confidence: 99%

Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

Hammer

Zagon

McLaughlin

2015

Brain Research Bulletin

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“…Cells were cultured (10 6 cells/ml) in complete medium containing Dulbecco’s minimal essential medium, 10% FCS, 100 U/ml penicillin plus 100 µg/ml streptomycin, 10 mM Hepes, 2 mM L-glutamine, and 50 µM 2-mercaptoethanol (all from Invitrogen, Carlsbad, CA) and stimulated with MOG peptide (27 µg/ml) or MIS416 (20 µg/ml) for 72 or 48 hours, respectively. These doses were based upon previously published dose-response curves for MOG [14], [15] and MIS416 [12].…”

Section: Methodsmentioning

confidence: 99%

Targeting Innate Receptors with MIS416 Reshapes Th Responses and Suppresses CNS Disease in a Mouse Model of Multiple Sclerosis

White

Webster²,

O’Sullivan

et al. 2014

PLoS ONE

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Modification of the innate immune cell environment has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticulate immune response modifier that targets myeloid cells, activating cytosolic receptors NOD2 and TLR9, and has completed a phase 1b/2a trial for the treatment of secondary progressive multiple sclerosis. Using a mouse model of multiple sclerosis, we are investigating the pathways by which activation of TLR9 and NOD2 may modify the innate immune environment and the subsequent T cell-mediated autoimmune responses. We have found that MIS416 has profound effects on the Th subset balance by depressing antigen-specific Th1, Th17, and Th2 development. These effects coincided with an expansion of specific myeloid subpopulations and increased levels of MIS416-stimulated IFN-γ by splenocytes. Additionally, systemic IFN-γ serum levels were enhanced and correlated strongly with disease reduction, and the protective effect of MIS416 was abrogated in IFN-γ-deficient animals. Finally, treatment of secondary progressive MS patients with MIS416 similarly elevated the levels of IFN-γ and IFN-γ–associated proteins in the serum. Together, these studies demonstrate that administration of MIS416, which targets innate cells, reshapes autoimmune T cell responses and leads to a significant reduction in CNS inflammation and disease.

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“…Single-cell suspensions were prepared from the spinal cords as described. 44 Briefly, the tissue was minced and digested with type II collagenase (2.4 mg ml À1 ; Invitrogen) at 37 1C for 30 min. Following passage through a 70-mm mesh cell strainer (BD Biosciences, Franklin Lakes, NJ, USA), cells were pelleted at 700 g for 3 min and resuspended in 10 ml of 37% Percoll (Sigma).…”

Section: Isolation and Culture Of Immune Cellsmentioning

confidence: 99%

Microtubule‐stabilizing agents delay the onset of EAE through inhibition of migration

et al. 2013

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We have shown previously that microtubule-stabilizing agents (MSA), a class of anti-proliferative compounds, can delay disease onset and reduce cumulative disease in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To explore how MSA could alter EAE disease processes, we compared the effect of administering MSA before or after peak antigen-specific proliferation and found that treatment before proliferation completely inhibited antigen-specific responses in the spleen; whereas administration of an MSA such as paclitaxel or docetaxel after peak proliferation did not. Despite the presence of antigen-specific responses in mice treated at the later time point, both treatment periods resulted in similar protection against EAE, suggesting that the protective effect of MSA in EAE could not be solely attributed to anti-proliferative activity. Instead, using in vivo migration assays, it was shown that MSA inhibit immune cell infiltration into the central nervous system (CNS). Furthermore, we found that the efficacy of an MSA could be enhanced by administering low doses of two different MSA together, such as peloruside A and ixabepilone, indicating that these MSA synergize in vivo to suppress disease. Taken together, these data suggest that MSA can suppress EAE by at least two distinct mechanisms of action--prevention of proliferation and inhibition of migration into the CNS. Finally, we have shown that a combination treatment with synergizing MSA may provide enhanced protection at lower therapeutic doses.

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Critical role of preproenkephalin in experimental autoimmune encephalomyelitis

Cited by 15 publications

References 30 publications

Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

Targeting Innate Receptors with MIS416 Reshapes Th Responses and Suppresses CNS Disease in a Mouse Model of Multiple Sclerosis

Microtubule‐stabilizing agents delay the onset of EAE through inhibition of migration

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