Fcγ receptor‐ligating complexes improve the course of experimental autoimmune encephalomyelitis by enhancing basal Th2 responses

Flamme, Anne Camille La; Harvie, Marina; McNeill, Andrea; Goldsack, Lisa; Tierney, Joanna; Bäckström, B. Thomas

doi:10.1111/j.1440-1711.2006.01464.x

Cited by 15 publications

(42 citation statements)

References 28 publications

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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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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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“…This activation state can impair anti-microbial effector functions but has been shown to protect against pathology in pro-inflammatory disease models such as EAE and septic shock. Our previous work has shown that this activation state is protective during EAE, and this protection is dependent upon IL-4 [8]. However, it is unknown how the Th2 environment, promoted by type II-activated macrophages, is induced nor how this environment, once induced, affects the macrophage’s effector functions.…”

Section: Introductionmentioning

confidence: 99%

“…These macrophages produce less IL-12 and significantly more IL-10 than classical macrophages while producing similar levels of TNF-α and NO [6]. Although the expression of CD40 and PD-L1 are significantly reduced, type II-activated macrophages are effective antigen-presenting cells and promote the development of Th2 cells both in vitro and in vivo [3], [7], [8]. This activation state can impair anti-microbial effector functions but has been shown to protect against pathology in pro-inflammatory disease models such as EAE and septic shock.…”

Section: Introductionmentioning

confidence: 99%

Type II-Activated Murine Macrophages Produce IL-4

et al. 2012

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BackgroundType II activation of macrophages is known to support Th2 responses development; however, the role of Th2 cytokines (esp. IL-4) on type II activation is unknown. To assess whether the central Th2 cytokine IL-4 can alter type II activation of macrophages, we compared the ability of bone marrow-derived macrophages from wild type (WT) and IL-4Rα-deficient mice to be classically or type II-activated in vitro.ResultsWe found that although both WT and IL-4Rα-deficient macrophages could be classically activated by LPS or type II activated by immune complexes plus LPS, IL-4Rα-deficient macrophages consistently produced much higher levels of IL-12p40 and IL-10 than WT macrophages. Additionally, we discovered that type II macrophages from both strains were capable of producing IL-4; however, this IL-4 was not responsible for the reduced IL-12p40 and IL-10 levels produced by WT mice. Instead, we found that derivation culture conditions (GM-CSF plus IL-3 versus M-CSF) could explain the different responses of BALB/c and IL-4Rα−/− macrophages, and these cytokines shaped the ensuing macrophage such that GM-CSF plus IL-3 promoted more IL-12 and IL-4 while M-CSF led to higher IL-10 production. Finally, we found that enhanced IL-4 production is characteristic of the type II activation state as other type II-activating products showed similar results.ConclusionsTaken together, these results implicate type II activated macrophages as an important innate immune source of IL-4 that may play an important role in shaping adaptive immune responses.

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“…Additionally, the presence of type II‐activated macrophages promotes the differentiation of Th2 cells and subsequent IL‐4 production 5 . Earlier work in our laboratory has shown that in vivo administration of FcγR‐ligating immune complexes alone enhanced Th2 responses and protected mice from developing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS) 6 …”

mentioning

confidence: 99%

Type II‐activated macrophages suppress the development of experimental autoimmune encephalomyelitis

2008

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Treatment with immune complexes, which ligate Fcc receptors (FccRs), suppresses the development of experimental autoimmune encephalomyelitis (EAE). To determine the mechanism of action, we investigated how these immune complexes affected type II activation of macrophages (that is, exposure to immune complexes in a proinflammatory environment). Our results show that lower doses of interferon-c (IFN-c) were more effective at priming bone marrow-derived macrophages (BMM/) to produce more interleukin 10 (IL-10) and less IL-12p40 in response to lipopolysaccharide (LPS) and immune complexes compared with LPS alone. Moreover, at the lowest level of IFN-c (20 U ml À1 ), a significant downregulation in the surface expression of CD40, CD80 and PD-L1 was observed in LPS and immune complex-stimulated macrophages (that is, type II activated) than macrophages stimulated with LPS alone (that is, classically activated). Finally, treatment of mice with type II-activated macrophages protected them from developing EAE, suggesting that administration of immune complexes is protective against EAE by inducing type II-activated macrophages.

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Fcγ receptor‐ligating complexes improve the course of experimental autoimmune encephalomyelitis by enhancing basal Th2 responses

Cited by 15 publications

References 28 publications

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

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

Type II-Activated Murine Macrophages Produce IL-4

Type II‐activated macrophages suppress the development of experimental autoimmune encephalomyelitis

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