Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation.

Cross, Anne H.; Girard, Tanya; Giacoletto, K S; Evans, Robert J.; Keeling, Richard M.; Lin, Robin F.; Trotter, John L.; Karr, Robert W.

doi:10.1172/jci117982

Cited by 150 publications

(74 citation statements)

References 50 publications

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“…Ž . molecules B7-1 CD80 and B7-2 CD86 play a role in Ž the disease Cross et al, 1995;Khoury et al, 1995;Kuchroo et al, 1995;Miller et al, 1995;Perrin et al, . 1995;Racke et al, 1995;Arima et al, 1996 .…”

Section: žmentioning

confidence: 99%

“…We focused on CD40-Ž . CD40L and B7-1rB7-2 CD80rCD86 in view of the Ž proposed roles of those molecules in EAE and MS see Cross et al, 1995;Khoury et al, 1995;Kuchroo et al, 1995;Miller et al, 1995;Perrin et al, 1995;Racke et al, Ly, lymphocytes; Men, meninges; Mo, monocytesrmacrophages; Opt, optic system; Thal, thalamus; Inflammation score: 0, no inflammation present; q Ž . Ž .…”

Section: In Situ Expression Of Accessory Moleculesmentioning

confidence: 99%

“…Several studies have investigated whether B7-1 and B7-2 costimulation is involved in EAErMS in the light of Ž preferential Th1 vs. Th2 activation Cross et al, 1995;Khoury et al, 1995;Kuchroo et al, 1995;Miller et al, . 1995;Perrin et al, 1995;Racke et al, 1995 .…”

Section: Accessory Molecules: B7-1 R B7-2mentioning

confidence: 99%

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Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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Ž .Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis MS and experimental autoimmune Ž . encephalomyelitis EAE in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of Ž . marmoset monkeys Callithrix jacchus with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions Ž . Ž . may result from local CD40-CD40L interactions. CD40 ligand CD40L and B7-2 CD86 were also expressed, but to a lower extent, Ž . while B7-1 CD80 expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual Ž . lesions during active disease IFN-a, IFN-g , TNF-a, IL-1a , IL-1b, IL-2, IL-4, IL-10 and IL-12 . This suggests that relative levels rather than sequential expression of Th1-and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention. q

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Section: žmentioning

confidence: 99%

Section: In Situ Expression Of Accessory Moleculesmentioning

confidence: 99%

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Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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“…Similarly, anti-B7-1 prevented further relapses in EAE by inhibiting epitope spreading. [12][13][14][15] T cells derived from mice deficient in CD28 were not able to produce IL-2 in response to stimuli, although they efficiently released interferon-␥, the prototypical T-helper 1 cytokine.…”

Section: Relevance Of Cd28/b7 Pathway In Autoimmune Diseasesmentioning

confidence: 99%

“…45,46 The mechanisms of EAE inhibition by blockade of the CD28-B7 co-stimulatory pathway by the fusion protein CTLA4Ig or anti-B7 monoclonal antibodies (mAbs) have been investigated by several laboratories. 12,14,26,47,48 Blockade of CD28-B7 or CD40-CD154 pathways was successful in preventing or ameliorating ongoing disease in numerous other autoimmune disease models. 27,42,49 -52 Furthermore, the approach of co-stimulatory signal blockade was successful in preventing transplant rejection.…”

Section: Co-stimulatory Blockade In Eae: An Animal Model Of Msmentioning

confidence: 99%

Modulating Co-Stimulation

Viglietta

Khoury

2007

Neurotherapeutics

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Summary:The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4ϩ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing autoantigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.

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Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis

et al. 1998

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It has been reported previously that the induction phase of experimental allergic encephalo-myelitis (EAE) is highly sensitive to systemic blockade of stimulation via MHC class II molecules and co-stimulation via the CD28 : CD80/CD86 pathways. In contrast, the effector phases of EAE were relatively unaffected by similar treatments using MHC class II antigen (Ag)-specific mAb and cytotoxic T lymphocyte antigen (CTLA)4-Ig fusion proteins in some studies. This has been attributed to different sensitivities of effector cell function or the poor penetrance of inhibitory proteins into the central nervous system (CNS). To examine this question further, MHC class II Ag-specific mAb and CTLA4-Ig were delivered directly into the CNS following EAE induction, and both were found to inhibit disease. While it was found that systemic administration of mouse CTLA4-Ig could also inhibit the progression of effector immune responses when administered shortly before or during clinical disease, these were significantly more active when delivered directly into the CNS, which probably involved an action on both CD28 ligands, CD80 and CD86. Although mouse CTLA4-human Ig was therapeutically less efficient than mouse CTLA4-mouse Ig protein, probably due to the enhanced immunogenicity and lower functional activity, gene delivery of CTLA4-human Ig into the CNS using a non-replicating adenoviral vector was more effective than a single injection of CTLA4-human Ig protein. Gene delivery significantly ameliorated the development of EAE, without necessarily inhibiting unrelated peripheral immune responsiveness. Local gene delivery of CTLA4-Ig may thus be an important target for immunotherapy of human autoim-mune conditions such as multiple sclerosis.

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Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation.

Cited by 150 publications

References 50 publications

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Modulating Co-Stimulation

Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis

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