Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

Schaub, Michael T.; Issazadeh, Shohreh; Stadlbauer, Thomas; Peach, Robert; Sayegh, Mohamed H.; Khoury, Samia J.

doi:10.1016/s0165-5728(99)00022-3

Cited by 37 publications

(30 citation statements)

References 29 publications

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“…8 Expression of CD80 on peripheral blood CD4 + T cells has been shown to be upregulated in patients with active multiple sclerosis (MS). 9 Furthermore, B7 blockage using anti-B7 antibodies or CTLA-4Ig can prevent the development of murine experimental autoimmune encephalomyelitis (EAE), a T cellmediated autoimmune disease that shares many clinical and histological features with human MS. [10][11][12][13] It was considered possible that structural variations as well as the dysregulation in the expression of the costimulatory molecules may be associated with susceptibility to autoimmune or chronic inflammatory diseases. It was reported that polymorphism within CTLA-4 exon 1 (49A/G) and that of the dinucleotide repeats within 3′-untranslated region (3′-UTR) seemed to be significantly associated with insulin-dependent diabetes mellitus (IDDM), 14,15 Graves' disease 16,17 or Hashimoto's thyroiditis.…”

Section: Introductionmentioning

confidence: 99%

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus

et al. 2000

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Section: Introductionmentioning

confidence: 99%

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus

et al. 2000

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“…These include CD40 and CD80/86 (B7-1/B7-2) with their respective ligands CD154 and CD28. These interactions are critical for T-cell activation and inflammation in models of adaptive immunity in vitro and in vivo (12)(13)(14). Data from our laboratory suggest that neutrophils (PMNs) can activate macrophages in vitro via engagement of the costimulatory receptors CD40 and CD80/86, establishing a potential role for these cascades in regulating inflammation in the innate immune response in vivo (11).…”

mentioning

confidence: 99%

CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis

Nolan¹,

Weiden²,

Kelly³

et al. 2008

Am J Respir Crit Care Med

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Rationale: Costimulatory molecules, including the CD40-CD154 and CD80/86-CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans. Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86 2/-mice, and novel CD40/ 80/86 2/-mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry. Measurements and Main Results: Lethal CLP was associated with upregulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86 2/-mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86 2/-mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived.Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.

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“…40 Other studies showed that anti-CD28 or CTLA4Ig used after the first clinical episode of disease, prevented additional relapses, thus suggesting that this approach may be useful even after the autoimmune disease is already established. 41,42 The contradictory results derived from studies on costimulation highlight the complexity of the fine interactions among the different molecules at different stages of the disease and in different models of the disease.…”

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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Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

Cited by 37 publications

References 29 publications

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus

New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus

CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis

Modulating Co-Stimulation

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