Distinct roles for B7-1 (CD-80) and B7-2 (CD-86) in the initiation of experimental allergic encephalomyelitis.

Racke, Michael K.; Scott, Dorothy E.; Quigley, Laura; Gray, Gary S.; Ryo, Akihide; June, Carl H.; Perrin, Peter J.

doi:10.1172/jci118274

Cited by 184 publications

(116 citation statements)

References 62 publications

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“…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%

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: In Situ Expression Of Accessory Moleculesmentioning

confidence: 99%

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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“…12 However, B7 blockade can also result in disease exacerbation, presumably by interfering with regulatory B7-CTLA-4 interactions. 13,14 Indeed, given the complexity of B7-CD28/CTLA-4 interactions, B7-mediated costimulation is not necessarily equivalent to CD28-mediated costimulation. Therefore, direct manipulation of CD28 and CTLA-4 may be preferable to B7 blockade.…”

Section: Introductionmentioning

confidence: 99%

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Zhu

Gao

et al. 2010

Cell Mol Immunol

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CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid (No. 9) with a molecular formula of C 21 H 29 N 3 O 7 , was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.

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“…Abatacept is a soluble fusion protein of the extracellular domain of CTLA-4 and the modified Fc portion of human IgG1 that eliminates complement activation (12,13). It has been shown to be effective in models of autoimmunity (14,15), which has led to its clinical application as a treatment for RA. As therapeutic approaches move increasingly toward early intervention and prevention, there is renewed interest in understanding the modes of action of existing biologic agents that might lend themselves to the earliest use in the autoimmune disease paradigm.…”

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confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Distinct roles for B7-1 (CD-80) and B7-2 (CD-86) in the initiation of experimental allergic encephalomyelitis.

Cited by 184 publications

References 62 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)

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

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