Cutting Edge: T Cells Trigger CD40-Dependent Platelet Activation and Granular RANTES Release: A Novel Pathway for Immune Response Amplification

Danese, Silvio; Motte, Carol A. de la; Reyes, Brenda M Rivera; Sans, Miquel; Levine, Alan D.; Fiocchi, Claudio

doi:10.4049/jimmunol.172.4.2011

Cited by 160 publications

(134 citation statements)

References 26 publications

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“…CD40-CD40L interactions can induce many cell-mediated inflammatory and immune responses. The release of such mediators can amplify the immune response to antigen by inducing further activation of T-lymphocytes (Danese et al, 2004). CD40L has been identified on activated platelets (Henn et al, 1998), and is functionally active, mediating IgM-IgG isotype switching, a crucial event in humoral immunity (Elzey et al, 2003).…”

Section: Platelet Involvement In Antigen Recognitionmentioning

confidence: 99%

“…CD40L has been identified on activated platelets (Henn et al, 1998), and is functionally active, mediating IgM-IgG isotype switching, a crucial event in humoral immunity (Elzey et al, 2003). CD40L can also lead to the activation of endothelial cells to have a proinflammatory phenotype (Danese et al, 2004). Indeed, stimulation of endothelial cells by platelets expressing CD40L significantly contributes to inflammatory cell recruitment in atherosclerosis (Buchner et al, 2003).…”

Section: Platelet Involvement In Antigen Recognitionmentioning

confidence: 99%

“…CD40L is therefore a very attractive drug target for inhibiting platelet activation as it can induce an inflammatory cascade centred on the activation of endothelium and T cells (Buchner et al, 2003;Danese et al, 2004). Few reports exist of studies describing CD40 antagonism, although a monoclonal antibody (5D12) is currently being tested for the treatment of Crohn's disease (Kasran et al, 2005).…”

Section: Future Drug Targetsmentioning

confidence: 99%

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Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford

2007

British J Pharmacology

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An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well‐characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non‐atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti‐platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases.British Journal of Pharmacology (2007) 152, 987–1002; doi:10.1038/sj.bjp.0707364; published online 2 July 2007

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Section: Platelet Involvement In Antigen Recognitionmentioning

confidence: 99%

Section: Platelet Involvement In Antigen Recognitionmentioning

confidence: 99%

Section: Future Drug Targetsmentioning

confidence: 99%

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Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford

2007

British J Pharmacology

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“…Moreover, CD40L-positive T cells have been shown to bind directly to CD40-expressing platelets, activate them, and trigger granular RANTES release, creating a T cell recruitment feedback loop in vitro. 17 Therefore, the aims of our study were (i) to investigate the recruitment of T cell subpopulations in the postischemic hepatic microvasculature in vivo, in particular, the type, microvascular localization, and kinetics of T cellendothelial cell interactions; (ii) to analyze whether and by which mechanisms T cells interact with platelets in the postischemic hepatic microcirculation; (iii) to test the hypothesis that T cells activate hepatic endothelial cells during I/R and in this way aggravate platelet and neutrophil accumulation and contribute to microvascular I/R injury.…”

Section: Iver Injury Induced By Ischemia/reperfusion (I/r)mentioning

confidence: 99%

CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets

et al. 2006

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The mechanisms by which T cells contribute to the hepatic inflammation during antigenindependent ischemia/reperfusion (I/R) are not fully understood. We analyzed the recruitment of T cells in the postischemic hepatic microcirculation in vivo and tested the hypothesis that T cells interact with platelets and activate sinusoidal endothelial cells, resulting in microvascular dysfunction followed by tissue injury. Using intravital videofluorescence microscopy, we show in mice that warm hepatic I/R ( L iver injury induced by ischemia/reperfusion (I/R) is the critical factor in delayed or lost graft function after transplantation. The hepatic microcirculation is considered as the primary target of I/R injury of the liver. [1][2][3][4] The microvascular hepatic I/R injury is initiated by the release and action of proinflammatory cytokines and oxygen radicals, which trigger upregulation of adhesion molecules, intravascular deposition of fibrinogen, and interaction of neutrophils as well as platelets with the endothelial lining of the hepatic microvasculature. [5][6][7][8] The failure of nutritive sinusoidal perfusion results in prolongation of focal hypoxia or anoxia and loss of endothelial integrity, which together lead to edema formation and oncotic necrosis. 1 Recent studies suggest that, in addition to neutrophils and platelets, T cells are involved in the induction of I/R injury of the liver. 9-11 Based on classic models of tissue injury, T cells were not suspected to play a role in postischemic tissue damage. However, the surprising protective effect of immunosuppressive drugs on the antigenindependent postischemic liver injury, 12,13 as well as reduction of hepatic postischemic damage in athymic mice, 9 point to a potential role of T cells. The mechanisms by which T cells contribute to hepatic I/R injury are

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“…Platelets were fixed in 1% paraformaldehyde and incubated with Abs against CD40L (FITC-conjugated-anti-CD40L; BD Biosciences), or CD42b (Santa Cruz Biotechnology), for 30 min at room temperature. PBT were analyzed before and after a 24-h stimulation with polystyrene beads coated with murine mAbs to human CD3 and CD28 (Dynal), in the presence or absence of infliximab, and stained for CD40L as described elsewhere (36). In some experiments, PBT were stained with propidium iodide and analyzed for DNA content (37).…”

Section: Flow Cytometric Studies For Detection Of Cell Surface Molecumentioning

confidence: 99%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

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153

101

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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

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Cutting Edge: T Cells Trigger CD40-Dependent Platelet Activation and Granular RANTES Release: A Novel Pathway for Immune Response Amplification

Cited by 160 publications

References 26 publications

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

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