Biomedical subjects

F Tacchini-Cottier

Publications and source records attributed to F Tacchini-Cottier.

21 records · Page 2Linked to original sources

PubMed1993

An effector role for platelets in systemic and local lipopolysaccharide-induced toxicity in mice, mediated by a CD11a- and CD54-dependent interaction with endothelium.

The role of platelets was investigated in two models of lipopolysaccharide (LPS)-induced toxicity in mice: the systemic reaction, provoked by intravenous LPS injection in D-galactosamine-sensitized recipients, which results in host death, and the local reaction, elicited in the skin by sequential injections of LPS and tumor necrosis factor alpha at 24-h intervals, which results in hemorrhagic necrosis. In both models, the depletion of platelets with a rabbit polyclonal or a mouse monoclonal antiplatelet immunoglobulin G afforded significant protection. In the local reaction, studies of the distribution of 111In-labelled platelets as well as optical and electron microscopy showed that platelets are localized in the dermal venules before hemorrhage occurs. Anti-CD11a (LFA-1) and anti-CD54 (ICAM-1) monoclonal antibodies prevented both platelet localization and hemorrhagic necrosis, and these determinants were detected on mouse platelets by immunofluorescence. The antiplatelet monoclonal antibody did not reduce the localization of polymorphonuclear leukocytes in the dermal venules, as shown by histological sections. Thus, in the local reaction, the stimulation with LPS and tumor necrosis factor alpha leads to a binding of platelets to the endothelium of venules by their beta 2 integrins, which seems necessary for the development of the hemorrhagic necrosis.

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PubMedDate not supplied

Some of the early events underlying Th2 cell maturation and susceptibility to Leishmania major infection in BALB/c mice.

The first experimental evidence for the development of polarized CD4+ Th1 and Th2 responses in vivo has been obtained using the murine model of infection with Leishmania major, an intracellular parasite of macrophages in their vertebrate host. Genetically determined resistance and susceptibility to infection with this parasite have been clearly demonstrated to result from the development of polarized Th1 and Th2 responses, respectively. Using this model system, the dominant role of cytokines in the induction of polarized CD4+ responses has been validated in vivo. The requisite role of IL-4 in mediating both Th2 differentiation and susceptibility to infection in BALB/c mice has directed interest towards the search for evidence of IL-4 production early after infection and identification of its cellular source. We have been able to demonstrate a burst of IL-4 production in susceptible BALB/c mice within the first day of infection with L. major and could establish that this rapidly produced IL-4 instructed Th2 lineage commitment of subsequently activated CD4+ T cells and stabilized this commitment by downregulating IL-12 Rbeta2 chain expression, resulting in susceptibility to infection. Strikingly, this early IL-4 response to infection resulted from the cognate recognition of a single epitope in a distinctive antigen, LACK, from this complex microorganism by a restricted population of CD4+ T cells that express Vbeta4-Valpha8 T cell receptors.

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PubMedDate not supplied

TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction.

Pathogenic mechanisms of brain microvascular injury were studied in an experimental model of cerebral malaria (CM). The lesion, leading to perivascular microhemorrhages, is due to cytokine overproduction, and is associated with the sequestration of macrophages and parasitized erythrocytes in cerebral venules. In this in vivo model, we demonstrate that platelets are critical effectors of the neurovascular injury. First, electron microscopy indicated that during CM platelets adhere to and probably damage brain endothelial cells. Second, radiolabelled platelet distribution studies indicated that platelets sequestered in the brain and lung vasculature during CM. Non-cerebral malaria was not associated with cerebral sequestration of platelets. Third, in vivo treatment with a mAb to LFA-1 (which is expressed on platelets) selectively abrogated the cerebral sequestration of platelets, and this correlated with prevention of CM. Fourth, malaria-infected animals rendered thrombocytopenic were significantly protected against CM, further indicating that platelets are central to the pathogenesis of CM. Thus, a CD11a-dependent interaction between platelets and endothelial cells appears pivotal to microvascular damage. These data suggest a novel mechanism of action for anti-LFA-1 mAb in vivo and illustrate an unexpected role of platelets, in addition to monocytes, in vascular pathology.

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