Role of polymorphonuclear neutrophil leukocytes and their integrin CD11a (LFA-1) in the pathogenesis of severe murine malaria.

Infection of CBA mice with Plasmodium berghei ANKA results in severe malaria, which is characterized by mortality 6 to 10 days after infection and is associated with alterations of the brain microcirculation. These alterations consist of (i) intravascular sequestration of monocytes, (ii) an increase in vascular permeability as documented by Evans blue diffusion, and (iii) microhemorrhages. This syndrome may be due to an increase of production of tumor necrosis factor alpha which upregulates the endothelial expression of ICAM-1 and thus leads to adhesion of CD11a/CD18 (LFA-1)-bearing cells. During severe malaria, we found an important sequestration of the CD11a-bearing polymorphonuclear neutrophil leukocytes (PMN) in the lung but not in the brain. Treatment with a monoclonal antibody (MAb) against PMN, which induces profound neutropenia, prevented mortality and Evans blue diffusion in the brain and the lung, while it unexpectedly increased the occurrence of microhemorrhages. The anti-PMN MAb abolished PMN sequestration in the lung and also partially decreased monocyte sequestration in the brain and the lung. Treatment with an anti-CD11a MAb also prevented mortality, Evans blue diffusion, and PMN and monocyte sequestration. This study shows that PMN contribute to the mortality and the microvascular lesions resulting from severe malaria. This may be due to their CD11a-dependent sequestration in the lung and also to their indirect influence on vascular permeability and the sequestration of monocytes.     

Le rôle des représentations de la maladie et de la douleur dans la relation patient-thérapeute

Résumé  La rencontre entre patient et thérapeute dans la relation de soins met en présence non seulement deux individus, mais aussi deux systèmes de pensée. Elle suppose donc l'articulation de deux types de savoirs, profane d'une part et scientifique d'autre part. La clarification et la prise en compte des représentations du patient à propos de l'atteinte dont il souffre constitue un enjeu important de la relation. Il en va de même des attentes du thérapeute par rapport à ce qu'il considère comme un comportement douloureux adéquat, par exemple. Faute de la prise en compte des modèles de référence explicites et implicites tant du patient que du thérapeute, la relation peut déboucher sur des malentendus, des réactions d'agressivité, d'anxiété, et conduire à une rupture de cette relation.

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Summary  The patient-therapist relationship involves not only two individuals, but also two systems of thinking. It calls forth lay knowledge on the one hand and scientific knowledge on the other hand. The patient's representations about his pain and suffering may play an important role in the patient-health care provider relationship and thus need to be clarified and taken into account. This need also holds true where the therapist's expectations are concerned, for example with regard to what is considered as an adequate pain behavior. Failing to take into account the explicit and implicit models of both the patient and the therapist may lead to misunderstandings, aggressive behaviors, anxious reactions, and thus hamper or even disrupt the patient-therapist relationship.

     

Role of mast cells and monoamines in the thrombocytopaenia and mortality elicited by tumour necrosis factor in mice.

We explored the thrombocytopaenia elicited by the i.v. injection of mouse recombinant tumour necrosis factor (TNF) in mice. Injection of 10 micrograms of TNF led to a thrombocytopaenia (evident after 0.5 hr) which was caused by decreased platelet survival, as seen by the injection of labelled platelets. TNF-induced thrombocytopaenia was not prevented by heparin, nor by depletion of either fibrinogen or C'. TNF-induced thrombocytopaenia was markedly attenuated in mice treated with reserpine, an agent that depletes monoamines from mast cells and other cells, and in the mast-cell-deficient WWv mice. In vitro, TNF elicited a modest release of monoamine from peritoneal mast cells and from a mast cell line. When mice are injected with 3H-serotonin (3H-5HT) before TNF, TNF injection increased the plasma 3H-5HT content 1 hr later, modifications absent in reserpine pretreated or mast-cell-deficient mice. 3H-5HT content of the small intestine was markedly depleted in TNF-injected mice, suggesting that this organ is the source of the plasma 3H-5HT. Drop in body temperature and mortality induced by TNF were also attenuated in mast-cell-deficient, and in reserpine pretreated mice. These results indicate that TNF can induce a release of monoamines from mast cells, mainly from those of the small intestine, a process that contributes to TNF-induced thrombocytopaenia and mortality.     

Transduction of dendritic cells by antigen-encoding lentiviral vectors permits antigen processing and MHC class I-dependent presentation

BACKGROUND: Because antigen-presenting dendritic cells (DCs) play a major role in the polarization of T cells, including T(H)2 cells involved in allergy, strategies to modify DCs genetically are required. OBJECTIVE: The purpose of this investigation was to transduce murine bone marrow-derived DCs with lentiviral vectors encoding antigen to demonstrate antigen processing and MHC class I-dependent presentation. METHODS: Bone marrow leukocytes were incubated with antigen-encoding lentiviral constructs and cultured with GM-CSF, IL-4, and Flt-3 ligand. The capacity of the resulting DCs to express, process, and present antigen was tested in vitro. RESULTS: An average of 40% of DCs expressed antigen after 1 week of culture when antigen encoded by the lentiviral vector construct was green fluorescent protein. To demonstrate that transduced antigen can be presented by DCs on MHC class I, we chose the lymphocytic choriomeningitis virus glycoprotein (gp) as a model antigen, inasmuch as it is recognized by CD8 T cells from transgenic mice expressing an MHC class I-restricted T-cell receptor specific for the epitope of positions 33 through 41 of gp. DCs transduced with lentiviral construct encoding gp and matured with LPS activated transgenic T cells in an antigen-specific fashion. Using transporter associated with antigen presentation (TAP)-deficient mice, we show that presentation of the gp33-41 epitope is TAP-dependent, confirming processing of gp by the endogenous pathway. CONCLUSIONS: These results demonstrate that CD8 T cells can recognize MHC class I epitopes processed from antigen in DCs transduced with lentiviral vectors. Lentiviral transduction of DCs and antigen presentation to CD8 T cells could be exploited for immunotherapy, because allergen-specific CD8 T cells have been shown to be suppressive in IgE-dependent allergy models.     

Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality.

The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.     

Involvement of tumour necrosis factor and other cytokines in immune-mediated vascular pathology

Vascular endothelial cells are actively involved in coagulation and inflammation processes and appear to represent an important element in cell-mediated immune responses. In this paper, the possible role of endothelial cells as a target for immunopathological reactions was analyzed. Experimental neurovascular lesions were studied in a model of cerebral malaria, with particular attention to the role of cytokine interactions in vivo.     

Expression and localization of tumor necrosis factor-alpha and its mRNA in idiopathic pulmonary fibrosis.

The expression of tumor necrosis factor alpha and its mRNA was investigated in surgical biopsies from idiopathic pulmonary fibrosis by immunohistochemistry, in situ hybridization, and Northern blotting. Normal areas of lungs resected for cancer were used as controls. Tumor necrosis factor alpha mRNA levels were higher in idiopathic pulmonary fibrosis than in normal lungs as determined by Northern blots. In normal lungs, tumor necrosis factor alpha and its mRNA were identified in alveolar and interstitial macrophages. In fibrotic lungs, tumor necrosis factor alpha was detected in macrophages and, to a greater extent, in epithelial cells (presumably type II cells) lining the thickened septae. Tumor necrosis factor alpha mRNA was found only in some interstitial cells and some of the cells lining the alveolar septae. An elevated concentration of tumor necrosis factor = alpha, particularly within the alveolar epithelium, might contribute to the alveolar damage and proliferation of interstitial cells in idiopathic pulmonary fibrosis.     

Identifying a Potential Therapeutic Host Target in Cutaneous Leishmaniasis

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