Late treatment with anti‐LFA‐1 (CD11a) antibody prevents cerebral malaria in a mouse model

Falanga, Pierre B.; Butcher, Eugene C.

doi:10.1002/eji.1830210938

Cited by 68 publications

(44 citation statements)

References 32 publications

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“…Numerous studies have illustrated that activated T cells that are sequestered in the brain contribute to CM (8,27). Treatment of mice with anti-LFA-1 mAb inhibiting LFA-1/ICAM-1 interaction and thereby adhesion of T cells to the endothelium prevents mice from developing CM (28,29). Moreover, the development of CM in PbA-infected C57BL/6 mice is strongly dependent on the production of proinflammatory cytokines during the course of infection (11,30).…”

Section: Discussionmentioning

confidence: 99%

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Lepenies

Pfeffer

Hurchla

et al. 2007

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA; CD272) is a coinhibitory receptor that is predominantly expressed on T and B cells and dampens T cell activation. In this study, we analyzed the function of BTLA during infection with Plasmodium berghei ANKA. Infection of C57BL/6 mice with this strain leads to sequestration of leukocytes in brain capillaries that is associated with a pathology resembling cerebral malaria in humans. During the course of infection, we found an induction of BTLA in several organs, which was either due to up-regulation of BTLA expression on T cells in the spleen or due to infiltration of BTLA-expressing T cells into the brain. In the brain, we observed a marked induction of BTLA and its ligand herpesvirus entry mediator during cerebral malaria, which was accompanied by an accumulation of predominantly CD8+ T cells, but also CD4+ T cells. Application of an agonistic anti-BTLA mAb caused a significantly reduced incidence of cerebral malaria compared with control mice. Treatment with this Ab also led to a decreased number of T cells that were sequestered in the brain of P. berghei ANKA-infected mice. Our findings indicate that BTLA-herpesvirus entry mediator interactions are functionally involved in T cell regulation during P. berghei ANKA infection of mice and that BTLA is a potential target for therapeutic interventions in severe malaria.

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Section: Discussionmentioning

confidence: 99%

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Lepenies

Pfeffer

Hurchla

et al. 2007

The Journal of Immunology

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“…This pathogenic hypothesis is supported by the increased expression of CD54 and CD106 in the brain microcirculation during SM and the delayed mortality seen in mice treated with anti-CD11a mAb (LFA-1, a ␤2 integrin determinant) 6,17 or in CD54-deficient mice. 18 CD40 is a cell receptor belonging to the TNF receptor superfamily that can modulate cell proliferation, differentiation, and death. 19 Studies based on mice genetically deficient in CD40 or its ligand CD40L (CD154) as well as the use of anti-CD40L mAb have demonstrated that this system plays an important role in both humoral and cellmediated immunity.…”

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confidence: 99%

Role of CD40-CD40L in Mouse Severe Malaria

Piguet

Kan

Vesin

et al. 2001

The American Journal of Pathology

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We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in ؉/؉ mice, but markedly decreased in CD40؊/؊ or in CD40L؊/؊ mice, as well as in ؉/؉ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected ؉/؉, but not in CD40؊/؊ mice. Thrombocytopenia was less severe in CD40؊/؊ mice than in the ؉/؉ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40؊/؊ or in CD40L؊/؊ mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected ؉/؉ or CD40؊/؊ mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption.

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“…Upregulation of ICAM-1 expression in the vascular endothelium is reported for human (24), simian (25), and murine (26,27) severe malaria. It has been demonstrated that ICAM-1 is coexpressed with CD36, thrombospondin, VCAM-1, and E-selectin on the brain microvasculature of postmortem samples of patients who had died of cerebral malaria.…”

Section: Discussionmentioning

confidence: 94%

“…It was found to bind IRBC in vitro (7). During acute-phase malaria, ICAM-1 is expressed by the vascular endothelium of the brain (24)(25)(26)(27). In the SCID mice used as Plasmodium hosts in these experi- ments, acute-phase ICAM-1 expression was induced by treatment with LPS.…”

Section: Resultsmentioning

confidence: 99%

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

Willimann

Matile

Weiss

et al. 1995

The Journal of Experimental Medicine

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SummaryCerebral malaria is a fatal complication of infection by Plasmodiumfakiparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P.fakiparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. fakiparum-infected erythrocytes to the ICAM-l-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study ofP.fakiparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.p , lasmodium falciparum, one of the four plasmodium spedes that infect man, produces a fulminant disease that can lead to severe cerebral symptoms. Every year, this parasite causes about 250 million clinical cases of malaria (1). Approximately 2 million individuals, mainly children under 5 years of age, die from the main complications, which are cerebral malaria and severe anemia. A special feature of P. falciparum pathology is the absence of mature intraerythrocytic stages of the parasite in the circulating blood. Mature forms are found attached to the lining of microvessels in peripheral organs. This adhesion of infected erythrocytes to the vascular endothelium is called sequestration. Clinically severe neurological symptoms correlate with a much higher frequency of sequestered parasitized erythrocytes in the brain vasculature compared to other organs (2).Sequestration is thought to depend on differences between P.fakiparum strains leading to the expression of different erythrocyte surface molecules mediating adhesion to endothelia, as well as variation in the production of endotoxins eliciting a TNF-ot response by host macrophages (3). Thus, sequestration depends also on the susceptibility of the host to endotoxins, the subsequent regulation of adhesion molecules, and the host's level of immunity (4). A key role is played by TNF. Its plasma concentration levels are elevated in patients with fatal cerebral m...

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Late treatment with anti‐LFA‐1 (CD11a) antibody prevents cerebral malaria in a mouse model

Cited by 68 publications

References 32 publications

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Role of CD40-CD40L in Mouse Severe Malaria

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

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