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American Journal of Pathology, Vol 150, 257-266, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Resistance to cerebral malaria in tumor necrosis factor-alpha/beta- deficient mice is associated with a reduction of intercellular adhesion molecule-1 up-regulation and T helper type 1 response

W Rudin, HP Eugster, G Bordmann, J Bonato, M Muller, M Yamage and B Ryffel
Swiss Tropical Institute, Basel, Switzerland.

Tumor necrosis factor (TNF) induced by Plasmodium berghei ANKA (PbA) infection was suggested to play an important role in the development of cerebral malaria (CM). We asked whether TNF-alpha/beta double-deficient mice, which have a complete disruption of the TNF-signaling pathways, are protected from CM and what might be the possible mechanisms of protection. PbA infection induces fatal CM in wild-type mice, which die within 5 to 8 days with severe neurological signs. In contrast, TNF- alpha/beta-deficient mice are completely resistant to PbA-induced CM. As PbA-induced up-regulation of endothelial intercellular adhesion molecule (ICAM)-1 expression as well as the systemic release of nitric oxide is found only in wild-type mice, TNF is apparently central for the recruitment of mononuclear cells and microvascular damage. Mononuclear cell adhesion to the endothelium, vascular leak and, perivascular hemorrhage are found only in the brain of wild-type mice. By contrast, the development of parasitemia and anemia is independent of TNF. Resistance to CM in TNF-alpha/beta-deficient mice is associated with reduced interferon-gamma and interleukin-12 expression in the brain, in the absence of increased T helper type 2 cytokines. In conclusion, TNF apparently is required for PbA-induced endothelial ICAM- 1 up-regulation and subsequent microvascular pathology resulting in fatal CM. In the absence of TNF, ICAM-1 and nitric oxide up-regulation are reduced, and PbA infection fails to cause fatal CM.

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