Essential role of tumor necrosis factor and other cytokines in the pathogenesis of cerebral malaria: experimental and clinical studies.
A natural body protein is probably a major cause of the deadliest complication of malaria, a finding that could point toward new methods of treatment. Studies in an experimental model indicate that tumor necrosis factor (TNF), a protein also known as cachectin, is an essential element in highly fatal cerebral malaria. This contention is supported by the following observations. First, during the course of an infection by P. berghei ANKA strain, mice of a CM-susceptible strain express markedly elevated levels of TNF in their serum at the time that neurological signs are evident. Second, in contrast, either mice from nonsusceptible strains, susceptible strains depleted of CD4+ T lymphocytes, or susceptible mice inoculated with malaria organisms incapable of producing CM all fail to express high serum TNF activity. Third, passive immunization against mouse TNF significantly prolong the survival of P. berghei-infected CBA/Ca mice, and prevented the development of neurologic signs to an extent that was highly significant. Treatment with the anti-TNF antibody also prevents the histopathological lesions that are characteristic of CM, i.e. plugging of cerebral vessels by macrophages, lymphoid and parasitized erythrocytes. We have recently shown that this increased TNF release and macrophage accumulation are schematically made of two components, each mediated by different cytokines presumably released by stimulated CD4+ T lymphocytes: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Thus, CM appears to be the result of a cytokine cascade mediated by the immune response. TNF might also be involved in the pathogenesis of human cerebral malaria. Indeed, we have recently shown that in african children with falciparum malaria, elevated serum concentrations of this molecule are associated with severe neurological involvement and fatal outcome. Clinical trials of treatment with monoclonal anti-TNF antibodies are presently underway in an attempt to reduce mortality and morbidity in african children with cerebral malaria.
Grau
G E
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Department of Pathology, University of Geneva, Zwitzerland.
D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002675:Child, Preschool; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008808:Mice, Inbred CBA; D011379:Prognosis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor