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Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral
G E Grau1, P Pointaire, P F Piguet
1Department of Pathology, CMU, University of Geneva, Switzerland.
Abstract:
We analyzed the role of adhesion molecules in the pathogenesis of experimental cerebral malaria (ECM), since tumor necrosis factor (TNF) plays a major role in this condition and has been shown to up-regulate in vitro expression of cell adhesion molecules (CAM), particularly intercellular CAM-1 (ICAM-1). We found increased expression of ICAM-1 on brain endothelial cells from mice with ECM. Treatment with monoclonal antibodies (mAb) directed against leukocyte function-antigen 1 (LFA-1, the ligand of ICAM-1) on days 6, 8 and 10 almost totally prevented ECM, while decreasing blood TNF levels. To exclude the possibility that the effects of anti-LFA-1 mAb resulted from an even partial inhibition of TNF overproduction, mice with signs of imminent death (hypothermia and neurologic defects) were treated with the anti-LFA-1 mAb, with dramatically protective effect. In contrast, injection of anti-ICAM-1 mAb on day 6 caused rapid death, while it was innocuous in normal mice. An mAb directed against complement receptor type 3 (CR3) was ineffective, as were injections of soluble human ICAM-1. These results suggest that adhesion of LFA-1+ cells to endothelial cells, stimulated by TNF to express high levels of ICAM-1, is critical in the pathogenesis of ECM. Emergency therapy at interfering with cytoadherence could be considered in the treatment of cerebral malaria in man, in which high blood TNF levels are also observed.
Insights
Targeting leukocyte function-antigen 1 (LFA-1) adhesion molecules with monoclonal antibodies prevented experimental cerebral malaria (ECM) and reduced tumor necrosis factor (TNF) levels, suggesting a critical role for cell adhesion in ECM pathogenesis.
Area of Science:
- Immunology
- Pathology
- Neuroscience
Background:
- Tumor necrosis factor (TNF) is crucial in experimental cerebral malaria (ECM) pathogenesis.
- TNF up-regulates cell adhesion molecules (CAMs), such as intercellular CAM-1 (ICAM-1).
- Increased ICAM-1 expression is observed on brain endothelial cells during ECM.
Purpose of the Study:
- To investigate the role of adhesion molecules in ECM pathogenesis.
- To evaluate the therapeutic potential of targeting ICAM-1/LFA-1 interactions.
Main Methods:
- Analysis of ICAM-1 expression in mice with ECM.
- Treatment with monoclonal antibodies (mAbs) against LFA-1, ICAM-1, and complement receptor type 3 (CR3).
- Assessment of ECM development, mortality, and TNF levels post-treatment.
Main Results:
- Increased ICAM-1 expression on brain endothelial cells in ECM mice.
- Anti-LFA-1 mAb treatment significantly prevented ECM and reduced TNF levels.
- Treatment with anti-LFA-1 mAb even in late-stage ECM showed protective effects.
- Anti-ICAM-1 mAb treatment exacerbated mortality in ECM mice.
- Anti-CR3 mAb and soluble ICAM-1 were ineffective.
Conclusions:
- Adhesion of LFA-1-expressing cells to TNF-induced ICAM-1 on endothelial cells is critical for ECM pathogenesis.
- Interfering with LFA-1/ICAM-1-mediated cytoadherence is a potential therapeutic strategy for cerebral malaria.
- This approach may be relevant for human cerebral malaria, which also involves elevated TNF levels.