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Late treatment with anti-LFA-1 (CD11a) antibody prevents cerebral malaria in a mouse model
1Department of Pathology, Stanford University Medical Center.
Abstract:
CBA/Ca mice injected with Plasmodium berghei develop cerebral malaria (CM) characterized by ataxia and progressive paralysis leading to death 7-9 days after experimental infection. The development of cerebral symptoms is a function of the immune response in susceptible strains, and depends on cell-cell interactions involving T helper cells and mononuclear phagocytes. Here we ask whether antibodies to cell adhesion receptors of the immune system can influence the development of CM in this mouse model. When administrated on day 6 after infection, antibody to the leukocyte integrin leukocyte function-antigen-1 (LFA-1) but not antibodies to MAC-1, LECAM-1 (the MEL-14 antigen), alpha 4 integrin or ICAM-1 dramatically reduced the incidence of CM, leading to survival of most mice until the later onset of anemia. Anti-LFA-1 treatment did not result in a substantial decrease in the monocyte accumulation observed in cerebral vessels of susceptible mice. Its efficacy may be related to the broader roles of LFA-1 in cell-cell interactions important in the later pathogenic stages of the immune response to the parasite. Perturbation of immune cell function through interference with cell adhesion mechanisms may offer an important therapeutic tool in acute, life-threatening immune-mediated disorders.
Insights
Targeting leukocyte function-antigen-1 (LFA-1) with antibodies significantly reduced cerebral malaria (CM) incidence in mice. This immune cell adhesion intervention offers a potential therapeutic strategy for severe immune-mediated disorders.
Area of Science:
- Immunology
- Parasitology
- Neuroscience
Background:
- Cerebral malaria (CM) in CBA/Ca mice infected with Plasmodium berghei causes ataxia, paralysis, and death.
- CM development is linked to immune responses and cell-cell interactions involving T helper cells and mononuclear phagocytes.
Purpose of the Study:
- To investigate if antibodies targeting immune cell adhesion receptors can prevent CM development in a mouse model.
- To assess the efficacy of antibodies against specific adhesion molecules in mitigating CM.
Main Methods:
- CBA/Ca mice were infected with Plasmodium berghei.
- Antibodies against leukocyte function-antigen-1 (LFA-1), MAC-1, LECAM-1, alpha 4 integrin, and ICAM-1 were administered on day 6 post-infection.
- Incidence of CM and survival rates were monitored.
Main Results:
- Antibody targeting LFA-1 dramatically reduced CM incidence, improving survival until later anemia onset.
- Antibodies against MAC-1, LECAM-1, alpha 4 integrin, or ICAM-1 did not significantly affect CM development.
- Anti-LFA-1 treatment did not substantially alter monocyte accumulation in cerebral vessels.
Conclusions:
- Interference with leukocyte function-antigen-1 (LFA-1) adhesion is a promising therapeutic strategy for cerebral malaria.
- Targeting cell adhesion mechanisms offers potential therapeutic avenues for acute, life-threatening immune-mediated disorders.
