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Iron chelators: correlation between effects on Plasmodium spp. and immune functions.
Jacob Golenser1, Abraham Domb, Talya Mordechai-Daniel
1Department of Parasitology-The Kuvin Center for the Research of Infectious and Tropical Diseases, The Hebrew University of Jerusalem, Jerusalem, Israel. golenser@md.huji.ac.il
The Journal of Parasitology
|April 25, 2006
Summary
Iron chelators show in vitro efficacy against malaria parasites but limited human protection. In vivo studies revealed that immune modulation, not just direct parasite killing, influences malaria recovery, suggesting a need to evaluate immune interactions for drug development.
Area of Science:
- Immunology and Infectious Diseases
- Pharmacology and Drug Development
Background:
- Iron chelating agents demonstrate in vitro effectiveness against Plasmodium falciparum.
- However, their therapeutic effect in human malaria is often transient and incomplete.
Purpose of the Study:
- To evaluate the in vitro and in vivo antiplasmodial efficacy of novel iron chelators (MoB) compared to established agents (DFO, SIH; together DoS).
- To investigate the impact of these iron chelators on immune cell proliferation, cytokine production, and radical scavenging.
Main Methods:
- In vitro assessment of iron chelators against Plasmodium falciparum.
- In vivo malaria model using Plasmodium vinckei-infected mice treated with iron chelators.
- Analysis of B cell and T cell proliferation, mixed lymphocyte reaction (MLR), and immune mediator (IL-10, gamma-IFN, TNF-alpha, radicals) production.
Main Results:
- MoB showed superior in vitro antiplasmodial activity compared to DoS.
- In vivo, DoS-treated mice survived Plasmodium vinckei infection, while MoB-treated mice succumbed, despite similar pharmacokinetics.
- Iron chelators broadly inhibited immune cell proliferation; DoS modulated cytokine profiles (decreased IL-10, increased gamma-IFN, TNF-alpha) correlating with survival, while MoB did not.
Conclusions:
- In vivo efficacy of iron chelators is influenced by their immunomodulatory effects, not solely direct antiplasmodial activity.
- Drugs that inhibit crucial protective immune responses, like MoB, may fail in vivo despite potent in vitro activity.
- Future antiparasitic drug development should consider immune system interactions to ensure therapeutic success and avoid detrimental effects.