Iron chelators: correlation between effects on Plasmodium spp. and immune functions.
Iron chelating agents, which permeate through erythrocytic and parasite membranes, are effective against Plasmodium falciparum in vitro. However, the protective effect in humans is transient. We examined the antiplasmodial capacity of several iron chelators in vitro and in vivo. The chelators 3/3hb/2m and 3/2hb/b (together, MoB) were more effective against P. falciparum in vitro than desferrioxamine (DFO) and Salicylaldehyde isonicotinoyl hydrazone (SIH) (together, DoS). Despite similar pharmacokinetics of all iron chelators, mice infected with Plasmodium vinckei and treated with MoB succumbed to malaria, whereas DoS-treated mice survived. However, even in the surviving mice, peak parasitemias were above 30%. These results indicate that the direct effects of the drugs on the parasites were not responsible alone for the complete recovery of the mice. We suggest that the recovery is related to differential effects of the drugs on various immune functions. We concentrated on the effect of the iron chelators on B cell and T cell proliferation and on allogeneic stimulation (MLR), interleukin-10 (IL-10), gamma-interferon (gamma-IFN), tumor necrosis factor-alpha (TNF-alpha), and radical production. All the iron chelators examined inhibited the in vitro proliferation of B cells and T cells, and MLR. This may explain why iron chelators are only slightly efficient in treating human malaria. However, the inhibitory effects of MoB on B cell and T cell proliferation and on MLR were more pronounced than those of DoS. In addition, the release of free radicals by effector cells was inhibited to a greater extent by MoB than by DoS. These results may explain why MoB, which was more efficient in vitro, was not effective in vivo. The DoS effects on the in vitro secretion of cytokines correlate with their in vivo effect; there was a decrease of IL-10 and a parallel increase in gamma-IFN and TNF-alpha production by human mononuclear cells. MoB, which could not rescue the animals from malaria, did not affect IL-10 and TNF-alpha, but reduced gamma-IFN levels. Identical results were obtained when using monocytes instead of mononuclear cells (except for gamma-IFN, which is not produced by monocytes). Our results indicate that an iron chelator, or any antiparasitic drug that kills the parasites in vitro, should also be selected for further evaluation on the basis of its reaction with immune components; it should not interfere with crucial protective immunological processes, but it may still alleviate parasitemia by positive immune modulation.
Golenser
Jacob
J
Department 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
Domb
Abraham
A
Mordechai-Daniel
Talya
T
Leshem
Benny
B
Luty
Adrian
A
Kremsner
Peter
P
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D049449:Luminescence; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D010961:Plasmodium / Q000187:drug effects* / Q000276:immunology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000447:Aldehydes; D006835:Hydrazones; D007502:Iron Chelating Agents; D014409:Tumor Necrosis Factor-alpha; C413684:salicylaldehyde isonicotinoyl hydrazone; D016753:Interleukin-10; D003676:Deferoxamine