Name: Ibrahim Mustafa
Date: Monday, July 18, 2011 at 9:00 AM
The Maldives has one of the highest incidences of ß thalassemia in the world. Treatment of ß thalassemia is characterized by two distinct phases: treatment of nature’s disease (anemia) and the secondary treatment of transfusional iron overload, a side effect of our cure. Interestingly, excess iron may also exert a negative effect on immune competence thus explaining the recurrent bacterial infections in these patients. Current iron chelation therapy using DesferalÒ (DFO) is challenging due to its short vascular half-life, frequency of injections, toxicity and expense. To address this problem, we have tested novel, low toxicity, high molecular weight (HMW) iron chelators. The utility of these chelators was tested in vitro using iron loaded (0-500 μM ferric (Fe3+) ammonium citrate, FAC; 0- 48 hours) HepG2 and dendritic cells (DC). Iron chelation studies utilized either single or combinational treatment with deferiprone (L1) or DFO (both low molecular weight chelators) and S-DFO (a HMW derivative of DFO) for 0-48 hrs. The efficacy of treatment was assessed by cellular ferritin, Perl’s iron stain, transmission electron microscopy (TEM), antigen presentation assays and cell viability assays. Iron treatment alone resulted in a significant increase in intracellular ferritin, histochemical iron staining and also resulted in a ~65.2% reduction in PBMC proliferation in response to the tetanus toxoid following 14 days of incubation.
Treatment with either L1 or S-DFO alone demonstrated modestly decreased ferritin levels and iron staining. Importantly, combination therapy (L1+S-DFO), resulted in an additive effect resulting in a 79% decrease in FAC-driven ferritin levels after 48 hours and TEM studies of FAC treated, but not control, cells. FAC treated cells also demonstrated organellular and structural changes with electron dense iron deposits. As hypothesized, iron chelators (e.g., 200 μM DFO or L1) restored the PBMC proliferation in a concentration dependent manner and reversed the ultra structural changes in organelles. The development of HMW chelators may provide better therapeutic value (less toxic and less frequent administration) in developing nations. Consequent to this, iron mediated pathology in patients would be diminished resulting in less cost to already strained public health budgets such as in Maldives.