The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379–385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279–281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and γ interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.

44 mg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kB (phospho-NF-kB p65), interferon-g (IFN-g), and A 2A R.Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-kB p65 and A 2A R expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-g expression was also significantly higher compared with controls (P 5 .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-kB p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P 5 .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 mg/kg/h during pVOC decreases activation of iNKT cells without toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01085201. (Blood. 2013;121(17):3329-3334)

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