Browsing Department of Pediatrics: Faculty Research and Presentations by Authors
FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid ProgenitorsMakala, Levi HC; Di Maro, Salvatore; Lou, Tzu-Fang; Sivanand, Sharanya; Ahn, Jung-Mo; Pace, Betty S.; Department of Pediatrics (2012-05-14)Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD.
Novel Therapeutic Approaches to Leishmania InfectionMakala, Levi HC; Baban, Babak; Department of Pediatrics; Department of Oral Biology (InTech, 2014-03-19)Leishmaniasis is a parasitic disease transmitted by phlebotomine sandflies. Approximately 1.2 million cases of cutaneous leishmaniasis (CL) and 500,000 cases of visceral leishmaniasis (VL), which is lethal if untreated, occur annually across the globe as per world health organization (WHO) estimates [1-3]. Current statistics and information relevant to leishmaniasis are summarized in Table 1. Leishmaniasis currently affects about 12 million people and it is estimated that approximately 350 million people live in risk of infection [1-3].The number of cases of leishmaniasis is probably underestimated because only 40 of the 88 countries where diseases frequently occur report them on a regular basis . Leishmaniasis, is caused by several leishmania spp., that are obligate intracellular and unicellular kinetoplastid protozoan flagellate that establish themselves within the phagolysosome of host immune competent cells, especially macrophages and dendritic cells (DCs). In 1903, W.B. Leishman and C. Donovan reported this new parasite at the turn of the century [5,6]. Ronald Ross christened the new genus leishmania and the new species donovani in year 1903 . L. major infection (leishmaniasis) in mice is a widely used model of human infection that has yielded critical insights into the immunobiology of leishmaniasis [8-10]. Leishmaniasis as a parasitic disease manifests itself mainly in 3 clinical forms; visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL), of which VL is the most severe form of the disease. VL is lethal if untreated and spontaneous cure is extremely rare. Cutaneous leishmaniasis usually has milder course and often results into a self-healing of ulcers. Resolution of leishmanial infection is dependent on the coordinated interactions between components of cell mediated immune response, specifically the activation of targeted T-cell populations for appropriate cytokine production and activation of macrophages. L. major infection of B6 and BALB/c mouse strains drives predominantly TH1 and TH2 responses, respectively [11-14]. In murine model, the development of Th1 response is associated with control of infection, and Th2 response is associated with disease progression. However, Th1 and Th2 dichotomy in the human system is not as distinct as in mice and the murine model does not strictly apply to human leishmaniasis.
The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infectionMakala, Levi HC; Department of Pediatrics (2012-01-9)Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections. It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic leishmania infection in mice.