EXPERIMENTAL IMMUNOREGULATION OF HOST RESPONSIVENESS TO ANTILEISHMANIAL CHEMOTHERAPY AND NEW TREATMENTS FOR PATIENTS WITH VISCERAL LEISHMANIASIS (KALA-AZAR)
BASIC RESEARCH LABORATORY. There is no vaccine to prevent human visceral leishmaniasis (VL), a disseminated intracellular protozoal infection, and the efficacy of conventional chemotherapy is declining. Thus, to develop new treatment strategies, this laboratory's research is focused on characterizing the immunoregulatory mechanisms of the successful host response to antileishmanial chemotherapy in a mouse model of VL. This project's objective is to experimentally manipulate these mechanisms in vivo in favor of the host receiving treatment to enhance the killing of intracellular Leishmania donovani and thereby optimize the host response to chemotherapy.
In vivo responses to two clinically appropriate chemotherapeutic probes, pentavalent antimony and amphotericin B, are used to test basic hypotheses to identify critical immunoregulation of the host response to treatment at four levels: (1) the basic antileishmanial pathways of the macrophage, the targeted host defense cell, (2) effector monocyte and T cell influx and action in parasitized tissue granulomas, (3) key activating and deactivating cytokines, and (4) in the intact animal with uncontrolled visceral infection.
Our basic aims in experimental VL are to: (1) characterize endogenous host defense mechanisms in the leishmanicidal action of antimony and amphotericin B, and immuno-logically enhance the efficacy of both of these clinically-relevant chemotherapeutic agents; and (2) then test the rational application of this combination immunochemotherapy in uncontrolled visceral infection in experimentally-infected animals.
CLINICAL INVESTIGATION UNIT (India). In our 15-year old, established clinical treatment trials and diagnostic unit in Bihar State, India (the epicenter of the world's largest focus of VL (kala-azar), we have carried out the studies which have defined the following in patients with VL: (1) the usefulness of experimental immunotherapy using interferon-gamma, (2) the high-level efficacy of short-course (even single-dose) treatment using lipid formulations of amphotericin B, (3) the high-level efficacy of the first effective oral treatment in VL, miltefosine, and (4) the effect of combination chemotherapy. Additional work has demonstrated the feasibility of non-invasive, rapid diagnosis of VL using fingerstick blood and an antibody-detecting strip test which can safely replace invasive tissue aspiration in diagnosis.