Abstract | BACKGROUND: Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. METHODOLOGY: To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. PRINCIPAL FINDINGS: CONCLUSIONS AND SIGNIFICANCE: Human PBMCs allow integrated ex vivo assessment of antileishmanial treatments, providing information on host and parasite determinants of therapeutic response that may be used to tailor therapeutic strategies to optimize clinical resolution.
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Authors | Laura Gonzalez-Fajardo, Olga Lucía Fernández, Diane McMahon-Pratt, Nancy Gore Saravia |
Journal | PLoS neglected tropical diseases
(PLoS Negl Trop Dis)
Vol. 9
Issue 5
Pg. e0003820
(May 2015)
ISSN: 1935-2735 [Electronic] United States |
PMID | 26024228
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antiprotozoal Agents
- IL10 protein, human
- IL13 protein, human
- Immunologic Factors
- Interferon-alpha
- Interleukin-13
- Organometallic Compounds
- TNF protein, human
- Tumor Necrosis Factor-alpha
- Phosphorylcholine
- Interleukin-10
- miltefosine
- Meglumine
- Meglumine Antimoniate
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Topics |
- Adolescent
- Animals
- Antiprotozoal Agents
(pharmacology, therapeutic use)
- Female
- Humans
- Immunologic Factors
(pharmacology, therapeutic use)
- Interferon-alpha
(metabolism)
- Interleukin-10
(metabolism)
- Interleukin-13
(metabolism)
- Leishmania
(drug effects)
- Leishmaniasis
(drug therapy)
- Leukocytes, Mononuclear
(metabolism)
- Macrophages
(parasitology)
- Male
- Meglumine
(pharmacology, therapeutic use)
- Meglumine Antimoniate
- Organometallic Compounds
(pharmacology, therapeutic use)
- Phosphorylcholine
(analogs & derivatives, pharmacology, therapeutic use)
- Tumor Necrosis Factor-alpha
(metabolism)
- Young Adult
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