Journal Article

Efficacy of an Immunotherapy Combining Immunogenic Chimeric Protein Plus Adjuvant and Amphotericin B against Murine Visceral Leishmaniasis

Martins, Vívian T., Ramos, Fernanda F., Coelho, Eduardo A. F., Bueno, Lílian L., Christodoulides, Myron, de Jesus, Marcelo M., Galdino, Alexsandro S., Pereira, Isabela A. G., Chávez-Fumagalli, Miguel A., Freitas, Camila S., Roatt, Bruno M., Moreira, Gabriel J. L., Tavares, Grasiele S. V., Ludolf, Fernanda, Lage, Daniela P., Bandeira, Raquel S., Machado, Amanda S., Fujiwara, Ricardo T., Vale, Danniele L.

2023

Overview

Visceral leishmaniasis (VL) in the Americas is a chronic systemic disease caused by infection with Leishmania infantum parasites. The toxicity of antileishmanial drugs, long treatment course and limited efficacy are significant concerns that hamper adequate treatment against the disease. Studies have shown the promise of an immunotherapeutics approach, combining antileishmanial drugs to reduce the parasitism and vaccine immunogens to activate the host immune system. In the current study, we developed an immunotherapy using a recombinant T cell epitope-based chimeric protein, ChimT, previously shown to be protective against Leishmania infantum, with the adjuvant monophosphoryl lipid A (MPLA) and amphotericin B (AmpB) as the antileishmanial drug. BALB/c mice were infected with L. infantum stationary promastigotes and later they received saline or were treated with AmpB, MPLA, ChimT/Amp, ChimT/MPLA or ChimT/MPLA/AmpB. The combination of ChimT/MPLA/AmpB significantly reduced the parasite load in mouse organs (p < 0.05) and induced a Th1-type immune response, which was characterized by higher ratios of anti-ChimT and anti-parasite IgG2a:IgG1 antibodies, increased IFN-γ mRNA and IFN-γ and IL-12 cytokines and accompanied by lower levels of IL-4 and IL-10 cytokines, when compared to other treatments and controls (all p < 0.05). Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant ameliorated the toxicity of AmpB to some degree. In addition, the ChimT vaccine alone stimulated in vitro murine macrophages to significantly kill three different internalized species of Leishmania parasites and to produce Th1-type cytokines into the culture supernatants. To conclude, our data suggest that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for L. infantum infection.

• Publisher: MDPI AG,MDPI
• Subject: adjuvants / Amphotericin B / Antibodies / Antigenic determinants / Antigens / Antiparasitic agents / Cell culture / chimera vaccine / Chromatography / Chronic infection / Cytokines / Drug therapy / Drug therapy, Combination / Epitopes / Immune response / Immunogenicity / Immunoglobulin G / Immunology / Immunosuppressive agents / Immunotherapy / Infection / Infections / Interleukin 10 / Interleukin 12 / Interleukin 4 / Kala-azar / Laboratory animals / Leishmania / Leishmania infantum / Leukocytes / Lipid A / Lipids / Lymphocytes / Lymphocytes T / Macrophages / Manufacturers / Medical research / Medicine, Experimental / mice / Monophosphoryl lipid A / mouse / mRNA / parasite load / Parasites / Parasitic diseases / Parasitism / Promastigotes / Proteins / recombinant fusion proteins / T cell response / T cells / T-lymphocytes / Toxicity / Vaccines / Viral antibodies / Visceral leishmaniasis / γ-Interferon