Effective immunotherapy against canine visceral leishmaniasis with the FML-vaccine. Vaccine

"Prof. Paulo de Góes", Instituto de Microbiologia, Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária, Ilha do Fundão, Caixa Postal 68040, Rio de Janeiro, CEP 21941-590 RJ, Brazil.
Vaccine (Impact Factor: 3.62). 07/2004; 22(17-18):2234-43. DOI: 10.1016/j.vaccine.2003.11.039
Source: PubMed


The potential effect of the fucose mannose ligand (FML)-vaccine on immunotherapy of canine visceral leishmaniasis was assayed on five mongrel dogs experimentally infected with Leishmania donovani and on 21 Leishmania chagasi naturally infected dogs when seropositive to FML but completely asymptomatic. The clinical signs of the experimentally infected, symptomatic dogs only disappeared after the complete vaccination. Protection was obtained in 3/5 animals that remained asymptomatic, IDR positive and parasite free, 1 year after infection. Furthermore, the asymptomatic, FML-vaccine treated dogs showed stable anti-FML IgG1 levels, increasing IgG2 levels and 79-95% of positive DTH response, during the whole experiment. Twenty-two months after complete vaccination, no obits due to visceral leishmaniasis were recorded and 90% of these dogs were still asymptomatic, healthy and parasite free. On the other hand, 37% (17/46 dogs) kala-azar obits were recorded in a control group that received no treatment during the same period, and that was FML-seropositive and asymtpomatic at the beginning of the assay. Our results indicate that the FML-vaccine was effective in the immunotherapy against visceral leishmaniasis of asymptomatic infected dogs. Normal proportions of CD4 and CD21 lymphocytes were detected in PBMC by FACS analysis, in dogs submitted to immunotherapy, suggesting their non-infectious condition. All animals showed as well significantly increased percents of CD8 lymphocytes as expected for Quillaja saponin (QuilA) vaccine treatments.

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Available from: Amanda Cruz Mendes, Sep 29, 2015
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    • "The discovery of novel compounds with both, immunostimulatory and leishmaniacidal properties with minimum or no side effects, is necessary for drug development. Clinical vaccination trials have been performed by various laboratories with variable degrees of success in preventing Leishmania infection [21] [22] [23] [24]. The following sections discuss the mechanisms of immunosuppression which take place during Leishmania donovani infection in human animal models from the perspective of effective prevention of fatality in visceral leishmaniosis. "
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    ABSTRACT: Dysfunction of T-helper 1 mediated immune responses is a hallmark of the progression of visceral leishmaniosis (VL). Several factors such as altered antigen presentation, and abnormalities in MHC/HLA, antigen processing, and T cell receptor recognition regulate the onset of immunosuppression. Recent investigations on VL patients suggest that susceptibility to visceral leishmaniosis is genetically determined and varies between populations in different geographical locations. Emerging evidence also indicates the importance of the role played by myeloid derived suppressor cells in progressive VL. This study provides a mechanistic view of means to target the signaling mechanisms of immunosuppression to determine potential therapeutic interventions.
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    • "Different studies are being done to evaluate the potential of fucose–manose-ligand (FML) antigen plus saponin as an immunotherapy. Borja-Cabrera et al. (118) used three vaccine doses (1.5 mg FML +1 mg saponin) in asymptomatic dogs and observed them for 22 months after immunotherapy was complete. No deaths due to disease were recorded, and 90% of the dogs remained asymptomatic, healthy, and parasite free. "
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    ABSTRACT: Leishmaniasis has several clinical forms: self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100-2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-γ associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease.
    Frontiers in Immunology 06/2014; 5(272). DOI:10.3389/fimmu.2014.00272
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    • "The early and persistent activation of neutrophils and monocytes have also been described (23). This increase in proportions of CD8+ T cells is expected for the QS21 saponin adjuvant of Leishmune® (24) and this was also described in the Leishmune® immunotherapy assays against naturally (25) and experimentally acquired canine VL leishmaniasis (26). Furthermore, the sustained or increased proportions of CD4+ and CD21-B lymphocytes (25, 26) and the reduced CD4+/CD25+ T cell counts (27) have also been described in Leishmune® vaccinated dogs. "
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    ABSTRACT: Nucleoside hydrolases of the Leishmania genus are vital enzymes for the replication of the DNA and conserved phylogenetic markers of the parasites. Leishmania donovani nucleoside hydrolase (NH36) induced a main CD4(+) T cell driven protective response against L. chagasi infection in mice which is directed against its C-terminal domain. In this study, we used the three recombinant domains of NH36: N-terminal domain (F1, amino acids 1-103), central domain (F2 aminoacids 104-198), and C-terminal domain (F3 amino acids 199-314) in combination with saponin and assayed their immunotherapeutic effect on Balb/c mice previously infected with L. amazonensis. We identified that the F1 and F3 peptides determined strong cross-immunotherapeutic effects, reducing the size of footpad lesions to 48 and 64%, and the parasite load in footpads to 82.6 and 81%, respectively. The F3 peptide induced the strongest anti-NH36 antibody response and intradermal response (IDR) against L. amazonenis and a high secretion of IFN-γ and TNF-α with reduced levels of IL-10. The F1 vaccine, induced similar increases of IgG2b antibodies and IFN-γ and TNF-α levels, but no IDR and no reduction of IL-10. The multiparameter flow cytometry analysis was used to assess the immune response after immunotherapy and disclosed that the degree of the immunotherapeutic effect is predicted by the frequencies of the CD4(+) and CD8(+) T cells producing IL-2 or TNF-α or both. Total frequencies and frequencies of double-cytokine CD4 T cell producers were enhanced by F1 and F3 vaccines. Collectively, our multifunctional analysis disclosed that immunotherapeutic protection improved as the CD4 responses progressed from 1+ to 2+, in the case of the F1 and F3 vaccines, and as the CD8 responses changed qualitatively from 1+ to 3+, mainly in the case of the F1 vaccine, providing new correlates of immunotherapeutic protection against cutaneous leishmaniasis in mice based on T-helper TH1 and CD8(+) mediated immune responses.
    Frontiers in Immunology 06/2014; 5:273. DOI:10.3389/fimmu.2014.00273
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