A specific Leishmania infantum polyepitope vaccine triggers Th1-type immune response and protects against experimental visceral leishmaniasis

Ostolin, Thais Lopes Valentim Di Paschoale; Gusmão, Miriã Rodrigues; Mathias, Fernando Augusto Siqueira; Cardoso, Jamille Mirelle de Oliveira; Roatt, Bruno Mendes; Aguiar-Soares, Rodrigo Dian de Oliveira; Ruiz, Jerônimo C.; Resende, Daniela de Melo; Brito, Rory Cristiane Fortes de; Reis, Alexandre Barbosa

doi:10.1016/j.cellimm.2022.104592

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…In agreement with our results, IFN-γ production by CD8 T cells and a decrease of IL-10 expression by both CD4 and CD8 T cells were observed in mice treated with liposomes containing MA ( 62 ). Furthermore, CD8 + IFN-γ + T cells correlated negatively and CD8 + IL10 + cells correlated positively with the number of amastigotes in the spleens of these mice ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis

de Franca,

Rodrigues,

Barreto

et al. 2024

Front. Immunol.

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IntroductionIn VL, a proinflammatory phenotype is typically associated with enhanced phagocytosis and a Th1 mediated immune response resulting in infection control. In contrast, an anti-inflammatory phenotype, associated with a predominant regulatory response, typically enables intracellular multiplication of Leishmania parasites and disease progression.MethodsTo investigate the impact of chemotherapy on Th2 and Th17 immune responses in patients with visceral leishmaniasis (VL), we assessed all combinations of intracellular expression of IFN-γ, IL-10, IL-4 and IL-17 in the CD4+ and CD8+ T cell populations of peripheral blood mononuclear cell (PBMC) samples from patients, after antigenic stimulation with Leishmania lysate, throughout treatment and follow-up. As increases in spleen and liver sizes and decreases in hematocrit, hemogloblin, erythrocytes, monocytes, leukocytes and platelets levels are strongly related to the disease, we studied the correlations between the frequencies of T cells producing the afore mentioned cytokines, individually and in combination, and these variables, as markers of disease or cure.ResultsWe found that the frequency of IFN-γ-producingCD4+ T cells increased until the end of chemotherapy with Glucantime® or AmBisome ®, while IL-10, IL-4 and IL-17-producing CD4+ T cells peaked on day 7 following the start of treatment. Although the frequency of CD4+IL-17+ cells decreased during treatment an increase was observed after clinical cure. The frequency of CD4+ T cells producing only IFN-γ or IL-17 correlated with blood monocytes levels. Frequencies of double-producers of IFN-γ and IL-10 or IL-4 correlated positively with eosinophils and platelets levels. Together, this suggest that IFN-γ drives the immune response towards Th1 at cure. In contrast, and associated with disease or Th2 response, the frequency of CD4+ IL-10+ cells correlated positively with spleen sizes and negatively with circulating monocyte levels, while the frequency of CD4+ producing both IL-4 and IL-10 correlated negatively with platelets levels. The frequency of CD8+ single-producers of IFN-γ increased from day 21 to 90 while that of single-producers of IL-10 peaked on day 7, of IL-4 on day 30 and of IL-17, on day 180. IFN-γ expression in CD8+ single- and double-producers of cytokines was indicative of an immune response associated with cure. In contrast, frequencies of CD8+ double-producers of IL-4 and IL-10, IL-4 and IL-17 and IL-10 and IL-17 and producers of three and four cytokines, were associated with disease and were low after the cure. Frequencies of CD8+ T cells producing IFN-γ alone or with IL-17 were positively correlated with platelets levels. In contrast, as markers of disease: 1) frequencies of single producers of IL-10 correlated negatively with leukocytes levels, 2) frequencies of double producers of IL-4 and IL-10 correlated negatively with platelet, leukocyte, lymphocyte and circulating monocyte levels, 3) frequencies of triple-producers of IFN-γ, IL-4 and IL-10 correlated negatively with platelet, leukocyte and neutrophil levels and 4) frequencies of producers of IFN-γ, IL-4, IL-10 and IL-17 simultaneously correlated positively with spleen size, and negatively with leukocyte and neutrophil levels.DiscussionOur results confirmed that the clinical improvement of VL patients correlates with the decrease of an IL-4 and IL-10 CD4+Th2 response, the recovery of CD4+ Th1 and Th17 responses and the frequency of CD8+ single-producers of IFN-γ and double producers of IFN-γ and IL-17.

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Section: Discussionmentioning

confidence: 99%

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis

de Franca,

Rodrigues,

Barreto

et al. 2024

Front. Immunol.

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“…Conversely, mice receiving ChimT/MPLA, ChimT/AmpB and mainly ChimT/MPLA/AmpB showed an up-regulation of IFN-γ and IL-12 cytokine production, which was associated with a decreased presence of Th2-type cytokines and reflected the induction of protective immunity against the disease. The dominant effect of a Th1-type response in these animals is the activation of microbicidal and effector killing mechanisms by the infected cells, which was reflected in the higher secretion of antileishmanial nitrite as a proxy for nitric oxide, which contributed to clearing Leishmania [ 42 ]. In addition, in vitro experiments using three Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

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

Vale

Freitas

Martins

et al. 2023

Biology

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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.

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“…The current course of treatment is based on chemotherapy using a small number of drugs. However, these drugs have shown significant drawbacks, e.g., high cost and toxicity, challenging routes of administration, and low efficacy in endemic areas (Baneth & Solano-Gallego, 2022;Ostolin et al, 2022;Tandon et al, 2023;Wu et al, 2020). On the other hand, diagnosing leishmaniasis (VL, CL, and MCL) is challenging due to the wide spectrum of clinical manifestations and parasite diversity.…”

Section: Introductionmentioning

confidence: 99%

Real-Time PCR Assay for detection and quantification of Leishmania: standardization, positive control, validation, and intra-laboratory assay

Hospinal-Santiani,

Soccol,

Karp

et al. 2023

Biotechnol. Res. Innov.

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A specific Leishmania infantum polyepitope vaccine triggers Th1-type immune response and protects against experimental visceral leishmaniasis

Cited by 6 publications

References 61 publications

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis

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

Real-Time PCR Assay for detection and quantification of Leishmania: standardization, positive control, validation, and intra-laboratory assay

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