Leishmania major p27 gene knockout as a novel live attenuated vaccine candidate: Protective immunity and efficacy evaluation against cutaneous and visceral leishmaniasis in BALB/c mice.
Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug).
Taken together, these studies suggest that <i>L. infantum</i> may modulate TREM-1 in neutrophils and high levels of this molecule is associated with severe VL.
We therefore investigated the possibility of using DNA-vaccination against Leishmania donovani infection with the A2 virulence gene and whether inhibiting the cellular p53 response could increase the effectiveness of the A2 DNA vaccine. p53, also known as the guardian of the genome, is activated following DNA transfection and has pleotropic effects on cells, which could have adverse effects on the effectiveness of DNA-vaccination.
Furthermore, reciprocal regulation of immune accessory surface molecules, Sema4A and OX40L critically determined Th1/Th2 response induced by these DC subsets during VL.
Taken together, these results suggest that BAFF is involved in strong B cell activation, which has a pathological role in splenomegaly but not in hepatomegaly or anemia, during VL.
The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-γ), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated <i>ex vivo</i> with <i>L. infantum</i> antigens.
However, lymphocytes from sVL stimulated with SLA had lower percentages of CD4<sup>+</sup> and CD8<sup>+</sup> cells expressing CD69 and CD8<sup>+</sup> cells expressing CD25, with no release of interferon-γ or tumor necrosis factor. sVL subjects had lower percentage of memory cells (CD4<sup>+</sup> CD45RO+), ex vivo, without SLA stimulation than RecVL, LST+, or LST- (<i>P</i> = 0.0022).
We performed combined blockade of IFN-γ and TNF-α in VL splenic biopsies and demonstrated it's impact on number of viable amastigotes and cytokine production.
Immunization with rLdp45 exerted considerable prophylactic efficacy (∼85%) supported by an increase in mRNA expression of iNOS, IFN-γ, TNF-α and IL-12 and decrease in TGF-β and IL-4, indicating its potential as a vaccine candidate against VL.
Thus, an aberrant activation of the TNF system with possible negative immunological and virological consequences is present in HIV-1-infected patients with VL.
Visceral leishmaniasis (VL) is associated with increased circulating levels of multiple pro-inflammatory cytokines and chemokines, including IL-12, IFNγ, and TNFα, and elevated expression of IFNγ mRNA in lesional tissue such as the spleen and bone marrow.
Efficacy against VL was mediated by a CD4<sup>+</sup>TNF-α T lymphocyte response against the NH36-F3 domain, while against tegumentary leishmaniasis (TL) a CD8<sup>+</sup> T lymphocyte response to F1 was also required.
Analyses showed that the distribution of TNFA RFLP alleles (TNF1 and TNF2) and the TNF MSM alleles (TNFa1 to TNFa15) differed between individuals with VL and those with DTH+ phenotypes.
Leptin-induced IFN-γ, IL-2, and TNF-α cytokines in the culture supernatant of splenocytes upon soluble leishmanial antigen (SLA) stimulation and significantly up-regulates serum IgG2a titers, which help to generate Th1 immune response in VL.
Leishmania major p27 gene knockout as a novel live attenuated vaccine candidate: Protective immunity and efficacy evaluation against cutaneous and visceral leishmaniasis in BALB/c mice.
Leishmania major p27 gene knockout as a novel live attenuated vaccine candidate: Protective immunity and efficacy evaluation against cutaneous and visceral leishmaniasis in BALB/c mice.
TLR9 and MyD88 are crucial for the maturation and activation of dendritic cells by paromomycin-miltefosine combination therapy in visceral leishmaniasis.