SLA-PGN-primed dendritic cell-based vaccination induces Th17-mediated protective immunity against experimental visceral leishmaniasis: a crucial role of PKCβ

Abstract

Emergence of drug resistance during visceral leishmaniasis (VL) is a major obstacle imposed during successful therapy. An effective vaccine strategy against this disease is therefore necessary. Our present study exploited the SLA (soluble leishmanial antigen) and PGN (peptidoglycan) stimulated bone marrow-derived dendritic cells (DCs) as a suitable vaccine candidate during experimental VL. SLA-PGN-stimulated DCs showed a significant decrease in hepatic and splenic parasite burden, which were associated with increased production of nitric oxide and pro-inflammatory cytokines such as IL-12, IFN-γ and IL-17. Elevated level of IL-17 was accompanied with the generation of more Th17 cells. Further studies on DC provided the evidence that these SLA-PGN-stimulated DCs played an important role in providing necessary cytokines such as IL-6, IL-23 and TGF-β for the generation of Th17 cells. Interestingly, inhibition of protein kinase C-β (PKCβ) in DCs led to decreased production of Th17 polarizing cytokines, causing reduction of the Th17 population size. Altogether, our finding highlighted the important role of DC-based PKCβ in regulation of the function and generation of Th17 cells.

Live Attenuated Leishmania donovani Centrin Gene–Deleted Parasites Induce IL-23–Dependent IL-17–Protective Immune Response against Visceral Leishmaniasis in a Murine Model

“…Similarly, in a recent study, we showed an increase in IL-17-secreting CD4 T cells in the PBMCs isolated from healed VL individuals after stimulation with LdCen −/− parasites ex vivo (65). In another study using Leishmania Ag-stimulated DCs as a vaccine, induction of IL-6, IL-23, and TGF-β expression was observed, which in turn resulted in IL-17-producing CD4 T cells leading to host protection against experimental VL (26). Thus, both experimental animal studies and observations from clinical studies in endemic areas support a strong role for Th17 in protection against VL.…”

“…Successful therapy of VL with different immune modulatory molecules has been shown to induce Th1 cytokines, along with IL-17, IL-22, and IL-23 (23–25). A recent report demonstrated that leishmanial Ag-stimulated DCs exhibit a potent anti-leishmanial role by the induction of proinflammatory cytokines and generation of Th17 cells during experimental VL infection (26). In contrast, in cutaneous leishmaniasis caused by L. major it has been shown that Th17 cells influence disease progression via regulation of tissue-destructive neutrophil recruitment at the lesion site (27).…”

Leishmania Hijacks Myeloid Cells for Immune Escape

“…DCs can be pulsed with parasite extracts alone ( Ahuja et al, 1999 ; Carrion et al, 2008 ; Majumder et al, 2012 ; Masic et al, 2012 ), combined with adjuvants such as CpG-ODN ( Carrion et al, 2008 ; Agallou et al, 2011 , 2012 ; Majumder et al, 2012 ; Masic et al, 2012 ) or peptidoglycan (ligand of the TLR-2) ( Jawed et al, 2016 ) or in DCs engineered to secrete IL-12 ( Ahuja et al, 1999 ). These different treatments boost their immunogenicity in murine models ( Ahuja et al, 1999 ; Majumder et al, 2012 ; Jawed et al, 2016 ), dampening IL-10 responses associated to parasite infection ( Schwarz et al, 2013 ), and decreasing the tissue damage induced by the inflammatory response after infective challenge in vaccinated animals ( Masic et al, 2012 ). Due to the high cost of these procedures, an alternative to the use of DCs primed with recombinant parasite proteins in humans will be to target Leishmania proteins to DCs by constructing recombinant chimeras, such as recombinant antibodies recognizing DC-specific receptors and containing leishmanial proteins.…”

Immune Checkpoints in Leprosy: Immunotherapy As a Feasible Approach to Control Disease Progression

“…On the other hand, DC vaccines have also been used to improve the immune response to the Th17 profile against Leishmania spp. infection ( 77 ). Application of DCs in IT against M. leprae has not been explored despite the potential for the stimulation of an efficient antibacterial immunity.…”

“…Application of DCs in IT against M. leprae has not been explored despite the potential for the stimulation of an efficient antibacterial immunity. In other disease, the results indicate that DC-based IT might be more effective in combination with conventional treatments because the association should modulate the immune system in a way that helps the host control or eliminate pathogens ( 68 , 77 , 78 ). Therefore, exploring strategies to shift the immune response to Th1 might achieve better outcomes in leprosy treatment, leading to reduced expression of M. leprae virulence factors, such as LAM, PGL-I, and lipid metabolism ( 9 , 10 ).…”