Download Dendritic cells in Leishmania infection

Microbes and Infection 6 (2004) 1402–1409
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Review
Dendritic cells in Leishmania infection
Olga Brandonisio a,*, Rosa Spinelli b, Maria Pepe b
a
Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Bari, Italy
b
Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
Available online 04 November 2004
Abstract
Dendritic cells (DCs) are key elements of the immune system, which function as sentinel in the periphery and alert T lymphocytes about
the type of invading antigen and address their polarisation, in order to mount an efficacious immune response. Leishmania spp. are parasitic
protozoa which may cause severe disease in humans and domestic animals. In this work, the main studies concerning the role of DCs in
Leishmania infection are reviewed, in both the murine and human models. In particular, the importance of the genetic status of the hosts and
of the different Leishmania species in modulating DC-mediated immune response is examined. In addition, different approaches of DC-based
vaccination against experimental leishmaniasis, which could have important future applications, are summarised.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Leishmania; Leishmaniasis; Dendritic cells; Vaccine
1. Introduction
expression and chemokine production, enabling DC migration and recruitment of other cell types (see in Ref. [2,3]).
Dendritic cells (DCs) are a family of professional antigenpresenting cells, which sit in an immature state, capable of
antigen uptake and processing, in all peripheral non-lymphoid
tissues and therefore function as sentinel of the immune system. After contact with microorganisms or substances associated with infection or inflammation, DCs undergo a process of maturation and migrate to the T-cell areas of lymphoid
organs. There they present antigens to naive T cells and modulate their responses [1]. The maturation process consists of
(1) increased expression of major histocompatibility complex (MHC) and costimulatory or adhesion molecules such
as CD40, CD80, CD86 and CD54; (2) down-regulation of
antigen-capture and phagocytic capacity; (3) enhanced cytokine secretion; (4) different patterns of chemokine receptor
DCs take up antigens via different groups of receptor families, such as Fc receptors for antigen–antibody complexes,
C-type lectin receptors (CLRs) for glycoproteins [4] and
pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs), which enable DCs to recognise a wide range of
microbial stimuli [5].
Abbreviations: BMD, bone marrow-derived; CLR, C-type lectin receptors; DCs, dendritic cells; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; LCs, Langerhans cells; LPG, lipophosphoglycan; MHC, major histocompatibility complex; MyD, myeloid differentiation; ODN,
oligodeoxynucleotides; SLA, soluble leishmanial antigen; TLR, Toll-like
receptor.
* Corresponding author. Present address: Microbiologia e Immunologia,
Policlinico, Piazza G. Cesare, I-70124, Bari, Italy. Tel.: +39-08-05478491; fax: +39-08-0547-8537.
E-mail address: [email protected] (O. Brandonisio).
1286-4579/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.micinf.2004.10.004
The information is passed from DCs to T cells via a complex structure, named immunological synapse, which is a specialised molecular organisation that occurs at the contact
region between DCs and T cells. It is essentially composed
of the T-cell receptor and the MHC molecule, which present
the antigenic peptide, but also includes costimulatory and
adhesion molecules (mainly CD40–CD40L and CD28–
CD80) and cytokine–cytokine receptors [6]. In addition, DCs
are essentially flexible and can promote T helper (Th)1, Th2 or
regulatory T-cell phenotypes, instructed by the priming signals from microbial and tissue-derived factors. Activated DCs
can produce IL-12p70, which regulates Th1 proliferation,
interferon (IFN)-c production and parasiticidal ability of activated macrophages; this is a critical process for the containment of infections caused by intracellular pathogens, even
including Leishmania infection. However, it is a specific,
tightly regulated mechanism requiring the signal mediated
by CD40L, in order to protect the host against the
O. Brandonisio et al. / Microbes and Infection 6 (2004) 1402–1409
potential harmful Th1-mediated immunopathological reactions. The secretion by DCs of anti-inflammatory cytokines,
like IL-10, can also prevent the induction of an exaggerated
immune response [6].
Human and mouse DCs can be divided into several subtypes on the basis of surface antigen differences. In humans,
they include CD11c+ myeloid DCs (DC1) circulating in the
blood, CD11c– plasmocytoid DCs (DC2), which are also
found in lymphoid organs, and Langherans’ cells (LCs) in the
skin. In mouse, high surface expression of the b2 integrin
p150/95 (CD1c) is a characteristic of mature DCs. On the
basis of the expression of CD8, CD4, CD205 and CD11b
surface markers, several murine DC subtypes can be characterised [7]. Human and mouse myeloid and plasmocytoid DC
subsets show partly different functions. However, even if
different DC subsets may have different functions in terms of
Th1/Th2 induction, cytokine production, and antigen recognition and presentation, these functions rather than being
intrinsic, are often related to different stimuli and the cytokine milieu [3]. In addition, immature DCs are considered
keepers of peripheral T-cell tolerance to self.
Leishmania is a parasitic protozoan, which causes severe
diseases in humans and dogs. Its life cycle includes an infective flagellated promastigote stage transmitted by phlebotomine sandfly vectors and an aflagellated amastigote stage in
vertebrate hosts. Control measures for leishmaniasis include
evaluation of new diagnostic tests [8], screening of new
compounds for chemotherapy [9] and development of an
affordable and effective vaccine for humans and dogs. For
the latter purpose, the precise knowledge of the protective
immune response against the parasite, including the role of
DCs in the course of the infection, plays a fundamental role.
2. Leishmania–DC interactions: studies in mice
2.1. A silent phase in the skin
Moll et al. [10] first demonstrated that murine LCs can
ingest Leishmania major and migrate in lymph nodes, where
DCs harbour persistent parasites and enable the maintenance
of T-cell memory. However, a recent paper indicates that
although parasites can be detected in mouse lymph nodes a
few hours after infection, none of the DC emigrants from the
skin harbours parasites. The authors conclude that DCs could
not be the vehicle that ferries the parasites from the skin to
the lymph nodes [11].
Interestingly, after L. major infection of C57BL resistant
mice with low parasite dose into a dermal site, there was a
prolonged silent phase of parasite amplification in the skin,
lasting 4–5 weeks, before the onset of lesions and immunity
[12]. The establishment of the infection can be favoured
through different evasion mechanisms, like the inhibition of
DC maturation (see below) or induction of regulatory T cells.
In fact, during infection by L. major in mice, CD4+ CD25+
regulatory T cells accumulate in the dermis, where they
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suppress, in part by IL-10 production, the ability of effector T
cells to eliminate the parasite [13].
2.2. IL-12 production
An impairment of IL-12 production was demonstrated in
bone marrow-derived (BMD) Leishmania-infected macrophages and was selectively observed in infected cells [14].
In contrast, DCs are the main source of IL-12 in early Leishmania infection. In fact, murine C57BL/6 skin-derived DCs
were recognised as the main source of IL-12p40 immediately
after dermotropic L. major infection [15,16], whereas IL12p70 release by DCs required IFN-c and prolonged (72 h)
incubation [15] or addition of CD40L [17]. After viscerotropic Leishmania donovani infection in BALB/c mice, splenic
DCs that are localised in the periarteriolar lymphoid sheath
are the critical source of early IL-12p40 production [18,19].
The effect of Leishmania infection on IL-12 induction and
DC maturation may vary according to DC subtype and to
Leishmania species. In fact, infection in vitro of murine
BMD DCs with L. mexicana promastigotes failed not only to
induce IL-12 release, but also to activate immature DCs. The
importance of additional stimuli is underlined in this work,
since the addition of IFN-c plus LPS restored DC maturation
and IL-12 production in infected cells [20].
Murine splenic DC subsets can vary in their ability to
produce IL-12 and carry out phagocytosis of L. major
amastigotes in mice. In fact, CD4+ CD8– DCs were the most
permissive cells, followed by CD4– CD8– DCs; CD4– CD8+
cells were the least permissive but the best IL-12 producer in
response to infection [21].
Moreover, it was found that resting murine and human
myeloid cells, including DCs, contain preformed,
membrane-associated IL-12p70 stores, which are released
within minutes after in vitro or in vivo contact with L.
donovani [22].
2.3. The role of genetic susceptibility/resistance
DC responses can also vary according to the genetic susceptibility or resistance of mice, on the basis of studies
performed mainly in the murine model of L. major infection.
Skin-DCs from L. major-infected C57BL/6 resistant mice
or BALB/c susceptible mice both exhibit up-regulation of
surface markers (MHC class I and II antigens, CD40, CD54,
and CD86) and release IL-12p70, thus suggesting that genetic susceptibility to L. major is not dependent on DC
inability to respond to the parasite [23]. However, an increased expression of IL-4R was observed on LCs infected
with L. major from susceptible but not resistant mice [24],
and the expression of the costimulatory molecule CD80 was
down-regulated on LCs from susceptible but not resistant
mice [25].
Moreover, in lymph node DCs from susceptible, but not
resistant mice in vivo infected with L. major, a decreased
CD40 activity was observed, which correlated with underproduction of IL-12p40 and IL-12p40 mRNA expression
[26].
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In addition, in a model of L. amazonensis infection, it was
shown that in both BALB/c and C3H/HeJ (resistant) mice,
amastigotes enter and activate BMD DCs, but in the former,
infection fails to induce CD40-dependent IL-12 release and
rather potentiates IL-4 production; transfer of infected
BALB/c DCs into syngeneic resistant recipients induces release of IL-4 and IL-10 by primed Th cells [27].
Susceptible and resistant mice infected with L. major
were also analysed for amastigote load and cell surface
phenotype of lymph node DCs [28]. Cells expressing the DC
specific marker CD11c were the most frequently infected
cells in draining lymph nodes of all mice tested. CD11c+infected cells from C57BL/6 mice displayed a weak parasitic
load, a typical dendritic morphology and frequently expressed CD11b or F4/80 myeloid differentiation (MyD)
markers. In contrast, some CD11c+-infected cells from
BALB/c mice were multinucleated giant cells, which presented a dramatic accumulation of parasites without differentiation markers at their surface.
However, data from a recent paper argue against a relevant
genetic difference in the DCs initiating the anti-parasite Th
cell response in C57BL/6 and BALB/c mice, but rather
underline the importance of DC turnover during the infection. In fact, in both strains there were two different waves of
antigen-containing DCs in vivo in experimental L. major
infection. In the first wave, DCs presented leishmanial antigens, produced IL-12 but were not infected, whereas DCs of
the second wave were able to ingest the parasites [29].
2.4. TLR involvement: studies in null mice
After the demonstration that TLR2 is essential for the
pro-inflammatory activity of the protozoan parasite Trypanosoma cruzi (the causative agent of Chagas’ disease) and that
the glycosylphosphatidylinositol (GPI) anchor of this parasite activates TLR2 [30], studies have been undertaken to
evaluate a possible involvement of TLRs in Leishmania infection. Firstly, studies were performed on a murine macrophage cell line transfected with a dominant-negative version of the MyD88, which is a protein adaptor involved in
TLR-signalling pathways and production of inflammatory
cytokines [5]. Transfection inhibited activation of the IL-1a
promoter, which is selectively activated by L. major infection. Furthermore, stimulation of IL-1a RNA expression by
L. major was inhibited in peritoneal macrophages from
MyD88–/–, compared to MyD88+/+ mice, thus indicating
that the parasite stimulates IL-1a promoter activity and
mRNA expression in macrophages through MyD88- and
TLR-dependent pathways [31].
Similar results showing that MyD88-dependent pathways
are essential for the development of the protective IL-12mediated Th1 response against L. major were obtained by
Muraille et al. [32] and de Veer et al. [33]. Following inoculation of L. major, MyD88(–/–) C57BL/6 mice presented
large footpad lesions containing numerous infected cells. In
response to soluble leishmanial antigens (SLAs), cells from
lesion-draining lymph nodes showed a typical Th2 profile,
similarly to infected BALB/c mice. Moreover, IL-12p40
plasma levels collapsed in infected MyD88(–/–) mice compared with infected wild-type C57BL/6 mice. Importantly,
administration of exogenous IL-12 rescues L. major-infected
MyD88(–/–) mice, demonstrating that the susceptibility of
these mice is a direct consequence of IL-12 deficiency [32].
Furthermore, among leishmanial major surface glycoconjugated molecules, a role for promastigote lipophosphoglycan (LPG) in TLR2 activation was demonstrated [33]. In fact,
LPG, but not LPG without the lipid portion nor glycoinositolphospholipids (GIPLs) or proteophosphoglycan, activates
IL-12p40 and tumour necrosis factor (TNF)-a synthesis in
macrophages from wild-type but not from MyD88-null mice,
thus indicating that LPG signals through a TLR pathway. In
this work, human kidney 293T cells were also transfected
with seven different human TLR expression constructs and
evaluated for NFkB and IL-8 promoter activation after addition of LPG. LPG stimulated both IL-8 and a synthetic
NFkB-luciferase reporter only in cells transfected with TLR2
[33].
As regards DCs, recent data on mice suggest that MyD88dependent receptors are implicated in their maturation in
response to Leishmania infection. In fact, L. donovaniinduced DC maturation in terms of up-regulated expression
of MHC II and costimulatory receptors (CD40,
CD80/B7.1 and CD86) was partially abolished in MyD88deficient mice [34]. Interestingly, in this work the use of a
green fluorescent protein-expressing parasite showed that
DCs undergoing maturation in vivo display no parasite internalisation, thus indicating that Leishmania-induced maturation results from direct recognition of Leishmania by DCs,
and not from DC infection [34].
3. Leishmania–DC interactions: studies in humans
The importance of CD40–CD40L interaction for IL12p70 production, which is also investigated for immunotherapy of infections, is underlined in a study on human
myeloid-derived human DCs [35]. The IL-12p70 production
by L. major-harbouring myeloid-derived human DCs
showed a CD40/CD40L-dependent process. In fact, DCs
which have ingested metacyclic promastigotes of L. major
up-regulated HLA-DR, CD86 and CD40 surface molecules,
thus suggesting a process of maturation. However, these cells
were unable to produce IL-12p70, IL-1b, IL-6, IL-10 or
TNF-a, while the addition of CD40 ligand trimer 8–10 h after
infection resulted in a marked IL-12p70 production. IL12 production by DCs in vitro required opsonisation of parasites with 5% normal human serum, mimicking the in vivo
infection. Interestingly, flow cytometry analysis by an antiIL12 and anti-LPG mAbs showed that IL-12 was colocalised to LPG+ (i.e. Leishmania-infected) DCs. In addition, when autologous primed T cells were co-cultured with
these infected cells, they were able to proliferate and produce
IFN-c [35].
O. Brandonisio et al. / Microbes and Infection 6 (2004) 1402–1409
The effect of infection on DCs may vary according to
Leishmania species in the human model also. In fact,
monocyte-derived DCs, infected with metacyclic promastigotes (i.e. parasites at infectious stage) and then stimulated
with CD40L, showed a different ability to secrete IL-12p70,
according to the Leishmania species employed for the infection. In fact, L. major, which is responsible for self-healing
cutaneous leishmaniasis, induced IL-12p70 release, differently from L. tropica, which may cause persistent cutaneous
lesions and from the viscerotropic species L. donovani [36].
These opposite effects may be related to the difference in
leishmanial surface molecules LPG and GIPLs, which show
a great diversity between the various species.
The response to different Leishmania species of
monocyte-derived DCs and macrophages from blood donors
was also investigated in a study assessing gene expression
profiles by microarray analysis [37]. Human DCs and macrophages shared a vast majority of genes expressed at baseline, but each cell type responded very distinctly to infection
with diverse pathogens. In particular, after infection with
metacyclic promastigotes of L. major or L. donovani, a small
number of genes, notably IFN-c-induced genes, were differentially regulated by the two species in macrophages and
DCs [37].
As regards TLRs, studies in humans were performed on
natural killer (NK) cells, which can also express these receptors. Interestingly, purified L. major LPG up-regulates both
mRNA and the membrane expression of TLR-2 in human
NK cells, and enhances IFN-c and TNF-a production and
nuclear translocation of NFkB. The activation effect was
more intense with LPG purified from infectious metacyclic
promastigotes than from non-infectious procyclic parasites.
Since the difference between the molecules derived from
these two stages lies exclusively in the number of phosphosaccharide repeat domains and in the composition of glycan
side chains that branch off these domains, TLR-2 could
distinguish between phosphorylated glycan repeats on LPG
molecules [38].
4. Evasion of Leishmania parasites from DC
presentation
4.1. Inhibition of DC migration
The inhibition of DC migration could represent a stratagem for the pathogens to escape the host immune system.
Products secreted by L. major promastigotes inhibit the
motility of murine splenic DCs in vitro [39], and L. major
LPG inhibits migration of murine LCs [40]. The chemokine–
chemokine receptor pathway may be involved in this inhibition. In fact, DCs can be selectively recruited due to their
expression of different chemokine receptors: chemokines
that arise under inflammatory conditions and act on CCR1,
CCR2, CCR5 and CCR6 attract immature DCs to the
affected sites. After antigen uptake, during maturation,
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chemokine receptor expression changes: CCR1, CCR2 and
CCR5 are down-regulated and replaced by CCR7 and
CXCR4, thus enabling DCs to migrate in the draining lymph
nodes in response to corresponding chemokines [41].
Absence of CCR2 shifts the L. major-resistant phenotype
to a susceptible state dominated by Th2 cytokines [42].
Furthermore, Leishmania infection can differently modulate
chemokine receptor expression on host cells [43]. Interestingly, after chronic infection with L. donovani in mice, there
was IL-10-mediated inhibition of CCR7 expression and inhibition of DC migration from the marginal zone to the T-cell
areas of the spleen, which may contribute to the development
of visceral leishmaniasis [44].
4.2. Inhibition of DC maturation
Results from different investigations suggest that Leishmania parasites tend to delay DC maturation to favour the
establishment of the infection before the onset of the acquired immune response.
As described above, after L. major infection in C57BL
resistant mice with low parasite dose into a dermal site, there
was a prolonged silent phase of parasite amplification in the
skin, before the onset of lesions and immunity, suggesting an
impairment of DC activation [10]. In mouse BMD DCs in
vitro infected with L. mexicana, an impairment of maturation
and IL-12 secretion was selectively induced by uptake of
parasites, whereas infected cells retained the capacity of full
activation after addition of LPS plus IFN-c [20] and retained
the capacity of exogenous antigen presentation [45].
In addition, metacyclic promastigotes of L. amazonensis
phagocytosed by murine DCs did not induce DC maturation,
which was instead elicited if parasites were previously opsonised with specific antibodies [46].
In lymph node of mice, CD11c+ L. major-infected DCs
express low MHC II levels and no detectable CD86 expression, thus suggesting that they might constitute a reservoir of
parasites [28].
In addition, L. donovani inhibits expression of the lipid
and glycolipid antigen-presenting molecules CD1 on human
BMD DCs, thus impairing CD1-mediated presentation of
lipid antigens and activation of T cells [47]. CD1 molecules
may be involved in the protective immune response against
Leishmania species, which harbour abundant glycolipid antigens.
4.3. Inhibition of IL-12p70 production by DCs
As mentioned above, studies in human myeloid DCs have
demonstrated the inhibitory effect of infection with L.
tropica and L. donovani, but not L. major, on IL-12p70 production after addition of CD40L [36].
4.4. Induction of IL-10
Finally, DCs could be indirectly modulated by Leishmania infection through the induction of IL-10, which can
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O. Brandonisio et al. / Microbes and Infection 6 (2004) 1402–1409
Table 1
Escape of Leishmania from DC presentation
DC subtype
LCs
Splenic DCs
Splenic DCs
BM-derived DCs
BM-derived DCs
Lymph node DCs
BM-derived DCs
Monocyte-derived DCs
Function inhibited
Migration
Migration
Migration and CCR7 expression
Activation markers expression
IL-12 secretion
Activation markers expression
MHC II and CD86 expression
Expression of CD1 molecules
IL-12p70 production
Host
BALB/c mice
BALB/c mice
C578L/6 mice
CBA mice
Parasite
L. major
L. major
L. donovani
L. mexicana
Reference
[40]
[39]
[44]
[20]
BALB/c mice
BALB/c and C57BL/6 mice
Humans
Humans
L.
L.
L.
L.
[46]
[28]
[47]
[36]
render DCs tolerogenic through the up-regulation of the
inhibitory receptor leukocyte immunoglobulin-like receptor
(LIR)-2, resulting in T-cell hyporesponsiveness in vitro [48].
The main escape mechanisms of Leishmania parasites
from DC-mediated immune-responses are listed in Table 1.
5. Targeting Leishmania–DC interaction
DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is
CLR which is expressed almost exclusively on differentiated
blood myeloid and tissue monocyte-derived DCs. It is being
extensively studied not only as pathogen-binding receptor,
but also as mediator of DC-T-cell interactions and as an
escape mechanism for intracellular pathogens, which can
target DC-SIGN to shift the protective Th1 towards Th2 cell
balance [49]. Interestingly, DC-SIGN was indicated as a
major ligand for the amastigote stage of L. pifanoi [50] and
for LPG of L. mexicana [51]. In addition, it was recently
demonstrated that DC-SIGN is a receptor for promastigote
and amastigote infective stages from both visceral (L. infantum) and New World cutaneous (L. pifanoi) Leishmania
species, but not for L. major metacyclic promastigotes, an
Old World species causing cutaneous leishmaniasis. However, in this work, Leishmania binding to DC-SIGN was
independent from LPG [52]. Since binding of DC-SIGN by
distinct Leishmania species and strains can favour parasite
survival and persistence, it was suggested that this receptor
might be a therapeutic target for both visceral and cutaneous
leishmaniasis [52].
6. DC-based vaccination and immunotherapy
Several studies suggest the potential of tumour Ag-pulsed
DCs or DCs engineered to secrete cytokines such as IL-12 or
IL-18 to induce anti-tumour immunity [53,54]. Moreover,
DC-based immunotherapy or vaccination is also emerging as
a tool to combat infectious diseases, since DCs can be longlived, thus ensuring the maintenance of an efficient presentation and stimulation for T cells in draining lymph nodes
[2,6,55].
The first studies demonstrating that LCs can be used as a
natural adjuvant to induce a protective immune response
amazonensis
major
donovani
tropica, L. donovani
against leishmaniasis were performed in a murine model of
L. major infection. A single i.v. application of LCs, pulsed
with promastigote lysate in vitro, induced protection in susceptible BALB/c mice against subsequent challenge with L.
major parasites. Development of resistance was paralleled by
a reduced parasite burden and a shift of the cytokine expression towards a Th1-like pattern [56]. In a murine BALB/c
model of L. donovani infection, DCs engineered to secrete
IL-12 and pulsed ex vivo with soluble L. donovani antigens
were potent vaccine [57].
Not only antigen-pulsed, but also Leishmania-infected
DCs were used for vaccination: in another work L. majorinfected syngeneic DCs protected BALB/c susceptible mice
against L. major challenge [23].
Moreover, LCs loaded with a mixture of the recombinant
leishmanial antigens LACK, KMP-11, gp63 and PSA or with
the single antigen LeIF mediated significant protection
against challenge with L. major parasites, upon adoptive
transfer into naïve susceptible mice [58]. In this work, the
protection was found to be dependent on IL-12, since in
Ag-pulsed LCs from IL-12-deficient mice, the capacity of
DCs to mediate protection was completely abrogated.
Another approach to vaccination is to deliver the antigen
to endogenous DCs with the aid of molecules, which bind
surface receptors on DCs and deliver an activating signal.
The importance of CD40L in DC activation and IL-12 production after Leishmania infection is underlined above. Interestingly, a robust induction of IL-12 production by DCs
was obtained by using murine L929 transfected cells expressing CD40L and the Leishmania antigen gp63 [17].
Vaccination with these co-transfected cells provided a significant degree of protection against challenge with virulent
L. major and L. amazonensis in genetically susceptible mice.
Oligodeoxynucleotides (ODNs) which contain immunostimulatory CG motifs (CpG ODN) and activate DCs by
promoting Th1 responses were also investigated as adjuvant
for vaccination against leishmaniasis in susceptible BALB/c
mice. Mice receiving SLA plus CpG ODN showed a highly
significant reduction in swelling compared to SLAvaccinated mice and enhanced survival compared to unvaccinated mice. The modulation of the response to SLA by
CpG ODNs was maintained even when mice were infected
6 months after vaccination [59]. CpG ODNs were also able to
reduce the pathogenicity of a live L. major promastigote
vaccine, without reducing its efficacy [60].
O. Brandonisio et al. / Microbes and Infection 6 (2004) 1402–1409
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Table 2
DC-based vaccines against experimental Leishmania infection
Vaccine
LCs pulsed with L. major lysate
DCs engineered to secrete IL-12 and pulsed with soluble L. donovani antigens
L. major-infected skin-derived DCs
Skin-derived DCs pulsed with LeIF antigen or LACK + KMP-11 + gp63 antigens
L. major Ag-pulsed, CpG ODN-activated BM-derived-DCs
The mechanism by which CpG ODNs mediate the adjuvant effect in vivo was investigated in BALB/c mice. Vaccination with leishmanial LACK antigen and CpG ODNs led to
the presence of CD11c+ DCs in the draining lymph nodes,
which were potent producers of IL-12p70 and IFN-c, and
were capable of vaccinating naïve BALB/c mice against L.
major infection [61]. However, in another work, IL12 expression by the immunising DCs was not required for
induction of host resistance in mice vaccinated with a single
dose of L. major Ag-pulsed BMD DCs, stimulated by prior in
vitro exposure to CpG ODN [62].
DCs pulsed with soluble L. donovani antigen were also
employed for immunotherapy of murine visceral leishmaniasis together with the conventional chemotherapy with sodium antimony gluconate. This combined treatment potentiates the antileishmanial effect of antimony and results in
complete clearance of parasites from both the liver and the
spleen [63].
Finally, targeting DCs with antigen-containing liposomes
was highly effective in inducing anti-tumour immunity [64]
and could be exploited for immunotherapy of leishmaniasis,
in which liposomal amphotericin B is the first-line treatment
in industrialised countries [65].
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
7. Conclusions
[13]
Possible applications of this type of vaccine include not
only human cutaneous and visceral leishmaniasis in hyperendemic countries, but also canine leishmaniasis in areas,
including Mediterranean countries and Latin America, where
the dog is the main domestic reservoir of the parasite. In these
areas, vaccination of dogs may be an important measure for
control of the human disease.
Route
i.v.
i.v.
i.d.
i.v.
i.v.
Challenge
L. major
L. donovani
L. major
L. major
L. major
Reference
[56]
[57]
[23]
[58]
[62]
References
The main investigations concerning DC-based vaccination against experimental leishmaniasis are summarised in
Table 2.
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activating factors like CD40L or cytokines (see also in Ref.
[55]).
Experimental model
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BALB/c mice
BALB/c
BALB/c
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[15]
[16]
[17]
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