ARTICLE
Auteur(s) :, Esther Von
Stebut*
Department of Dermatology, Johannes Gutenberg-University,
Langenbeckstrasse 1, 55131 Mainz
accepté le 7 Decembre 2006
Leishmaniasis is one of the most important infectious diseases
worldwide. Currently, 12 million people in 88 (mostly developing)
countries are infected with ~ 2 million new infections per year.
Unfortunately, 60,000 annual deaths result from leishmaniasis.
Recently, the number of affected individuals has increased even in
Europe due to co-infections with HIV. A vaccine does not exist at
present and some treatment options are expensive and can cause
major side effects [1].The disease is caused by an obligate
intracellular parasite inoculated into the skin by the bite of a
sand fly [2]. Humans as well as small animals (e.g. rodents) and
dogs are natural reservoirs for the parasite (figure 1). Upon feeding,
the flagellated, infectious stage life form of the parasite
residing in the sand fly’s salivary glands is transmitted into the
upper dermis of the skin (figure 2). These
promastigotes are rapidly phagocytosed by macrophages (MΦ) and
transform into the obligate intracellular life form, the
amastigote. These amastigotes then replicate within MΦ and are
ultimately released into the tissue to infect more cells. The life
cycle is completed when a sand fly picks up the parasite when
feeding at infected skin sites. At present, more that 20 species of
Leishmania are known, which are primarily characterized by their
tissue tropism (cutaneous, mucocutaneous and visceral infection).
Ninety percent of all Leishmania infections are restricted to the
skin, but this limitation is also dependent on the host immune
response; even species normally inducing ‘only’ cutaneous disease
may promote more severe forms of disease (chronic, recurrent,
disseminated, anergic or visceral disease [3]). Thus, protective
immunity against Leishmania is critical for the host defence
against this important pathogen.
Immunity against Leishmania major
In human and experimental cutaneous leishmaniasis, development of
protective immunity is dependent on the generation of
IFNγ-producing T cells. IFNγ activates infected MΦ to eliminate the
parasites via NO [2, 4] (figure 2). Healing in
cutaneous leishmaniasis is thus dependent on the generation of T
helper (Th) type I cells. Recently, we and others have shown that
cytotoxic T cells capable of releasing IFNγ (so called Tc1 cells)
also promote protection [5]. The key player for the induction of
Th1 and Tc1 immunity is interleukin (IL)-12, although additional
factors may be involved (e.g. IL-27, IL-23, IL-1, TNFα) [2, 4].
Thus, the goal of the infected host’s immune system is to generate
antigen-specific T cell-dependent immunity (Th1/Tc1) to fight this
important human pathogen.
Most of the immunological facts described above were the result
of extensive research using murine experimental leishmaniasis. Some
findings have now been confirmed in humans. Murine leishmaniasis is
generally induced by inoculation of “supra” physiological doses
(≥ 106 parasites subcutaneously into foot pads) of
L. major. Recently, a more physiological infection model was
established that closely mimics natural transmission of the
parasite by the bite of the sand fly. The differences between the
former “high dose” model and this model are (i) inoculation of only
10-1,000 parasites, and (ii) intradermal inoculation imitating the
bite of the sand fly. The resulting ‘physiological’ anti-Leishmania
immune response can be separated into distinct phases with regard
to the cell types activated in each respective phase [5]: In the
first phase, silent invasion of skin resident MΦ occurs. In the
second phase, immigration and activation of cells of the innate
immune system (e.g. resident mast cells, neutrophils, monocytes) is
most prominent and skin lesions develop. The third phase is
characterized by the immigration of dendritic cells (DC) and T
cells and coincides with lesion involution. Finally, in the chronic
phase, persisting parasites may contribute to the maintenance of a
life-long resulting immunity. Using this “low-dose” model, critical
observations from the standard high dose model were confirmed and
supplemented by identification of interesting additional factors
(e.g. the requirement for antigen-specific CD8 responses) [5,
6].
In this review the induction of protective immunity will be
described in more detail. The complex interplay of cells of the
innate immune system (e.g. phagocytes), which are the first to be
in contact with invading Leishmania parasites, with cells of the
adaptive immune response regulates if and how protective immunity
evolves. Modulation of life-long immunity, which is the goal of
vaccination strategies, can only be achieved when we understand how
the induction of protection takes place. Here, the focus will lie
on a description of the events taking place in mouse strains which
are genetically resistant to Leishmania infection (e.g. C57BL/6
mice), since they best recapitulate major hallmarks of human
infections. C57BL/6 mice, as well as humans, develop self-healing
skin lesions that become prominent several weeks post infection and
resolve within months post infection (figure 3).
The silent phase
Invasion of resident MΦ
Phagocytosis is generally defined as a process in which phagocytes
(e.g. MΦ) engulf and digest micro-organisms and cellular debris.
Phagocytosis thus serves as an important defense against infection.
On the other hand, Leishmania parasites take advantage of cellular
uptake, since they are obligate intracellular protozoan
microorganisms. Thus, after inoculation into mammalian skin by the
bite of the sand fly, Leishmania spp. have evolved to promote their
own phagocytosis by exploiting and activating components of the
complement system, resulting in an opsonization of the parasite’s
surface with C3bi and C3b. At the same time, Leishmania
promastigotes are relatively resistant against the lytic complex of
complement [2]. The main receptor responsible for Leishmania entry
into MΦ is complement receptor (CR) 3 [2].
From an immunological point of view, the CR3-mediated early
infection of resident skin MΦ with L. major is a silent
process and, furthermore, results in selective inhibition of the
IL-12 synthesis pathway in infected MΦ [2, 7, 8]. Once within MΦ,
the infectious stage promastigotes transform into the amastigote
life form of the parasite capable of surviving inside of
phagosomes. During this early silent phase, lasting 4-5 weeks, post
infection without visible clinical skin affection, the parasites
replicate (up to 1,000-fold) until finally more infectious
amastigotes are released into the tissue from lysed MΦ [5].
The second phase
Recruitment of inflammatory MΦ and neutrophils
In the second phase, development of clinically evident lesions
occurs coincident with the influx of inflammatory cells, including
neutrophils, eosinophils and MΦ [5] (figure 3). MΦ comprise the
major parasite reservoir in vivo and represent the primary host
cell. Even though they fail to produce IL-12 after infection with
L. major, MΦ are capable of producing proinflammatory
cytokines at sites of infection and they are also ultimately
responsible for parasite killing and elimination via NO. Thus, MΦ
are crucial effector cells in the induction of protective cutaneous
responses against microbes (e.g. Leishmania, Mycobacteria) or
foreign bodies. MΦ induce the recruitment of proinflammatory cells
(neutrophils, eosinophils, mast cells) and thus are involved in
granuloma formation aimed at clearing or restricting the growth of
micro-organisms at sites of infection [9].
How the inflammatory ‘wave’ in this second phase is initiated is
not fully understood yet, but it appears that complement [10] and
cutaneous mast cells (MC) [11] critically contribute to this
response. C3 cleavage is required for the attraction of neutrophils
[10]. In addition, using different disease models (foreign body
granuloma induction, L. major infection), we have recently
shown that MC mediate the recruitment of neutrophils and MΦ to the
inflamed tissue [9, 11]. Release of TNFα from MC promotes influx of
neutrophils, which release chemokines (such as MIP-1α/β, MIP-2),
which in turn results in the recruitment of MΦ. Interestingly and
surprisingly, if one factor in this chain of events is missing,
inefficient immigration of inflammatory MΦ into skin is the result.
This finding was confirmed by the facts that, in leishmaniasis,
extensive dermal MC degranulation is found at sites of early
infection [11, 12] and that MC co-incubated with L. major in
vitro reportedly release preformed TNFα within minutes [13]. In
addition, van Zandbergen et al. have recently demonstrated that
infected human neutrophils secrete high levels of MIP-1β, thus
attracting MΦ [14].
Function of neutrophils in cutaneous leishmaniasis?
As compared to MΦ, the role of neutrophils for immunity against
Leishmania is less clear. As described above, neutrophils are among
the first cells recruited to L. major lesions [5]. Apart from
the importance of neutrophils for granuloma formation, they also
appear to play a major role in the development of protective
immunity [15]. Early depletion of neutrophils from resistant
C3H/HeJ exacerbated disease and led to enlargement of lesions,
elevated levels of IL-4 and increased parasite burdens [15],
suggesting that resistance to L. major infection requires the
immigration of neutrophils at early stages of the infection. The
mechanism of action is still not fully understood. A recent report
demonstrated that interaction of L. major-infected MΦ with
dying neutrophils from C57BL/6 mice induced parasite killing
mediated by neutrophil elastase and TNFα production from
neutrophils [16]. Ingestion of infected, apoptotic neutrophils by
MΦ was survived by the parasite, which were then able to multiply
within the MΦ [14]. Interestingly, in L. major infections, MΦ
were also responsible for the induction of neutrophil apoptosis
through membrane TNFα [17], suggesting that in cutaneous
leishmaniasis, MΦ and neutrophils both critically contribute to
parasite clearance and protective immunity.
The third phase
Recruitment and activation of DC
The third phase is the time point when DC appear in lesional
L. major-infected tissue. Approximately 6 weeks post infection
(low dose inocula), the number of CD11c+ DC increases as
does the percentage of infected DC [5, 18]. Several factors may
contribute to DC recruitment, e.g. MC-derived mediators [11],
IgG-mediated mechanisms [18], cytokine and chemokine release [19].
The appearance of DC coincides with the detection of
IL-12-producing cells, the immigration of CD4+ and
CD8+ T cells into the skin compartment, parasite killing
and lesion involution [5].
Interestingly, and in contrast to MΦ, DC have been shown to
phagocytose only the amastigote life form, but not infectious stage
promastigotes [20-25]. We have shown that DC take up L. major
via a different receptor [18]. Unlike MΦ, which initially utilize
CR3 to bind and phagocytose Leishmania promastigotes, DC mainly
acquire the parasite through Fcγ receptor (FcγR) I and
FcγRIII-mediated uptake of amastigotes. In mice without B cells or
functional FcγR, decreased numbers of infected lesional
CD11c+ DC were found [18].
Infection of DC with L. major results in activation of the
cells associated with upregulation of MHC class I and II expression
as well as costimulatory molecules [22, 26]. In parallel, infected
cells release a variety of proinflammatory cytokines including
IL-12 and various types of infected DC efficiently promoted
protection against infections with L. major via release of
IL-12 [23, 26-29]. In addition, pre-treatment of susceptible BALB/c
mice with recombinant Flt3 ligand induced an expansion of the
CD11c+ DC compartment, resulting in increased IL-12
production and partial protection of infected mice [30].
Induction of adaptive T cell responses by DC
Antigen presenting cells (APC) in the skin (e.g. DC and MΦ)
function as cellular bridges between innate and adaptive immunity
[31]. Skin DC, epidermal Langerhans cells (LC) and the less
frequent dermal DC, belong to the most potent APC of the organism.
Infected MΦ as well as DC can present Leishmania antigen to primed
T cells.
It was recently shown that activated DC are the only cells
capable of processing Leishmania antigen in both the MHC class I
and II pathways [5]. After infection, LC downregulate E-cadherin
expression [22], which mediates LC adherence to surrounding
keratinocytes, and thus migrate towards the skin draining lymph
nodes. Infected DC were able to prime both CD4+ as well
as CD8+ T cells [32, 33]. MΦ, in contrast, express only
low levels of MHC class II and costimulatory molecules and are
unable to prime naïve T cells against Leishmania antigen [34]. In
addition, MΦ were unable to present parasite antigen in a MHC class
I context and did not re-stimulate Leishmania-specific CD8 T cells
[5]. The reason for the different behaviours of DC and MΦ after
infection may be the utilization of different receptors to
recognize and ingest L. major [18]. Cross-presentation of
Leishmania antigen in an MHC class I context to CD8 cells is the
result of FcγR-mediate phagocytosis, whereas CR3-mediated
phagocytosis by MΦ leads exclusively to MHC class II-restricted
antigen presentation. These results bear some similarity to
experiments evaluating the role of FcγR in anti-tumor immunity:
effective cross-presentation of tumor antigens by DC and the
generation of cytotoxic CD8+ T cells was also dependent
on FcγR-dependent activation [35, 36]. Later on, in established
infections, MΦ may also develop into more potent APC by exposure to
mediators such as IFNγ and GM-CSF [37].
Mature DC cannot only trigger T cells, but also shape adaptive
immunity by regulating Th development. Most of the time, activated
DC induce Th1 immunity, but under certain conditions, DC are also
capable of inducing Th2 development [38]. The ability of DC to
induce Th1 or Th2 immunity may depend on the milieu that is present
in the periphery when DC encounter antigen. However, in cutaneous
infections DC preferentially induce Th1/Tc1 immunity. Although
IL-12 was initially detected in MΦ, prior data indicates that DC
are the primary source of IL-12 in lymphoid tissues [22, 39]. IL-12
is the key cytokine for induction of Th1 immunity. Recently, other
members of the IL-12 family, e.g. IL-27 and IL-23, or
proinflammatory cytokines (e.g. IL-1) have also been shown to
contribute to the induction and maintenance of Th1 responses
[40-42]. In Leishmania infections, IL-12 and related cytokines
(IL-27, IL-1) are primarily released by infected DC very early on
post infection thus efficiently inducing Th1-mediated protection
[22, 23, 27, 28, 42-44]. Interestingly, sustained release of IL-12
is also important for the perpetuation of Th1 immunity [45]. The
cellular origin of the continuous IL-12 release at later stages
post infection has not been identified so far.
DC, parasite persistence and regulatory T cells
Control of a primary infection is not associated with the full
elimination of all parasites from the organisms, a fact that can be
problematic since it can result in reactivation of disease (as
observed in some HIV-infected patients) [46]. On the other hand,
antigen persistence has been shown to be important for the
maintenance of T cell memory in the model of cutaneous
leishmaniasis. In the absence of IL-10, chronic L. major
infections completely resolved and sterile cure was observed.
However, this was associated with a loss of effector memory cells
and life long immunity [47]. Persisting parasites were found in DC
from long-term infected mice and DC were suggested to contribute to
the maintenance of memory responses [48]. Recently, Zaph and
co-workers have shown that persisting parasites are required for
the generation and maintenance of skin-homing effector memory T
cells, whereas long-lived central memory T cells that migrate
through lymph nodes mediate long term protection even in the
absence of parasites [49].
What is the source of IL-10 that promotes parasite persistence?
Several cells may be responsible for IL-10 production at these
later stages post infection. Among these, MΦ and regulatory T cells
(Treg) are critically involved. Mosser and co-workers have
demonstrated that at later time points post infection,
FcγR-mediated Leishmania uptake of amastigotes by MΦ may also
become important. FcγR-ligation on infected MΦ induced IL-10
release, which in turn prevented parasite elimination and promoted
disease progression [50]. In addition, blocking of the IL-10
receptor prevented antibody-mediated disease exacerbation [51].
Endogenous CD4+ CD25+ FoxP3+
Treg have recently been described for their capacity to control
excessive or misdirected immune responses. There is growing
evidence that Treg play a fundamental role in various infectious
diseases, e.g. L. major infections [52]. During leishmaniasis,
many features characteristic of Treg function, such as high levels
of IL-10, TGF-β or immunosuppression, have been described. Treg
appear to control L. major infections by modulating the
effector immune response. They control protective Th1 responses
allowing for parasite survival and maintenance of memory responses
[52]. Even though a precise role of DC for the generation of memory
T cells as well as Treg against Leishmania is not known yet, it can
be assumed that infected or antigen-loaded DC modulate these
resulting T cell-dependent immune functions as well.
Which DC subtype is responsible for the induction of effective
anti-parasite immunity?
This topic is currently investigated by many laboratories and the
final answer is not available yet. Since Leishmania parasites are
inoculated into skin via sand flies, most likely skin-associated DC
subtypes are involved. Based on their expression of different
lineage markers, 6 mouse DC subsets are currently known and 3
skin-draining DC can be dissected [53]: (i) Langerhans cells (LC),
(ii) dermal DC, and (iii) monocyte-derived inflammatory DC.
Initial studies have critically involved epidermal LC [21, 54]
as the primary cells to transport L. major antigen to the
lymph nodes and initiate efficient T cell priming in vivo. In mice
with MHC class II expression restricted to LC, these cells were the
key initiators of primary immune responses after infection [55]. In
addition, in L. major-infected CCR2–/– mice,
impaired migration of LC induced a non-healing phenotype in these
otherwise genetically resistant mice [19]. But it is unclear how
epidermal LC would gain access to a parasite that is inoculated
into the upper dermis and later on primarily resides in dermal MΦ.
Some studies suggested that proinflammatory cytokines and
chemokines released by e.g. infected MΦ (such as IL-1, IL-6) may
mobilize LC to migrate from the epidermis to the site of
inflammation allowing for the uptake of viable L. major
amastigotes [34, 56].
Recent studies have shown that cells other than LC, e.g. dermal
DC [57, 58] or lymph node resident DC [59], transport antigen to
the draining lymph nodes and initiate protective immunity. Most of
these studies, however, used high doses of L. major inocula
for infection (5 × 105 – 2 × 107 stationary
phase promastigotes) [19, 55, 57-60]. In addition, some authors
determined infection of DC subtypes by detecting live or whole
parasites inside of DC [57, 60, 61], whereas others concentrated on
the DC’s capacity to present L. major antigen to T cells [19, 55,
58, 59] independent of how and where they acquired the antigen. In
the infection models using un-physiologically high doses of
parasites, the preparations consist of live, but also dead
parasites as well as soluble antigen that may gain access to DC at
various sites distant from the inoculation site (skin) via draining
through the conduit network [59]. Myeloid DC, skin immigrants
residing in T cell areas of lymph nodes, take up this antigen and
induce efficient priming of naïve T cells within a few hours after
antigen inoculation [62, 63]. In addition, accumulation of
antigen-bearing skin-derived DC in lymph nodes was found to peak
~24 hours post inoculation [62]. The question remains as to which
of the described pathways is more relevant (and beneficial?) for
immunity against infectious organisms. Effector memory T cells
preferentially home to the skin only if antigen-presentation
occurred via the skin route [64]. Using infections with
physiologically low doses of parasites (1,000 metacyclic
promastigotes of L. major mimicking natural transmission),
Baldwin and co-workers found the highest parasite burden 3 weeks
post infection in dermal DC and in LC that have migrated to lymph
nodes, but additionally reported that all other CD11c+
DC subsets in lymphoid tissue also contained viable parasites in
vivo [61].
Despite the interesting controversy about the nature of the DC
subset, all authors independently found that CD11c+ DC
are the primary cells responsible for the initiation of protective
immunity in vivo. Whereas Gr-1+ neutrophils and
CD11b+ MΦ were the predominant cell population infected
in the skin, CD11c+ DC represented the most frequently
infected cells in draining lymph nodes [60].
Role of B cells for protection
B cells, another APC subset of the host, do not appear to
accumulate in skin infected with intracellular pathogens, e.g.
L. major [18] or Mycobacteria sp. [65]. However, B
cell-derived antibodies play important roles for resulting adaptive
immune responses. Among other functions, antigen-specific IgG as
well as natural IgG are responsible for the opsonization of
pathogens, so that components of the innate immune system will
recognize them as foreign. In mice without B cells or functional
FcγR, decreased numbers of infected lesional CD11c+ DC
were found [18]. These normally resistant mice became susceptible
to disease, as did animals genetically lacking the relevant FcγR
for IgG binding. In both cases, disease susceptibility was directly
attributable to a failure of DC to prime T cells efficiently and,
consequently, to a reduced production of IFNγ. This pivotal role
for antibodies to parasites in the priming of T cell immunity by
DCs raises the interesting question of how the initial B cell
response to the parasite itself develops in the absence of T cell
help. In the initial phase early on after infection with
L. major, natural IgG produced by B-1 cells may also play an
important role for the opsonization of the parasite [66, 67].
Reasons for impaired immunity against L. major
As discussed above, most mouse strains develop self-healing skin
lesions, while a few others (e.g. BALB/c mice) cannot control
parasite proliferation, show enhanced visceral dissemination of
organisms and ultimately succumb to infection. This response has
been associated with a ‘wrong’ Th2 immunity. Similarly, in
localized cutaneous leishmaniasis (L. braziliensis or
L. major) of man, Th1 cells predominate over Th2 cells. IL-4,
a marker for Th2 immunity, was detected only in cases of diffuse,
mucocutaneous leishmaniasis [68]. Even if IL-13 and IL-4 were
detected in skin after initial lesion development, cure was
regularly associated with IFNγ production only, whereas IL-10 was
present in persisting lesions [69, 70]. In parallel, disease
exacerbation has been observed in patients with HIV infections, who
started to show lower CD4 counts [46]. Studies of patients with
leprosy have been very important for the validation of the Th1/Th2
paradigm [71]. Patients with limited ‘tuberculoid’ disease exhibit
Th1-dominated cytokine profiles, whereas patients with exuberant
‘lepromatous’ M. leprae-rich lesions feature CD8+ T cell
containing infiltrates associated with Th2 cytokine production
[71].
In murine experimental cutaneous leishmaniasis, genetically
determined disease outcome is an important aspect and has been
studied extensively [2]. Several factors contribute to genetic
disposition. Susceptibility is a multigenetic phenomenon and T cell
dependent mechanisms are very important (for reviews compare [2,
4]). These include a relative lack of IL-12 release, IL-4-mediated
aberrant downregulation of the IL-12Rβ2 chain on Th2 cells and
more. But, in addition, genetically determined factors on the level
of neutrophils, MΦ, B cells and DC are also present, which are
relevant for disease outcome (compare table 1( Table 1 )).
These cells of the innate immune system have been the focus of
the present review. But how do they contribute to disease outcome?
Increased numbers of neutrophils were found in lesions of
susceptible as compared to genetically resistant animals [72, 73]
and persisting tissue infiltration with neutrophils plays an
important role in disease susceptibility [16, 74]. What regulates
both recruitment and delayed/absent neutrophil clearance is unclear
to date, but depletion of neutrophils from BALB/c mice improved
disease outcome, reduced parasite loads and suppressed Th2
development [16, 74]. In contrast to C57BL/6 MΦ, in which
neutrophils induce parasite killing, interaction of infected BALB/c
MΦ with dying neutrophils led to uncontrolled parasite replication
via TGF-β and PGE2[16].
Several weeks post infection, a significantly higher percentage
of MRP14-positive MΦ was detected in BALB/c lesions as compared to
lesional infiltrates in resistant C57BL/6 mice [75] and these less
mature MΦ were impaired in their ability to kill L. major
parasites [76]. In contrast to DC, MΦ do not release IL-12 after
infection with L. major. However, otherwise activated MΦ from
BALB/c mice showed significantly reduced production of IL-12 [8,
77]. Thus, during later stages post infection when IL-12 may be
produced by IFNγ-activated MΦ as well as DC, impaired IL-12
production from BALB/c MΦ may contribute to disease outcome.
Since infected DC are the critical cells for the induction of
protective immunity, we and others have studied the biological
behaviour of DC from BALB/c mice in great detail [32, 33]. The
phagocytic capacity of BALB/c and C57BL/6 DC was similar, as was
their activation status, IL-12 production and immigration into skin
of L. major-infected mice [23, 33]. Interestingly, however,
C57BL/6 DC produced more IL-1α/β than BALB/c DC [42, 43]. IL-1α/β
facilitates Th1 priming and protective immunity [41-43, 78-80].
Additional DC-derived factors, not fully characterized yet, might
also contribute to genetic determination of disease outcome.
Polyclonal activation of human B cells leads to production of
parasite-specific and nonspecific IgM and IgG [81]. IgG-mediated
effects differ significantly, depending on the genetic background
of the mice [18]. As described above, in mice on a genetically
resistant background, B cells and B cell-derived IgG are beneficial
for the host response. BALB/c mice, in contrast, are characterized
by excessive production of IgG during later phases of infection,
probably due to their strong Th2 cytokine profile. In addition, the
presence of functional B cells or administration of IgG worsened
disease outcome in BALB/c mice [82-84] via induction of IL-10
release from infected MΦ [50].
In summary, mast cells, skin phagocytes (MΦ and neutrophils) as
well as DC all critically contribute to the development of a
protective immunity against intracellular pathogens such as
Leishmania major. Vaccines that utilized e.g. infected DC or
DC loaded with antigen have already proven to be effective against
leishmaniasis [85]. Thus, modulation of the function of cells of
the innate immune system may represent new therapeutic approaches
to achieve long-lasting protection.
Table 1 Genetic differences in phagocyte behaviour in
cutaneous leishmaniasis
|
BALB/c
|
C57BL/6
|
REF
|
|
Neutrophils
|
+++
|
+
|
72, 73
|
|
Persisting infiltration of lesions
|
|
Depletion improved disease
|
Depletion worsened disease
|
16, 74
|
|
Interaction of inf. MΦ with apopt. Neutrophil: TGFβ +
PGE2
|
Interaction of inf. MΦ with apopt. Neutrophil: TNFα
|
16
|
|
→ parasite persistence
|
→ parasite killing
|
|
MΦ
|
Less mature (MRP14+)
|
More mature (F4/80+)
|
75
|
|
reduced killing efficiency
|
better killing efficiency
|
76
|
|
Relative IL-12 release ↓
|
IL-12 ↑↑
|
8, 77
|
|
DC
|
IL-1α/β ↓
|
IL-1α/β ↑↑
|
42, 43
|
|
IL-12p70
|
IL-12p70
|
33
|
|
IL-12p40 ↑
|
IL-12p40 ↓
|
33
|
|
IL-12p80 ↑↑
|
IL-12p80 ↓
|
33
|
|
? (unknown)
|
IL-27
|
44
|
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
548 and SFB 490) and the Dr. Jürgen Manchot-Stiftung.
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