NDT Advance Access originally published online on October 12, 2004
Nephrology Dialysis Transplantation 2004 19(12):2948-2951; doi:10.1093/ndt/gfh497
Nephrol Dial Transplant Vol. 19 No. 12 © ERA-EDTA 2004; all rights reserved
Editorial Comment
Current paradigms about chemokines as therapeutic targets
Hans-Joachim Anders,
Volker Vielhauer and
Detlef Schlöndorff
Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University Munich, Germany
Correspondence and offprint requests to: PD Dr H.-J. Anders, Medizinische Poliklinik der LMU, Pettenkoferstr. 8a, 80336 Munich, Germany. Email: hjanders{at}med.uni-muenchen.de
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Introduction
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After the recognition of
chemotactic cyto
kines as mediators
of inflammation about a decade ago, specific chemokine antagonists
are now approaching first clinical trials for non-renal indications
[
1]. In the field of nephrology, the potential of targeting
the chemokine system has also gained much interest. In general,
cytokines orchestrate cell–cell communication in order
either to maintain tissue homeostasis or to initiate response
mechanisms during tissue injury triggered by e.g. trauma, toxicity,
immunological insults and infection. Among the cytokines, the
chemokines are a distinct group of peptides involved in leukocyte
trafficking, which mediate their biological effects through
a group of G protein-coupled receptors, the chemokine receptors
(CCRs) (reviewed in [
2]). In this article we present current
paradigms of chemokine biology and indicate future perspectives
towards new therapeutic options for the treatment of kidney
diseases.
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Paradigm no. 1: some chemokines are involved in tissue homeostasis
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A subgroup of chemokines within the chemokine family contributes
to tissue homeostasis either by supporting the structural and
functional integrity or by mediating leukocyte migration for
physiological immune surveillance and preservation of tolerance.
For example, one of the homeostatic chemokines is CCL21, which
binds to CCR7 and is critical for the structural and functional
organization of secondary lymphoid tissues (reviewed in [
3]).
In the healthy kidney, CCL21 is secreted by podocytes and binds
to CCR7 on mesangial cells where it appears to contribute to
glomerular homeostasis and regeneration [
4]. Furthermore, dendritic
cells upregulate CCR7 upon stimulation and migrate to regional
lymph nodes where the CCR7 ligand CCL21 is expressed at high
levels [
5]. Depending on the presence or absence of an additional
E-L-R-CXC amino-acid motif, chemokines may also promote or inhibit
angiogenesis.
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Paradigm no. 2: some chemokines mediate compartment-specific leukocyte recruitment in the initiation phase of renal injury
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The regulatory role of chemokines for leukocyte recruitment
during inflammatory tissue injury has gained most interest over
the last decade. In the kidney, all types of renal cells have
been shown to produce inflammatory chemokines upon various kinds
of injury, including CCL2, CCL3, CCL4, CCL5 or CXCL10 (reviewed
in [
6]). Local production of these chemokines initiates recruitment
of macrophages, natural killer cells and T-cell subsets, which
leads to subsequent glomerulonephritis in the glomerular compartment
and to interstitial nephritis in the tubulointerstitium (
Figure 1).
Secreted chemokines bind to endothelial surfaces or interstitial
matrix components and mediate leukocyte migration through their
corresponding CCR on the surface of the leukocyte. The specificity
of recruiting a particular leukocyte subset is provided by specific
surface expression patterns of CCR. For example, neutrophils
but not macrophages express CXCR1, which facilitates recruitment
upon recognition of the neutrophil attractant chemokine CXCL8.
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Fig. 1. Compartment-specific expression of CCL2/MCP-1 in the kidney. In glomerular injury, renal chemokine expression is restricted to the glomerulus as illustrated by immunostaining for CCL2/MCP-1 in immune complex glomerulonephritis of MRLlpr/lpr mice. In tubulointerstitial injury, CCL2/MCP-1 is produced by tubular cells and interstitial cells, e.g. during renal fibrosis after unilateral ureteral ligation in C57BL/6 mice.
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Glomerular and interstitial leukocyte recruitment is regulated
by different chemokines. For example, CCL5 is critical for glomerular
macrophage recruitment, as CCL5 blockade reduces glomerular
macrophage counts during immune complex glomerulonephritis [
7],
but CCL5 blockade or lack of the CCL5 receptor CCR5 has no effect
on interstitial macrophage and T-cell accumulation after unilateral
ureteral obstruction [
8]. In contrast, CCR1 is critical for
interstitial macrophage and T-cell recruitment during progressive
lupus nephritis, but CCR1 blockade does not affect the number
of glomerular macrophages in that model [
9].
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Paradigm no. 3: infiltrating leukocytes contribute to local chemokine production in the amplification phase of nephritis and bias towards resolution or progression of disease
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In addition to their role in the initiation of local inflammation,
chemokines play a critical role for resolution or progression
of inflammatory lesions in either glomerulonephritis or interstitial
disease (reviewed in [
10];
Table 1). This is facilitated by
additional chemokine production by infiltrating leukocytes and
continuous chemokine expression by renal cells [
11–13].
However, cessation of the initial insult can down-modulate local
chemokine production as a premise for disease resolution. For
example, proteinuric immune complex glomerulonephritis can be
induced in Balb/c mice by daily injection of apoferritin. Glomerular
macrophage infiltrates are triggered by local production of
CCL2 and CCL5, but discontinuation of antigen exposure stops
local chemokine production followed by complete resolution of
proteinuria and histopathological changes [
14]. In contrast,
if local chemokine production by glomerular macrophages is augmented
by external stimuli, such as bacterial DNA, mice with apoferritin-induced
glomerulonephritis develop severe and irreversible lesions associated
with additional glomerular macrophage recruitment [
15]. This
mechanism may be relevant in acute forms of glomerulonephritis,
e.g. IgA nephropathy and post-infectious nephropathy, but may
also apply to disease flares of chronic nephropathies, e.g.
lupus nephritis.
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Paradigm no. 4: non-redundant chemokines or CCR represent therapeutic targets
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Similar expression patterns for chemokines and CCRs in different
renal disease models led to the assumption of a high degree
of redundancy within the chemokine network [
16]. However, recent
studies with targeted deletions of chemokines or CCRs in mice
or chemokine antagonists have disclosed the specific functions
of individual chemokines and CCRs for renal inflammation [
17].
For example, CCR1 and CCR5 are both expressed on macrophages
and T cells, but regulate different stages of the rolling
adhesion
(CCR1)
transmigration (CCR1 and CCR5) sequence of the endothelium–leukocyte
interaction [
18]. Treatment with a CCR1 antagonist lowers interstitial
leukocyte counts associated with less renal fibrosis after unilateral
ureteral obstruction [
19] or after induction of focal segmental
glomerulosclerosis with adriamycin [
20]. Late onset of CCR1
blockade also preserves renal function in progressive lupus
nephritis of MRLlpr mice [
9] and improves survival of collagen
IVA3-deficient mice with Alport's disease (unpublished data).
Another target for therapeutic intervention in kidney disease is CCL2. Deletion of the Ccl2 gene dramatically reduced tubulointerstitial injury in mice with nephrotoxic serum nephritis or lupus nephritis of MRLlpr mice [21,22]. Gene transfer of a truncated human CCL2 protein demonstrated beneficial effects in renal fibrosis after unilateral ureteral obstruction in mice [23], protein-overload disease in rats [24], ischaemic acute renal failure in mice [25] and in MRLlpr mice with lupus nephritis [26]. Epidemiological studies in renal transplant recipients with mutations in chemokine or CCR genes support the relevance of such rodent data in human kidney disease [27,28]. These data suggest that interstitial fibrosis, the common final pathway of most chronic nephropathies, may be susceptible for therapeutic blockade of selected chemokines or chemokine receptors.
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Paradigm no. 5: inflammatory chemokines have additional immunoregulatory functions
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Studies with chemokine antagonists or mice with targeted deletions
of chemokine genes have generated some unexpected findings in
renal disease models. In general, it can be concluded that these
findings are related to the additional functions of chemokines
in regulating immune responses. For example, CCR2+CD4+CD25+regulatory
T cells control the proliferation of antigen-specific or autoreactive
T cells [
29]. Blockade of CCR2 late during the course of lupus
nephritis in MRLlpr mice may aggravate renal disease through
such a mechanism [
30]. Another example is therapeutic blockade
of CCL5 in apoferritin-induced glomerulonephritis. The two antagonists
Met-RANTES and AOP-RANTES aggravated glomerulonephritis despite
blocking glomerular macrophage recruitment through agonistic
effects on CCR5 on resident macrophages, leading to the release
of proinflammatory mediators and impaired uptake of apoptotic
cells [
7]. The selective inhibition of the CCR5-mediated FAK
kinase signalling pathway but not of the JAK/STAT signalling
pathway by these antagonists may account for this observation.
As another example, mice lacking the
Ccr1 gene had aggravated
nephritis after injection of nephrotoxic serum in association
with a shift in the Th1/Th2 balance towards a Th1-type response
[
31]. These data led to the assumption that CCR1 would not be
a valuable therapeutic target. However, such effects were never
observed in a number of studies with CCR1 antagonists using
protocols where the antagonist is given after the disease is
already established [
8,
9,
20]. Together, these data indicate
that interfering with the chemokine system can modulate disease
through additional mechanisms than renal leukocyte recruitment.
Furthermore, data from studies with knockout mice may not be
able to predict the therapeutic potential of chemokine antagonism,
as in the knockout mice the lack of the chemokine or CCR exists
since conception, so that the entire immune system may be altered.
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Paradigm no. 6: the chemokine network is species specific
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Despite significant homologies of cDNA sequences between different
species, considerable distinctions exist that may affect the
interpretation of data derived from rodent disease models to
humans [
32]. In fact, chemokine antagonists developed for the
human system commonly have different pharmacological properties
in other species, obviating their use for interventional experiments
[
1,
33]. Therefore, species specificity of the chemokine or CCR
antagonist must be demonstrated before its use in animal disease
models.
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Conclusion
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Chemokines are a group of cytokines that mediate the initiation
and progression of renal disease by leukocyte trafficking into
the kidney. Furthermore, chemokines facilitate other functions,
including physiological leukocyte migration, tissue homeostasis,
angiogenesis, dendritic cell migration and modulation of adaptive
immune responses. Therapeutic chemokine blockade has to face
these multiple roles of chemokines. As the timing of chemokine
blockade is critical, knockout mice may not always be useful
in predicting the outcome of therapeutic blockade of a specific
chemokine. Therefore, chemokine antagonists must be used to
predict the outcome of therapeutic antagonism in relevant treatment
protocols.
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Acknowledgments
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The work was supported by grants from the Deutsche Forschungsgemeinschaft
(LU 612/4-1) and the Wilhelm Sander Foundation to H.J.A. and
a grant from the EU Network of Excellence ‘MAIN’
(FP6-502935) to H.J.A. and D.S.
Conflict of interest statement. None declared.
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Introduction
Paradigm no. 1: some...