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Chemokines as Drug Targets in Type 1 Diabetes
Urs Christen*
Pharmazentrum Frankfurt / Zentrum fur Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES), Johann Wolfgang
Goethe University, Frankfurt am Main, Germany
Abstract: Acute or chronic inflammation is thought to play a major role in the etiology and/or pathogenesis of autoimmune disease. Often viral infections are the initial cause for a local inflammatory reaction resulting in tissue infiltration by
activated leukocytes. The activation and trafficking of these leukocytes to the site of inflammation is conducted by
chemoattractant cytokines, termed chemokines. Depending on the genetic background and the history of previous infections, such infiltrating leukocytes can potentially include autoaggressive lymphocytes with specificity to tissue antigens.
The number of specific precursor lymphocytes, strength of activation and degree of counteracting immunoregulatory
measures determine whether such an autoimmune incident ultimately results in autoimmune disease. Thus, by blocking
the initial inflammatory insult one could in theory prevent the excessive attraction of autoaggressive lymphocytes to the
inflammation site and the subsequent formation of a pattern that leads to autoimmune disease. This review focuses on
blocking of chemokines in animal models of type 1 diabetes and discusses the possible applications of such treatments in
human autoimmune disease.
INTRODUCTION
It is generally believed that autoimmune diseases occur
as a result of genetic predisposition and environmental triggering. Acute and/or chronic inflammation caused by acute
and/or persistent pathogen infection is one of the triggering
factors suspected to play a major role in the etiology of human autoimmune diseases in susceptible individuals. Thus,
targeted blocking of critical inflammatory mediators might
prevent the subsequent development of autoimmunity.
Chemokines are among the first inflammatory mediators
expressed after pathogen infection. These chemoattractant
cytokines are predominantly released locally by resident
cells (endothelial cells, resident macrophages, stromal cells)
upon activation by pro-inflammatory cytokines, such as Interferon (IFN), (Interleukin 1) IL-1 or tumor necrosis
factor (TNF). The pattern of chemokine secretion determines the composition of immune competent cells recruited
to the site of infection (for review see [1-3]).
CHEMOKINES AND TYPE 1 DIABETES
In the past few years, several chemokines that might have
an influence on the pathogenicity of type 1 diabetes (T1D)
have been identified in animal models (see below). Unfortunately, only a handful of studies have been conducted in humans and most of them were limited to the analysis of
chemokine levels in the peripheral blood. Most prominently,
it was found that patients with T1D display an elevated level
of CXC chemokine ligand 10 (CXCL10), a chemokine that
is predominantly attracting T-cells of the more aggressive
Th1-type [4, 5]. In contrast, in a recent study with a group of
susceptible individuals who did not progress to clinically
over T1D, Hanifi-Moghaddam et al. could not detect elevated serum levels of CXCL10 and other classical Th1associated cytokines and chemokines, such as IFN, Inter*Address correspondence to this author at the Pharmacenter, Johann Wolfgang Goethe University, Theodor-Stern Kai 7, 60590 Frankfurt am Main,
Germany; Tel: +49-69-6301-83105; Fax: +49-69-6301-7942;
E-mail: [email protected]
1871-5303/07 $50.00+.00
leukin 12 (IL-12) and CC chemokine ligand 5 (CCL5) [6].
They found however, in this cohort of islet-autoantibodypositive first-degree relatives of T1D patients significantly
increased serum levels of CCL3 and CCL4 [6]. In another
study, Lohmann et al. found increased levels CCL2, CCL3,
CCL4, or CCL5 in the blood of newly diagnosed T1D patients [7]. Interestingly, the authors revealed a decreased
presence of PBMCs expressing the CC chemokine receptor
CCR5 (receptor for several chemokine ligands, such as
CCL3, CCL4, and CCL5) and the CXC chemokine receptor
3 (receptor for CXCL9, CXCL10, and CXCL11) [7]. These
data indicate a relocalization of chemokine receptor bearing
PBMCs into the inflamed pancreas. Interestingly, CCL2 was
found to be produced by human pancreatic islets upon stimulation with IL-1 or TNF [8, 9].
In contrast to studies in humans, more indications towards the role of chemokines during T1D have been derived
from animal models. However as in humans, the helper Tcell 1 (Th1)-type chemokine CXCL10 seems to play a central role in the pathogenesis of T1D in both spontaneous
(nonobese-diabetic (NOD) mouse, BB rats) as well as inducible models (RIP-LCMV mouse (see below), Insulinpromotor controlled influenza virus hemagglutinin (Ins-HA)
mouse). In the NOD mouse, it was demonstrated that Th1type T-cells, which produced CCL5, CCL7, CCL12 and
CXCL10 migrate much quicker into the pancreas of immunodeficient NOD.scid (NOD x severe combined immunodeficient) mice and only Th1-type but not helper T-cell 2
(Th2)-type cells induced diabetes [10]. In a recent study,
Bouma et al. analyzed pancreas lysates and found a massive
increase in CXCL10 levels around week 10 of age, which
then decreased again back to baseline levels at week 20 of
age [11]. In contrast, pancreatic expression of CCL5, which
was found to be upregulated around week 10 as well, remained high until at least week 20 of age [11]. These increased CCL5 levels most likely reflect the degree of infiltration of pancreatic islets by autoaggressive T-cells, which
are very well capable of producing CCL5. Similar data have
been reported in recent publication by Gysemans et al., who
© 2007 Bentham Science Publishers Ltd.
8 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 1
demonstrated expression of CXCL10 as well as CCL2 and
CCL20 at week 8 of age in female NOD mice [12]. Interestingly in this study, in vivo treatment of mice with 1,25Dihydroxyvitamin D3 diminished the release of these
chemokines in pancreatic islets and abrogated disease [12].
In another exciting study, Cameron et al. found that a high
ratio of CCL3 to CCL4 expression correlated with destructive insulitis and progression to diabetes in NOD vs. NOR
(nonobese diabetes-resistant) mice [13]. Furthermore, when
NOD mice were treated with IL-4, which prevents T1D in
NOD mice by polarizing intra-islet T-cell response towards a
‘regulatory’ Th2-type response, a dramatically diminished
ratio of CCL3:CCL4 and a decreased expression of islet
CCR5 was observed [13]. These data indicate that the pattern
of pancreatic chemokine expression not only determines the
population of infiltrating leukocyte, but subsequently also
influences the outcome of disease in the NOD mouse. In
another animal model for spontaneous T1D, the BB rat, it
was found in a microarray study with pancreatic RNA that
CCL11, a chemokine, which predominantly attracts eosinophils, was most prominently upregulated during a critical
phase of disease development [14]. However, although analysis of chemokine expression in sera of T1D patients or in
the pancreas of animals which develop spontaneous T1D
gives some indication about the mechanisms involved in the
ongoing destruction of the insulin-producing -cells, only
limited information can be obtained about the factors involved in the initiation of disease. The problem here lays in
the fact that human individuals as well as individual mice,
which develop spontaneous disease, are at a very heterogeneous stage of disease pathogenesis at the time of diagnosis
or experimental analysis, respectively. However, there is a
possibility to coordinate/accelerate the pathogenetic processes in the NOD mouse by injection of cyclophosphamide
at around 6-8 weeks of age, which allows analysis of early
events in a synchronized population of mice. By such an
approach Matos et al. conducted microarray studies and
found a prominent expression of CXCL1, CXCL5, CXCL9,
CCL2, CCL5 and CCL7 [15].
However, the only reliable way to minimize the problem
of inter-individual heterogeneity the autoaggressive immune
response and the pathogenesis of disease is the use of an
entirely inducible animal model for T1D, in which the starting point of disease pathogenesis is clearly defined and the
initiating antigens are very well characterized. The RIPLCMV mouse model, which uses a viral protein as a target
antigen in the -cells, is probably the model system that was
most often used in the past decade and I will discuss the data
we obtained with this system in more detail below. Briefly,
infection of RIP-LCMV mice (see below) with LCMV (lymphocytic choriomeningitis virus) causes a massive and
unique expression of CXCL10 in the pancreas [16]. It was
further found that CXCL10 was mainly produced by the cells themselves [17]. Since CXCL10 predominantly attracts
those activated T-cells, which are of the more aggressive
Th1-phenotype [18, 19], and more than 95% of LCMVprotein (target antigen)-specific autoaggressive CD8 T-cells
express CXCR3 (the CXCL10 receptor) [16], we hypothesized that CXCL10 might imprint a pattern of inflammation
for the subsequent development of autoimmune disease. We
used the RIP-LCMV model for T1D to test this hypothesis in
Urs Christen
more detail. In the following I will focus on our experiences
with chemokine blockade in this virus-induced animal model
and will discuss possible applications in therapy of human
T1D.
THE RIP-LCMV MODEL FOR TYPE 1 DIABETES
One possible mechanism of how pathogens can initiate
autoimmunity is molecular mimicry. This hypothesis involves breaking existing self-tolerance due to an inherent
structural similarity of pathogen molecules to self-components [20-25]. The concept of molecular mimicry has been
successfully integrated into animal models for various human autoimmune diseases such as T1D, multiple sclerosis,
or systemic lupus erythematosus (for review see [23]).
Among these models, the RIP-LCMV mouse model for T1D
was established in 1991 in the laboratories of Michael Oldstone [26] and Rolf Zinkernagel [27]. RIP-LCMV transgenic
mice express the glycoprotein (GP) or nucleoprotein (NP) of
LCMV under the control of the rat insulin promotor (RIP)
selectively in the insulin-producing -cells of the islets of
Langerhans in the pancreas. The transgenically expressed
viral protein is considered a component of ‘self’ and thus
RIP-LCMV mice are tolerant and do neither generate an
LCMV-specific immune response nor develop insulitis or
T1D. However, upon infection with LCMV itself this selftolerance is broken, auto-aggressive LCMV-specific T-cells
are generated and expanded, the -cells are being destroyed
and ultimately clinical overt diabetes results.
Similar to the proposed mechanisms involved in human
T1D, the onset of diabetes in RIP-LCMV mice depends on
autoreactive CD4 and CD8 T-cells and correlates with the
numbers of autoaggressive lymphocytes generated. In accordance, the incidence of disease varied between the individual
transgenic lines ranging from 2 weeks (RIP-LCMV-GP
lines) to 1-6 months (RIP-LCMV-NP lines). Further studies
revealed the mechanism involved in the rapid compared to
the slow onset diabetes: LCMV-GP transgenic mice expressed the GP exclusively in the -cells of the islets and
manifested rapid-onset T1D (10-14 days after viral challenge) [28]. In these mice the high systemic numbers of
auto-aggressive CD8 T-cells were sufficient to induce diabetes and did not require ‘help’ from CD4 cells. In contrast,
LCMV-NP transgenic mice expressed the NP-transgene in
both the -cells and in the thymus and thus anti-self (viral)
cytotoxic T lymphocytes (CTL) were of lower affinity and
CD4 T-cell ‘help’ was essential to generate anti-self (viral)
CD8 lymphocyte-mediated T1D, which took much longer to
occur following LCMV infection [28]. Importantly in context with this review, mouse models in which transgeneencoded ‘target-antigens’ are expressed in the pancreatic cells, such as the RIP-LCMV and the INS-HA [29, 30] mouse,
have demonstrated that the presence of auto-aggressive Tcells alone is not enough to cause disease. For example,
crossing RIP-LCMV mice with an IFNR deficient mouse
line resulted in a drastically reduced diabetes incidence [31].
Furthermore, blockade of TNF at an early stage after
LCMV-infection of RIP-LCMV mice abrogated T1D [32].
These data indicate that unspecific ‘bystander factors’, such
as cytokines and chemokines generated during the acute inflammation after LCMV infection, are important to drive the
Chemokines as Drug Targets in Type 1 Diabetes
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 1 9
auto-aggressive response (-cell destruction) in ‘antigenspecific’ models for T1D.
EARLY INFLAMMATORY EVENTS AFTER LCMV
INFECTION IN THE PANCREAS
quired a whole body of information that helped us modeling
a script of individual immunopathogenic events directing
from LCMV-infection of the pancreas to establishment of
overt diabetes (Fig. 1). Chemokines, most prominently
CXCL10, were the first inflammatory mediators we could
detect after LCMV-infection [16]. These chemokines can be
generated by endothelial cells as well as by -cells themselves [17]. This expression of CXCL10 is most likely induced by the presence of high local concentrations of TNF
released by virally activated resident macrophages. In a second step, the high chemokine concentrations attract LCMVspecific and non-specific leukocytes which extravasate into
the islets of Langerhans. Some initial damage is done by
LCMV-specific CD8 T-cells in a perforin-dependent manner
to some -cells. This initial -cells destruction is not sufficient to cause overt diabetes, since the remaining -cell
population upregulate insulin-production to compensate for
the smaller total number of -cells. In the following additional -cell antigens are presented by antigen-presenting
cells (most likely in the pancreatic draining lymph node or
alternatively directly in the islets themselves) and most of
the -cells are destroyed by expanded LCMV-specific CD8
T-cells as well as by other islet-specific T-cells resulting in
clinically overt diabetes.
Here I will focus on the initial inflammatory reactions
generated as a direct response to virus infection as the initiating event in LCMV-induced T1D. In the past years we ac-
Interestingly and similar to previous reports for the infection of the CNS by various viruses [37-41], infection of
wildtype and RIP-LCMV mice with LCMV caused a very
Hence, the RIP-LCMV model has become a very useful
tool to study the etiology and the mechanisms of human
autoimmune diabetes and to evaluate possible treatments,
such as blockade of specific inflammatory factors, as discussed below [16, 32], oral tolerance induction [33] or DNAvaccination [34]. The strengths of the RIP-LCMV models
are (i) a clearly defined initiation point (LCMV-infection),
which allows studying the precise kinetics of immunopathogenesis, (ii) an autoimmune-mediated disease that is restricted to the islets of Langerhans and (iii) the presence of
extensively characterized target antigens (GP, NP). Importantly, the immune response against these target antigens can
be easily visualized using flow cytometry by stimulation of
splenocytes with LCMV-peptides and subsequent analysis of
intracellular cytokine expression (ICCS) or direct detection
of CD8 T-cells with MHC class -LCMV-peptide tetramers
[35]. In addition, we recently demonstrated tracking of
LCMV-specific CD8 T-cells by in situ MHC class -peptide
staining of quick-frozen tissue sections [36].
Fig. (1). Overview of immunopathogenic events following LCMV-infection in the RIP-LCMV model for type 1 diabetes. LCMVinfection of the pancreas (1) causes the release of ‘pro-inflammatory’ cytokines, such as TNF, by resident macrophages (2). In turn,
chemokines are released by activated endothelial cells as well as -cells (3). Among them CXCL10 is the earliest chemokine to be expressed
leading to high local concentrations at a very early time after LCMV-infection. CXCL10 predominantly attracts activated T-cells of the more
aggressive Th-1 phenotype, which migrate into the inflamed tissue (4). Infiltrating LCMV-specific T-cells start destroying some -cells in a
perforin dependent manner (5). At a later stage these autoaggressive cells with the help of T-cells with specificity to other islet antigens and
of unspecific bystander factors destroy most of the remaining -cells resulting in over diabetes.
10 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 1
rapid and strong expression of CXCL10 in the pancreas [16].
Importantly, CXCL10 was the only chemokine whose expression was strongly induced as early as 1 day after infection. The other two CXCR3 chemokine ligands were either
expressed later (CXCL9) or were only faintly upregulated
(CXCL11). Other chemokines such as CCL3 or CCL5 were
not increased until day 7 post-infection, a time where most
pro-inflammatory cytokines including TNF, and IFN are
strongly expressed as well [16]. The immediate upregulation
of CXCL10 was not restricted to LCMV-infection. We observed that all viruses that directly infect the pancreas, such
as the LCMV strains Armstrong and Pasteur, encephalomyocarditis virus variant B (EMC-B) or Coxsackie virus B4
(CVB4), caused a rapid and strong pancreatic CXCL10 expression, whereas viruses with a tropism for other organs
(encephalomyocarditis virus variant D (EMC-D), Theiler’s
murine encephalomyelitis virus) did not cause any CXCL10
expression in the pancreas [16].
In summary these data suggest that LCMV-induced
CXCL10 expression was direct consequence of virus infection and is not linked to the RIP-LCMV model system as
such. CXCL10 was suggested to function as a ‘sentinel
molecule’ in host defense against viruses before [42] and
was shown to be generated very early after infection with a
wide variety of viruses such as HIV, adenovirus, LCMV,
Theiler’s murine encephalomyelitis virus, and mouse hepatitis virus [37-41]. In general, the ligands of the CXCR3
chemokine receptor (CXCL9, CXCL10, and CXCL11) have
been suggested to play an essential role during inflammation
and autoimmunity. They are mainly expressed by keratinocytes, macrophages, fibroblasts, and endothelial cells upon
stimulation with IFN or TNF [43, 44] but are also generated by activated T-cell hybridomas, normal T-cells, thymocytes and diabetogenic T-cell clones [45, 46]. CXCR3 is
predominantly found on activated Th1-type T-cells [18, 19].
Thus, CXCR3 chemokine ligands are thought to direct the
anti-viral defense towards the more aggressive Th1-type
immune response and act as ‘bystander effectors’ that unspecifically activate T-cells (including autoreactive T-cells).
Subsequently they propel an auto-aggressive immune response in a way that may result in autoimmune disease. Indeed, CXCL10 seems to have a significant impact on the
subsequent development of autoimmunity, since blocking of
CXCL10 by neutralizing antibodies abrogated T1D [16].
NEUTRALIZATION OF CXCL10 ABROGATES TYPE
1 DIABETES
We used a very well characterized neutralizing monoclonal antibody to CXCL10 that was previously shown to
block the biological activity of CXCL10 Toxoplasma gondii
infection model [47] and was used to neutralize CXCL10 in
the CNS of mice with experimental autoimmune encephalomyelitis (EAE) [48]. In our system, blockade of CXCL10
with this neutralizing antibody abrogated T1D in >60% of all
LCMV-infected mice [16]. Mechanistically, CXCL10 neutralization interfered with the expansion of LCMV-specific
auto-aggressive CD8 T-cells and their migration to the islets
of Langerhans [16]. It is important to note, that the treatment
had to be administered at the precise time when CXCL10
was expressed at high density. Rescued mice received 5 intravenous injections of 100 μg neutralizing antibody at days
Urs Christen
0, 1, 2, 4, and 6 post infection. Treatment of mice before
LCMV-infection or at a later time (days 7-14) was not successful in preventing autoimmune disease (U.CH. unpublished observations and reference [16]).
UNIQUE ROLE OF CXCL10 IN IMPRINTING A
PATTERN FOR AUTOIMMUNE DISEASE
Among the inflammatory mediators generated upon
LCMV-infection of the pancreas, CXCL10 proved to play a
key role in imprinting a pattern for the subsequent development of autoimmune disease in the RIP-LCMV model. Recently, we could further confirm the important role of
CXCL10 during virus-induced diabetes by investigating the
kinetics of T1D in RIP-CXCL10 / RIP-LCMV double transgenic mice [49]. We generated transgenic mice which express CXCL10 under the control of the rat insulin promotor
specifically in the -cells. Such RIP-CXCL10 mice showed a
spontaneous infiltration of islets by a mixed leukocyte population [49]. These mice were not diabetic but had a reduced
capacity to response to a high glucose challenge possibly due
to ‘inflammatory stress’ to the islets [49]. When crossed to
the RIP-LCMV mouse lines the RIP-CXCL10 mice had accelerated T1D after infection with LCMV. Interestingly,
islet-specific expression of CXCL10 in RIP-LCMV-NP
mice, which in its single transgenic RIP-LCMV-NP state
display a slow onset of disease, accelerated T1D to a degree,
where its kinetic appeared very similar to the rapid-onset
disease observed in RIP-LCMV-GP mice [49].
CXCL10 NEUTRALIZATION A POSSIBLE CURE
FOR HUMAN T1D?
Based on these study one might come to the conclusion
that CXCL10 is a prime candidate for therapy of human
T1D. However, there is one major problem in translating the
data obtained from the inducible RIP-LCMV mouse model
to the human situation, namely the exact timing of CXCL10
neutralization. As mentioned before, the administration of
neutralizing antibodies to CXCL10 had to be administered at
the time of maximal CXCL10 expression, which was immediately after infection of mice with LCMV. Neutralization of
CXCL10 at a later time had no influence on the course of
disease, since CXCL10 is not persistently expressed during
the ongoing autoimmune destruction of the -cells. Therefore, when the theory that environmental triggering factors,
such as viruses, are responsible for the initiation of T1D in
susceptible individuals indeed holds true, we are still in the
unfortunate position of not knowing when the detrimental
triggering event is taking place. At the time of disease diagnosis (or even of islet-autoantibody detection) the triggering
virus might be long gone and may not even leave any traces
behind that would allow proving its existence. This circumstance has been as well hampering the attempt of firmly
proving that viruses indeed are the initiating factors for human T1D and the ‘virus-hypothesis’ therefore is still based
on indirect prove and epidemiological studies associating
virus-infection with T1D (see [50, 51] for recent reviews on
that topic).
There is however, a situation in which blockade of
CXCL10 might be successful: Islet transplantation. Transplantation of islets has become one of the major hopes for
patients suffering from T1D and several clinical trials are
Chemokines as Drug Targets in Type 1 Diabetes
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2007, Vol. 7, No. 1 11
currently being conducted. Most of these trials follow the
‘Edmonton Protocol’ according to which isolated islet transplants are being injected into the recipient’s hepatic portal
vein [52]. Islet clusters subsequently settle down in the liver
and start insulin production. Although the ‘Edmonton Protocol’ provides a steroid-free immuno-suppression regimen, a
constant delivery of immunosuppressive drugs, such as sirolimus, tacrolimus, and daclizumab has to be maintained to
prevent acute islet allograft rejection [52]. At the end islet
transplantation is not a cure for the disease, it merely reestablishes a state of regulated insulin-production. From the
viewpoint of the autoreactive immune system islet transplantation provides new ‘food’ for the auto-aggressive isletspecific T-cells. Only little is known about how autoaggressive CD8 T-cells are attracted to and infiltrate into islet allografts. However, CXCR3 chemokine ligands are likely
candidates for mediating the recruitment of destructive cells
to the transplanted islets because, first, CXCR3 chemokines
are held responsible for initiating allograft rejection of various tissues including heart, lung, liver, cornea, kidney and
the skin [53-58]. Second, islets are capable of producing
CXCR3 chemokine ligands after virus infection [16, 17].
Therefore, blocking of CXCR3 chemokine ligands, such as
CXCL10, which has been proven to be a driving force behind virus-induced T1D in the mouse, should be considered
for administration during islet transplantation therapy. Thus,
CXCL10 could indeed be a drug target for the treatment of
human T1D, if not to directly reverse the ongoing destruction of insulin-producing -cells, then at least to prevent or
delay islet graft rejection.
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