Stroke-Induced Immunodepression

Experimental Evidence and Clinical Relevance

Ulrich Dirnagl, MD; Juliane Klehmet, MD; Johann S. Braun, MD; Hendrik Harms, MD;
Christian Meisel, MD; Tjalf Ziemssen, MD; Konstantin Prass, MD; Andreas Meisel, MD
AbstractStroke affects the normally well-balanced interplay of the 2 supersystems: the nervous and the immune system.
Recent research elucidated some of the involved signals and mechanisms and, importantly, was able to demonstrate that
brain-immune interactions are highly relevant for functional outcome after stroke. Immunodepression after stroke
increases the susceptibility to infection, the most relevant complication in stroke patients. However, immunodepression
after stroke may also have beneficial effects, for example, by suppressing autoaggressive responses during lesioninduced exposure of central nervous system-specific antigens to the immune system. Thus, before immunomodulatory
therapy can be applied to stroke patients, we need to understand better the interaction of brain and immune system after
focal cerebral ischemia. Until then, anticipating an important consequence of stroke-induced immunodepression,
bacterial infection, preventive antibiotic strategies have been proposed. In mouse experiments, preventive antibiotic
treatment dramatically improves mortality and outcome. Results of clinical studies on this issue are contradictory at
present, and larger trials are needed to settle the question whether (and which) stroke patients should be preventively
treated. Nevertheless, clinical evidence is emerging demonstrating that stroke-induced immunodepression in humans not
only exists, but has very similar features to those characterized in rodent experiments. (Stroke. 2007;38[part 2]:770773.)
Key Words: brain infarction brain ischemia experimental focal ischemia immunology infectious disease
inflammation treatment

ecently, major advances have been made in our understanding of the roles of both cellular and humoral
inflammation in cerebral ischemia. In particular, it is emerging that innate and adaptive immunity play an important role
for the outcome after focal cerebral ischemia (stroke). Stroke
has dramatic consequences for the normally well-balanced
interplay of the two supersystems, the nervous and the
immune systems: brain inflammation and immunodepression.
We are only beginning to understand that the consequences of
brain-immune interactions after stroke are neither good nor
bad, an insight that might imply that targeted therapeutic
intervention (anti-inflammation; immunomodulation,
etc) may prove to be less straightforward as initially hoped
for. Here we briefly review stroke-induced inflammation, and
focus on stroke-induced immunodepression, a recently described phenomenon that may be the key factor underlying
susceptibility to infection after stroke.

Stroke Induces Local Inflammation In Situ

After stroke, leukocytes home toward the lesion, and brain
parenchymal cells (microglia, astrocytes, endothelia, even

neurons) transform to an inflammatory phenotype. Most of

the available literature links stroke induced inflammation to
the progression of damage. Thus, inhibition of inflammation
would seem to be the most straightforward therapeutic
strategy. However, inflammation is a key mechanism of any
tissue to cope not only with the invasion of pathogens but also
with tissue destruction. Inflammation plays an important part
in the clearing of damaged tissue, and in the ensuing processes of angiogenesis, tissue remodeling, and regeneration.
This is probably best studied in wound healing, which is
severely compromised if inflammation is inhibited.1,2 The
potential benefits of inflammation after stroke have received
relatively little attention so far, but indirect evidence suggests
that certain kinds of inflammatory reactions are neuroprotective and neuroregenerative.3,4 In brief, macrophages and
microglia produce a host of trophic cytokines when activated,
and macrophages or T-cells exposed to certain central nervous system (CNS)-specific antigens ex vivo partake in tissue
repair and recovery after nerve transsection and spinal cord
injury. However, these benefits may be at least partially offset
not only by bystander toxicity of inflammation but also by

Received May 17, 2006; final revision received September 4, 2006; accepted September 13, 2006.
From Department of Neurology (U.D., J.K., J.S.B., H.H., K.P., A.M.), Department of Experimental Neurology, Center for Stroke Research and
Department of Medical Immunology (C.M.), Charite Universitatsmedizin, Berlin, Germany; Department of Neurology (T.Z.), University of Dresden,
Germany.
Correspondence to Prof Dr Ulrich Dirnagl, Department of Experimental Neurology, Charite Universitatsmedizin Berlin, Chariteplatz 1, 10098 Berlin,
Germany. E-mail ulrich.dirnagl@charite.de
2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/01.STR.0000251441.89665.bc

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Dirnagl et al

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771

administration of IFN at day 1 after focal cerebral ischemia

greatly decreases the bacterial burden. Importantly, the IFN
deficiency and the occurrence of bacterial infections can be
prevented by blocking the sympathetic nervous system, but
not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the -adrenoreceptor blocker propranolol
drastically reduces mortality after middle cerebral artery
occlusion.9 Immunodepression after stroke can be detected
within a few hours after induction of ischemia, and lasts for
several weeks. These and other studies indicate that a catecholamine-mediated defect in early lymphocyte activation is
the key factor in the impaired anti-bacterial immune response
after stroke.

Is Stroke-Induced Pneumonia a Result of

Aspiration, Immunodepression, or Both?

Figure 1. Experimental stroke induces immunodepression via

the hypothalamic pituitary axis (HPA) and the sympathetic nervous system (SNS). SNS plays a key role because -receptor
blockade exerts comprehensive effects on stroke induced alterations of the immune system and outcome (box). Blockade of
the HPA axis with the glucocorticoid receptor antagonist RU486
only improves lymphopenia and monocyte deactivation.9

scar formation, which in peripheral tissues is key to wound

closure, but in the brain is a major impediment of regeneration and plasticity.5 A recent example for the dual nature and
complexities of ischemia-induced inflammation has been the
uncovering of a regenerative role for matrix metalloprotein
activation,6 enzymes that were previously almost exclusively
linked to blood brain barrier disruption and lesion expansion.

Stroke Induces Systemic Immunodepression

Infections are a leading cause of death in patients with stroke.
Eighty-five percent of all stroke patients have relevant complications; of which, infection is the most frequent (23% to
65%). Infection also is the most relevant complication during
rehabilitation, and infection is the number one cause of death
in stroke after day 1. It has become clear that CNS injury is
an independent risk factor, which specifically and significantly increases susceptibility to infection. Only recently it
has been realized that CNS injury, including stroke, induces
immunodepression, and that this is the mechanism by which
CNS injury leads to secondary immunodeficiency (CNS
injury-induced immunodepression [CIDS]7) and infection.
Results from our laboratory and other groups have explored
the mechanisms how stroke downregulates peripheral immunity (Figure 1). In brief, within 3 days after focal cerebral
ischemia, mice develop spontaneous pneumonia and septicemia. Focal cerebral ischemia induces an extensive apoptotic
loss of lymphocytes and a shift from T helper cell (Th)1 to
Th2 cytokine production. Secondary lymphatic organs like
spleen and thymus atrophy after focal cerebral ischemia.8
In parallel to the changes in the adaptive immune system,
monocyte counts and function are compromised as well.
Adoptive transfer of T and natural killer cells from wild-type
mice, but not from interferon (IFN)-deficient mice, or

Bacterial pneumonia is the most common cause of death in

acute stroke patients. Reduction of bulbar reflexes, drowsiness, dysphagia, and subsequent aspiration are considered to
be major contributors to the high incidence of bacterial
pneumonia after stroke.10 In a murine model of aspiration
pneumonia, we have evaluated whether stroke-induced immunodepression contributes to the development of pneumonia after stroke. We were able to show that intranasal
aspiration of only 200 colony-forming units of Streptococcus
pneumoniae cause severe pneumonia and bacteremia in mice
after transient middle cerebral artery occlusion. In contrast,
200 000 colony-forming units are needed to induce pneumonia of similar severity, but fail to induce bacteremia in sham
animals. Aspiration pneumonia in animals after focal cerebral
ischemia was prevented by -adrenoceptor blockade, suggesting that immunodepression by sympathetic hyperactivity
is essential for poststroke pneumonia.11 Therefore, the deleterious combination of stroke-facilitated aspiration and
stroke-induced immune deficiency drastically increases the
susceptibility to infection.

What Causes
Stroke-Induced Immunodepression?
Although the phenomenon of stroke-induced immunodepression is well-established, it remains unclear which signals and
mechanisms trigger the sympathetic nervous system and the
hypothalamicpituitary axis to downregulate immune responses after brain ischemia. Several lines of clinical and
experimental evidence indicate that pro-inflammatory cytokines produced by damaged brain tissue can directly lead to
hypothalamicpituitary axis and CNS activation. Increased
levels of cytokines, such as interleukin-1, tumor necrosis
factor-, and interleukin-6, have been measured after stroke
in brain parenchyma and cerebrospinal fluid. Because the
autonomic system of the CNS is hard-wired with secondary
lymphoid organs, interruption of these circuits can result in
immune dysfunction. Stroke can lead to direct damage of
sympathetic CNS structures involved in vegetative neuroimmunomodulation. Further support for the concept of an at
least partially neurogenic nature of CIDS comes from studies
on the lateralization of the autonomic nervous system in the
brain. Lateralization of the structures of the vegetative nervous system might also serve to explain some localization-

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772

Stroke

February 2007 Part II

dependent effects of neural-immune interactions subsequent

to stroke.7 Therefore, multiple causesunspecific stress
response, CNS injury-specific neurogenic signaling, and local
CNS inflammation have to be considered as triggers of
systemic immunodepression.

Does Immunodepression After Stroke Protect

the Brain?
At least in animal experiments it has been demonstrated that
stroke-induced immunodepression underlies the increased
rate of infection and unfavorable outcome after focal cerebral
ischemia.9 In principal, immunomodulatory therapy (eg,
IFN, granulocyte colony-stimulating factor, thymopentin)
to reverse the immunodepression after stroke might seem to
be a straightforward strategy to reduce the negative consequences of CIDS. However, too little is known about CIDS to
rule out that it is an adaptive response, which is CNS
protective at the price of an increased risk of infection. For
example, it has been demonstrated that T lymphocytes and
IFN contribute to the inflammatory and thrombogenic brain
injury that results from cerebral ischemia.12 Therefore, depletion of circulating T-cell populations and suppression of
IFN expression, which is the key mechanisms of strokeinduced immunodepression, might counteract the inflammatory brain after stroke.7 Indeed, recent evidence from our
laboratory indicates that stroke-induced immunodepression
suppresses autoaggressive Th1 responses. The blood brain
barrier disruption and tissue destruction after stroke expose
brain epitopes that are normally invisible to the immune
system. This may induce autoregulatory, anti-inflammatory,
and potentially regenerative T-cell responses,13 or rather
prime the immune system to attack the CNS that may be a
particular problem in the context of systemic inflammatory
response14 or a second ischemic event.
In a mouse model of focal cerebral ischemia we detected
increased numbers of myelin oligodendrocyte glycoprotein
(MOG) specific T-cells in the spleen, and an increased influx
of MOG-specific T-cells into the brain. After experimental
stroke, mice transgenic for a MOG-specific T-cell receptor
developed clinical signs of mild experimental autoimmune
encephalitis, which is the animal model of multiple sclerosis.
Transfer of T-cells of MOGT-cell receptor transgenic mice
induced experimental autoimmune encephalitis in naive mice.
Adoptive transfer of wild-type splenocytes (which were
harvested after focal cerebral ischemia) before induction of
focal cerebral ischemia worsens outcome, whereas transfer of
naive splenocytes has no effect (manuscript in preparation).
These findings indicate that stroke triggers an autoreactive
phenotype, against which stroke-induced immunodepression
may partially protect (Figure 2). Clearly, further research is
needed before immunomodulation should be considered in
the treatment of human stroke.

Cell Therapy and the Immune System in

Stroke: A Hypothesis
Recently, a number of groups have demonstrated that treatment with various types of stem or progenitor cells can
favorably improve outcome after experimental stroke. For
example, hematopoietic or mesenchymal stem cells, even

Figure 2. Hypothesis of adaptive function of stroke induced

immunodepression.

when given via a systemic route, seem to foster recovery.15

Most of the research in this field has concentrated on the
homing of these cells toward the ischemic lesion, and their
putative differentiation to neuronal phenotypes. However,
autologous, heterologous, or xenologous transplantation have
multiple and complex effects on the immune system. These
may be the result of the presentation of foreign epitopes (even
in autologous transplantation, because cells are often cultivated in the presence of sera containing xenologous growth
factors), the apoptotic death of a substantial number of
transplanted cells,16 or endogenous production of immunomodulators by stem cells (eg, indoleamine17). Because
long-term outcome after stroke is heavily modulated by the
immune system, we hypothesize that the recently discovered
effects of cell therapy in stroke are at least partially the result
of its action on the immune system of the host. Clearly,
further research is needed to clarify this issue.

How to Prevent the Negative Consequences

of Immunodepression?
Because infection, particularly pneumonia, appears to be the
clinically most significant consequence of stroke-induced
immunodepression, and because immunomodulation at present is not a viable therapeutic option, preventive antibiotic
therapy has been proposed as a measure to improve outcome
after stroke. In an animal model of stroke, prophylaxis against
bacterial infection dramatically improved mortality and reduced infarct sizes.18 In a recently published randomized
clinical trial (ESPIAS trial19), the fluochinolone levofloxacin
did not prevent infections in patients with acute stroke. In
the PANTHERIS trial (http://controlled-trials.com/isrctn/
trial/PANTHERIS/0/74386719.html), we are currently testing whether another fluochinolone, moxifloxacin, prevents
infections in patients with severe stroke. PANTHERIS is a
double-blind, randomized, controlled phase IIb multicenter
trial in which 80 patients with severe stroke (National
Institutes of Health Stroke Scale 11) of the middle cerebral
artery territory were randomized to receive moxifloxacin
(400 mg intravenous daily) or placebo for 5 days starting
within 36 hours after stroke onset. Seventy-nine patients were
analyzed in the intention-to-treat population and 66 in the
per-protocol population. In the intention-to-treat analysis,
patients receiving moxifloxacin showed a strong tendency
toward a lower infection rate compared with patients receiving placebo. Per-protocol analysis revealed a significant

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Dirnagl et al
reduction of the cumulative infection rate (mainly pneumonia) in the moxifloxacin compared with the placebo group.
Patients with infectious complications showed strong signs
of systemic immunodepression (monocyte deactivation, T-cell
dysfunction, etc) before clinical onset of infection. Our data
(manuscript in preparation) indicate that preventive antibacterial therapy with moxifloxacin prevents infectious complications in patients with severe stroke. In addition, inhibition
of cellular immune function after acute stroke appears to
increase the risk of infectious complications. The conflicting
results of the ESPIAS and PANTHERIS may be explained by
patient selection, differences in antibiotics, dosages, and
duration of treatment. Larger trials are needed to characterize
stroke-induced immunodepression in humans and to answer
the questions whether immunodepression and consequently
infection have a clinical impact that can be positively affected
by preventive anti-infective therapy.

Conclusions
There is emerging experimental and clinical evidence that
brainimmune interactions play an important role for outcome after stroke. Because these interactions may have
protective, destructive, or regenerative effects in the brain,
and also impact the organism as a whole, development of
therapeutic strategies is not straightforward. Further research
is needed to understand the signals and mechanisms by which
the adaptive and innate immune systems react to brain tissue
damage, and to unravel the consequences that this has for the
patient.

Sources of Funding
This study was supported by the Hermann and Lilly Schilling
Foundation and the Helmholtz-Gemeinschaft.

Disclosures
U.D., C.M., K.P., and A.M. are inventors on a patent application
(owner: Charite-Humboldt University) in which stroke-induced immunodepression is claimed.

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Stroke-Induced Immunodepression: Experimental Evidence and Clinical Relevance

Ulrich Dirnagl, Juliane Klehmet, Johann S. Braun, Hendrik Harms, Christian Meisel, Tjalf
Ziemssen, Konstantin Prass and Andreas Meisel
Stroke. 2007;38:770-773
doi: 10.1161/01.STR.0000251441.89665.bc
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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