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Response to Letter Regarding Article,
“Blocking of α4 Integrin Does Not Protect
From Acute Ischemic Stroke in Mice”
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Finally, we only partly agree on the statement that “natalizumab has a well-established (…) pharmacological profile.”
Even if the relevance of VLA-4 for immune cell trafficking is
beyond doubt, we still have to learn much more about its effects
on different immune cell populations under different disease
states. For example, recent findings suggest that lymphocyte
trafficking into the central nervous system of patients with multiple sclerosis receiving natalizumab can occur by using the
alternative adhesion molecules, P-selectin glycoprotein ligand-1
(PSGL-1) and melanoma cell adhesion molecule (MCAM), the
latter representing an exclusive pathway for T helper 17 (TH17)
cells to migrate over the blood–brain barrier.6
Taken together, any effort to substantially improve current
stroke treatment is greatly appreciated. Clinician scientist should
team up with partners from the industries to identify the most
promising drug targets. Clearly, the immune system represents one
of these innovative approaches, and the results from the ACTION
trial are eagerly awaited.
We thank Elkins et al1 for their interest in our study2 and their
thoughtful comments.
We fully agree that preclinical stroke models can only mimic
certain aspects of this heterogeneous disease and the decision
to enter into clinical trial programs should not only depend on
the results from animal studies albeit the predictive value of
experimental stroke studies is probably better than previously
perceived.3
In fact, based on our neutral findings regarding the efficacy of
blocking very late antigen-4 (VLA-4) in mouse models of brain
ischemia,2 we never claimed to halt or delay the ongoing Phase
2 ACTION trial (NCT01955707) testing natalizumab in patients
with ischemic stroke. Instead, we think that modulating the
immune system could become an attractive strategy to positively
influence stroke outcome,2 and we appreciate the commitment of
any pharmaceutical company in the stroke field in a time when
industry, because of countless disappointments, has almost completely pulled out of stroke research.
However, we still doubt whether in ischemic stroke the role
of T lymphocytes, which are the main target of any anti–VLA-4
strategy, is already adequately understood to justify large-scale
clinical trials. Fundamental questions remain unresolved. For
instance, we currently cannot even be sure about the net biological effect (detrimental versus beneficial) of T cells or certain
T-cell subsets in the ischemic brain4 and whether or not these
complex and highly diverse immune cells contribute to infarct
growth or tissue regeneration probably depends on the stage of
infarction, that is, acute versus chronic. Accordingly, studies on
other immunomodulators (FTY720, glatiramer acetate) derived
from the multiple sclerosis field likewise produced conflicting
results in preclinical stroke5 and blocking the transmigration of
neutrophils into the ischemic brain has proven unsuccessful under
clinical conditions.
Safety is another key point. Although we concede that the
safety profile of natalizumab is well established in multiple sclerosis, it remains unclear whether this can be easily transferred
to the situation in ischemic stroke, which triggers substantial
immunodepression. None of the existing preclinical studies on
VLA-4 blockade in rodent stroke specifically addressed safety
aspects, and although the probability of developing progressive
multifocal leukoencephalopathy after a single infusion of natalizumab during the acute phase of an ischemic insult is indeed
very low, the consequences of anti–VLA-4 strategies for JC
virus homeostasis are still incompletely understood. Moreover,
it is at least conceivable that natalizumab induces serious infections other than progressive multifocal leukoencephalopathy in
patients with stroke, for example, pneumonia, which is known to
worsen stroke outcome.
Disclosures
Drs Kleinschnitz and Wiendl have received consulting fees, speakers’
honoraria, and research support from Biogen Idec.
Christoph Kleinschnitz, MD
Friederike Langhauser, PhD
Department of Neurology
University Clinics Würzburg
Würzburg, Germany
Heinz Wiendl, MD
Department of Neurology
University of Münster
Münster, Germany
1. Elkins JS, Johnston SC, Elkind MSV. Letter by Elkins et al regarding
article, “Blocking of α4 integrin does not protect from acute ischemic
stroke in mice. Stroke. 2014;45:e195.
2. Langhauser F, Kraft P, Göb E, Leinweber J, Schuhmann MK, Lorenz K,
et al. Blocking of α4 integrin does not protect from acute ischemic stroke
in mice. Stroke. 2014;45:1799–1806.
3. Dirnagl U, Endres M. Found in translation: preclinical stroke research
predicts human pathophysiology, clinical phenotypes, and therapeutic
outcomes. Stroke. 2014;45:1510–1518.
4. Kleinschnitz C, Wiendl H. Con: Regulatory T cells are protective in ischemic stroke. Stroke. 2013;44:e87–e88.
5. Kraft P, Göb E, Schuhmann MK, Göbel K, Deppermann C, Thielmann
I, et al. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke.
2013;44:3202–3210.
6. Schneider-Hohendorf T, Rossaint J, Mohan H, Böning D, Breuer J,
Kuhlmann T, et al. VLA-4 blockade promotes differential routes into
human CNS involving PSGL-1-rolling of T cells and MCAM-adhesion
of TH17 cells. J Exp Med. In press.
(Stroke. 2014;45:e196.)
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.006634
e196
Response to Letter Regarding Article, ''Blocking of α4 Integrin Does Not Protect From
Acute Ischemic Stroke in Mice''
Christoph Kleinschnitz, Friederike Langhauser and Heinz Wiendl
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Stroke. 2014;45:e196; originally published online July 24, 2014;
doi: 10.1161/STROKEAHA.114.006634
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Copyright © 2014 American Heart Association, Inc. All rights reserved.
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