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Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat.

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Anti-CD1 l b Monoclonal Antibody Reduces
Ischemic Cell Damage after Transient
Focal Cerebral Ischemia in Rat
H. Chen, MD,4 M. Chopp, PhD,*$ R. L. Zhang, MD,* G. Bodzin, BS," Q. Chen, PhD,?$
J. R. Rusche, PhD,§ and R. F. Todd 111, MD, PhD'
We investigated the effect of an anti-CDllb monoclonal antibody (1B6c) on ischemic cell damage after transient
middle cerebral artery occlusion. We divided animals into three groups: MAb 1 group (n = 5)-rats were subjected
to 2 hours of transient occlusion and I B6c (1mgikg) was administered intravenously at 0 and 22 hours of reperfusion;
MAb 2 group (n = 5)-same experimental protocol as MAb 1 group, except that the initial dose of IB6c was increased
to 2 mg/kg; and control group (n = 5)-same experimental protocol as MAb 2 group, except that an isotype-matched
control antibody was administered. Animals were weighed and tested for neurological function before and after
occlusion of the middle cerebral artery. Forty-six hours after reperfusion, brain sections were stained with hematoxylin
and eosin for histology evaluation. We observed a significant reduction of weight loss and improvement in neurological
function after ischemia in the MAb 2 animals compared to MAb 1 and vehicle-treated animals ( p < 0.05). The lesion
volume was significantly smaller in the MAb 2 group (19.5 2 1.9%) compared to MAb1 (29.9 f 2.6%) and vehicletreated (34.2 2 5.496) groups ( p < 0.01). Tissue polymorphonuclear cell numbers were reduced in both 1B6cadministered groups. Our data demonstrate that administration of antLCD1 1b antibody results in a dose-dependent,
significant functional improvement and reduction of ischemic cell damage after transient focal cerebral ischemia in
the rat.
Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF 111. Anti-CDl lb
monoclonal antibody reduces ischemic cell damage after transient focal cerebral
ischemia in rat. Ann Neurol 1994;35:458-463
Polymorphonuclear leukocytes (PMNs, predominately
neutrophils) and monocytesimacrophages have been
found in the central nervous systems of clinical stroke
patients 111 and in animal models of cerebral ischemia
12-51, The activation and migration of PMNs may
contribute to ischemic tissue damage by reducing microvascular blood flow, initiating thrombosis, and releasing oxygen free radicals and proteinases L6-9). Reduction of the numbers of peripheral neutrophils has
been shown to be beneficial in reducing ischemic cell
damage in the heart [10-12), lung [13, 141, liver [Is],
and central nervous system [ l b , 17). However, elimination or reduction of circulating leukocytes in order
to reduce ischemic injury may not be practical for clinical patients. Alternative methods, by which postischemic cerebral inflammation is suppressed and tissue
injury reduced, would be welcome.
CDl Ib is a subunit of the leukocyte integrin Mac-I,
predominantly expressed by neutrophils and monocytes/macrophages. Mac- 1 mediates the binding of ac-
tivated leukocytes to vascular endothelial cells 118, 191.
Anti-Mac-I antibodies have been shown to prevent
the migration of leukocytes into the inflamed tissues,
and to reduce cell damage after canine myocardial ischemia and rat liver ischemia {20-22). However, the
effect of the anti-Mac-I antibody on cerebral focal
ischemic injury has not been investigated. We therefore tested the effect of the anti-CDllb antibody on
cerebral ischemic cell damage in rats subjected to transient (2-hour) occlusion of the middle cerebral artery
(MCA) and 46 hours of reperfusion.
From the Deparrnienrs of "Neurology and ?Radiation Oncology,
Henry Ford Hospital, Detrior; iDepartment of- Phvsics, Oakland
Keceived Mar 31, 1993, and in revised form Jun 3 and Srp 3. Acceoted for Dublication SeD 9. 1993.
Materials and Methods
Male Wistar rats (weighing 270-300 gm, n = 23) were used
in the experiment. Transient occlusion of the MCA was induced by advancing a 4-0 surgical nylon suture into the internal carotid arterty (ICA) to block the origin of the MCA 123,
241. This model has been modified in our laboratory 131.
Briefly, animals were anesthetized with 3.5% halothane, and
maintained with 1.0 to 2.0% halothane in 7076 nitrous oxide
and 30% oxygen using a face mask. Rectal temperature was
458 Copyright 0 1904 by the American Neurological Association
maintained at 37°C throughout the surgical procedure using
a feedback-regulated water-heating system. The right femoral
artery and vein were cannulated for measuring blood gases
(pH, oxygen tension [Po,], carbon dioxide tension [PcoJ)
before ischemia, for monitoring blood pressure during the
surgery, and for drug administration, respectively. The right
common carotid artery (CCA), external carotid artery (ECA),
and ICA were exposed. A length, 18.5 to 19.5-mm of 4-0
surgical nylon suture, determined by the animal weight, was
advanced from the ECA into the lumen of the ICA until it
blocked the origin of the MCA. Two hours after transient
occlusion of the MCA, animals were reanesthetized with
halothane, and reperfusion was performed by withdrawal of
the suture until the tip cleared the ICA lumen.
Animals were fasted overnight before surgery, but had free
access to water. Animals were randomly divided into three
groups: animals in MAb 1 group (n = 5) were subjected to
transient occlusion of the MCA and an anti-rat CD1 l b integrin monoclonal antibody {25]; clone 1B6c, kindly provided
by Repligen (Cambridge, MA) was infused intravenously
over a 3-minute interval at a dose of 1 mgikg, immediately
after withdrawal of the suture (0 hour of reperfusion) and at
22 hours after reperfusion. Animals in MAb 2 group ( n =
5 ) were subjected to transient occlusion of the MCA and
lB6c was administered at the same time as in MAb 1 group;
however, an increased dose of 2 mgikg was administered at
0 hour of reperfusion. Control animals (n = 5 ) were subjected to transient occlusion of the MCA and were administered an isotype-matched control antibody (mouse lgG, from
Caltag Laboratories, CA) at 0 and 22 hours of reperfusion,
using the same volume doses as MAb 2 group.
An additional 8 animals, without ischemia, were used to
measure the peripheral blood leukocyte counts after lB6c
or control antibody infusion. Animals were administered (intravenously) 1B6c ( n = 4 ) or control antibody ( n = 4 ) at a
dose of' 2 mgikg at 0 hour and 1 mg/kg at 22 hours after
the first infusion. Peripheral blood samples were obtained
before and 15 minutes after each antibody administration,
and at 46 hours after the first infusion.
Ischemic animals were weighed before fasting and at 22
and 46 hours after reperfusion. A neurological examination,
as described by Zea Longa and coauthors 1241, was performed 1 hour after occlusion, and at 22 and 46 hours of
reperfusion. A scoring scale from 0 to 4 was used: 0, normal;
1, failure to extend the left forepaw; 2, circling to the left;
3, falling to the left; and 4, did not walk spontaneously and
exhibited a depressed level of consciousness.
Plasma samples (500 pl) from selective animals of MAb 1
and MAb 2 groups were obtained before and 15 minutes
after each 1B6c infusion and before they were killed, to
determine the blood level of antibody after administration of
1B6c, using an enzyme-linked immunosorbent assay
(ELISA). Briefly, ELISA plates were coated with purified
Mac-I at a 1/20 dilution. A standard curve was generated
using purified lB6c diluted into 10% normal rat plasma at
the following concentrations: 3, 1, 0.33, 0.11, 0.037, 0.012,
and 0.004 yg1ml. The rat plasma samples containing antibody
were run at the following dilutions: 1/10, 1/30, 1/90, 11270,
11810, 117,290, 112 1,870. A horseradish peroxidase-labeled
anti-mouse IgG was used as the secondary antibody. The
plate was developed using 2,2'-azinobid( 3-ethylbenzthiazol-
inesulfonic acid) (ABTS), a chromogenic substrate for peroxidase. The plate was allowed to develop for 30 minutes and
was then read on a V, microplate reader. The antibody
concentrations were extrapolated from the standard curve
using the SOlTmax software package from Molecular Devices (Menlo Park, CA).
Measurements of peripheral white blood cell (WBC)
counts and differentials were performed manually using a
hemocytometer, and by blood smears stained with WrightGiemsa stain, respectively. One hundred cells were counted
for each of the differentials. The percentage of differentials
was multiplied by the WBC counts to obtain the absolute
number per milliliter of blood.
Ischemic animals were anesthetized (intramuscularly) with
ketamine (44 mgikg) and xylazine (13 mgikg) at 46 hours of
reperfusion. Rats were transcardially perfused with heparinized saline solution and 109; buffered formalin, and brains
were removed. To confirm that the inserted suture passed
the origin of the MCA, animals were injected (intravenously)
with 1 ml of 2 9 , Evans blue dye 30 minutes before perfusion.
The Evans blue dye stains the vascular wall along the path
of the suture. Each brain was cut into 2-mm-thick coronal
blocks, for a total of 7 blocks per animal, using a rat brain
matrix. The brain tissue was processed and embedded in
paraffin, and 6-ym-thick sections from each block were cut
and stained with hematoxylin and eosin (H&E) for histopathological evaluation. No histological examination of tissue was
performed on the animals without ischemia.
One coronal section, located approximately at the level of
interaural 8.2 mm, bregma 0.8 mm 1261, was used to count
PMNs in each ischemic animal. PMNs were identified by
the morphology of the nuclei [2-4,2 11. PMNs were counted
using a light microscope in six high-power fields ( x 100)
within the lesion area. These six fields were selected randomly in the cortex and the basal ganglion. P M N data are
presented as numbers in an average of the six fields.
Tissue volume was measured, using an Imagist-2 image
analysis system (PGT, Princeton, NJ). Each H&E-stained section was evaluated at x 2.5 magnification. The lesion area
and the ipsilateral hemispheric area (square millimeters) were
calculated by tracing the areas on the computer screen, and
the volumes (cubic millimeters) were determined by multiplying the appropriate area by the section interval thickness
[27]. The lesion volume size was presented as the percentage
of lesion to the ipsilateral hemisphere, to avoid errors associated with processing of tissue for histological analysis.
Statistin
A Kruskal-Wallis test was performed at each time to compare
the neurological test values in the three groups that underwent MCA occlusion. If a significant difference ( p < 0.05)
was detected, then a group-to-group comparison was performed. Paired t tests were performed on the peripheral
WBC and differential counts in the antibody administrationonly groups and on the animal weights in the three groups
that underwent MCA occlusion, in order to detect differences in values between pre- and post-antibody administration or ischemia within each group. One-way analysis of variance was performed on the lesion volume and tissue PMN
numbers in the three occlusion groups. If a significant difference was detected, then a two-sample t test with Bonferroni
Chen et al: Anti-CDllb in Cerebral Ischemia
459
administration value ( p < 0.05). However, all the
WBC and differential values were within a normal
physiological range.
Figure 1 is a plot of the neurological deficit scores
at 1 hour after onset of MCA occlusion, and 22 and
46 hours after reperfusion in the three ucclusion
groups. MAb 2 animals exhibited a significantly improved neurological function (lower score) than either
the control or MAb 1 group of animals at 22 hours of
reperfusion ( p < 0.05).
Figure 2 shows the mean animal weights before
MCA occlusion, and at 22 and 46 hours of reperfusion.
Within each group, a significant decline of weight was
detected at 22 and 46 hours of reperfusion when compared to the preocclusion value, in all three groups of
animals ( p < 0.05). Animals from control and MAb 1
groups continued to lose weight at 46 hours of reperfusion. In contrast, the MAb 2 group of animals gained
weight at this time. At 46 hours of reperfusion, the
MAb 2 group of animals exhibited a significantly
higher weight than did both control and MAb 1 groups
of animals ( p < 0.05).
Evans blue staining at 46 hours of reperfusion confirmed the successful placement of the suture past the
MCA in all animals. Both control and MAb 1 animals
exhibited an ischemic lesion within the MCA territory
(Fig 3A). The cerebral tissue exhibited a sharply demarcated ischemic infarct (death of brain parenchymal
correction was performed to detect differences between
groups. All the measurements were performed blindly (by
H. C., R. L. Z., and G. B.). All data are presented as means
standard deviations.
*
Results
Blood gases were within a normal physiological range
in all three occlusion groups of animals. Blood pressure
was stable during the infusion of antibodies, in 1B6c
and control antibody groups (Table 1). No anti-CD1 I b
antibody was detected in the plasma samples taken before the initial antibody injection. A free antibody concentration (> 0.5 pgiml) that saturates all C D l l b receptors was detected in all the plasma samples taken
after 1B6c administration (from 15 minutes up to 48
hours after injection) in both MAb 1 and MAb 2
groups (data not shown).
Table 2 shows the peripheral WBC and differential
counts in lB6c and control antibody infusion-only
groups. No difference was detected in WBC counts
after antibody administration in both groups. A decrease of neutrophils and monocytes was detected in
the lB6c infusion group ( p < 0.05) at 15 minutes after
the second antibody administration when compared to
pre-antibody administration values. Likewise, an increase of lymphocytes was detected in the lB6c group
before and after antibody administration at 22 hours
of reperfusion, when compared to the pre-antibody
?’able 1 . Blood Gasec and Blood Pressure., (BPs) (Means
-t
Standard Detmztiom! In the Three Oc(luszot1Groupr
pH
(mm Hg)
POL
(mm Hg)
Antibody Injection
before (mm Hg)
Antibody Injection
after (mm Hg)
7.41 2 0 03
7 43 ir 0.03,
7.42 2 0 03
35 L 6
38 2 5
12 2 8
128
113
122
95 2 9
NIA
98 f 10
100 f 9
NIA
101 +
Pco,
Groupsa
Control ( n
MAb 1 (n
MAb 2 ( n
=
=
=
5)
5)
5)
2
&
*
13,
11
11
”Groups are defined in text.
NIA
=
not measured.
Table 2. Peripheral Whrte Blood Cell IWBC) and Differential Valuer i x 1.000lmm’: hleati
after Antibody Admznzstration z?z Nonischemzc Control and 1861 Animals
Groups
Control (n
=
4)
lB6c (n = 4 )
Time
WBC
Before
15 min
22 hr
22 hr 15 min
46 hr
Before
15 min
22 hr
22 hr 15 min
46 hr
7.4 0.2
6.8 ? 0.2
7.1 i 0.4
7.0 2 0.4
7.1 i 0.4
7.0 ? 0.6
6.8 f 0.4
6.8
0.2
6.6 5 0.4
6.5 2 0.5
6.0-17.0
Normal range”
*
*
’From Harkness and Wagner 132).
bp < 0.05 compared to the “before” value.
460 Annals of Neurology Vol 35 No 4 April 1994
t
Standard Dwiationi before iknd
Lymphocyte
Ncurrophil
Monocyte
4.0
0.3
0.5
2.8
4.6 c 0.7
1.7
4.6
4.7 f 2.7
4.6 f 1.1
2.6
2.2
2.2
4.9 t 0.4
1.7
5.1
5.9
0.7
?
~t2.0
* 0.4
* 0.25
5.8 +- 0 . Y
5.4 i 0.4
-3.9-14.5
0.7
0.6
i 1.0
f 1.0
t 1.0
i 0.7
2
?
-t 0.2
0.2 f 0.1
0.1 f 0.1
1.5 t 0.7
0.1
0.3
0.3
0.4
0.2
0.1
0.6
O.lb
0.8 2 0.2
0.5-5.8
0.3
0.2
0-0.9
*
+
0.2
0.2
i 0.2
2 0.1
2 0.1
i
i
0.0 f 0 . l b
*
Control
MAbl
MAb2
0
0
-1
AAA
00000
OoCm
22
46
46
Reperfusion T i m e (Hours)
F i g I . Plot o/' the neurological dejicit Jcores at 1 hour after occlusion o/' the middle cerebral arter),, and 22 and 46 hours ufter reperfusion in the whicle-treated group (closed circles),M A b 1
group (open triangles), and M A b 2 group (open squares). Asterisk indicates p < 0.0j.
200
1
-10
pre-MCAo
22
46
50
Fig 3. Hematoxylin and eo.rin staining of6-~m-thick,
puruffin-embedded sections from representatiw animah o/ the 1Jehdetreated group iA, and the MAb 2 group (B).
Reperfusion Time (Hours)
F i g 2. Means f standard deuiationr of animal uvigbts befort
middle cerebral arteq occlwion (MCAo), and 22 and 46 hours
ufter reperfiaion in the vehicletreated group (closed circles),
MAb 1 group (open triangles), and MAC 2 group (open
squares). Asterisk indicutes p < 0.05.
cells, including neurons and glia), both in cortex and in
basal ganglion. In MAb 2 animals, infarct was primarily
localized to the basal ganglion (Fig 33).The cortex
exhibited selective eosinophilic neurons. PMNs were
detected within the lesion, in all three groups of animals.
Table 3 summarizes the absolute values of the ipsilateral hemisphere and the lesion volumes, the percent
volume of the lesion, and the PMN numbers within
the lesion in the three occlusion groups. Analysis of
variance demonstrated significant differences among
groups in lesion volume and tissue PMN numbers ( p
= 0.002). No difference in lesion volume was detected
between the MAb 1 group and the control group.
MAb 2 animals exhibited a significantly smaller lesion
volume, when compared to the control group ( p <
0.01) and MAb 1 group ( p < 0.01). Both MAb 1
and MAb 2 animals exhibited significantly lower tissue
PMN counts when compared to control animals (p <
0.01 and p < 0.001, respectively), while no difference
was detected between the two antibody groups.
Discussion
Our data demonstrate that intravenous administration
of an appropriate dose of a monoclonal antibody
against the leukocyte adhesion molecule Mac-1 significantly inhibits postischemic weight loss, reduces
neurological dysfunction, reduces the ischemic lesion
volume, and inhibits the infiltration of PMNs into the
ischemic tissue after transient focal cerebral ischemia.
A significant difference of ischemic lesion volume
was detected between MAb 1 (1Bbc dose of 1 mgikg)
and MAb 2 (1Bbc dose of 2 mgikg) groups. However,
the plasma levels of free antibody concentration were
saturated in both groups. At this time, we can not deChen er al: A n t i - C D l l b in CLerebral lschemia
461
Table 3 Absolute Hemisphere and Leston Volumes. the Percent Leszon Volume to the lpsilateral Henzzsphere. and Tmue (Mean ?
Standard Dmzatton) Polymorphonuclear Celk (PMNs) In the Three Oiilurzon Groups iniectn i SO)
Control (n = 5 )
MAb 1 (n = 5 )
MAb 2 (n = 5 )
Hemisphere (mm”l
Lesion (mrn’i
2 Lesion Volume
PMNs ( x 100)
450.9 t 56.2
479.7 t 17.3
424.3 & 37.8
157.3 ? 38.1
143.5 t 11.5
83.1 k 12.Ybb
34.2
29.9
19.5
33
20
15
2
2
?
I
5.4
2.6
1.9”3”
*3
f
6“
k
4”
“p < 0.01 compared to the vehicle group.
bp < 0.01 compared co the MAb 1 group.
termine whether the detected plasma antibody concentration reflects the actual concentration of the antibody
in the brain microenvironment. Since both doses of
antibody would saturate CD1 1b receptors on the circulating granulocytes, whole-blood receptor binding does
not appear to strictly correlate with efficacy. Further
investigation of the dose response of ischemic protection is required.
There are multiple mechanisms involved in the antiCD1 I b antibody protection in cerebral ischemia.
Anti-Mac- 1 antibodies have been demonstrated to inhibit PMN infiltration and reduce ischemic injury in
heart and liver C20, 21). Our results correlating reduced numbers of tissue PMNs with smaller lesion
volume after 1BGc treatment in MAb 2 group suggest
that one mechanism in which anti-CD1 1b antibody attenuates ischemic injury is by inhibiting PMN infiltration. However, Simpson and colleagues 122) reported
a significant reduction in infarct size after myocardial
ischemia by the administration of an anti-Mac- 1 antibody, without observing an attentuation of inflammatory cell infiltration. In our study, we also observed a
significant reduction of PMN numbers in the low-dose
lB6c treatment animals (MAb 1 group) with no concomitant reduction of ischemic lesion size. An inhibition of oxygen free radical production by neutrophils
after administration of the anti-CD 1 I b antibody has
been observed in vivo in a model of rat liver ischemia
1201and in vitro in cultures of activated neutrophil and
endothelial cells {28]. Thus, it is possible that administration of the antLCD1 l b antibody in the low-dose
group reduces PMN traffic into the tissue, but not
enough to block the cytotoxic effects of free radicals
produced by the PMNs.
The antiinflammatory effect of antiintegrin antibodies on the response of the central nervous system to an
ischemic insult is controversial. Anti-CD 18 antibody
lessens behavioral deficits in rabbits after reversible spinal cord ischemia [291 and improves the microcirculation in a baboon model of transient focal ischemia 1301.
However, Takeshima and coworkers [31) failed to detect a beneficial effect of an anti-CD18 antibody on
cerebral blood flow and ischemic infarct volume after
transient occlusion of the MCA in cats. CD11 (a, b, c)
and CD18 are subunits of leukocyte B, integrin family
462 Annals of Neurology Vol 35 No 4 April 1994
(LFA-1, Mac-1, and P150,95) which function in adhesion-dependent, leukocyte-mediated inflammatory response. The effect of various antiadhesion antibodies
in reducing ischemic cell damage may be model dependent. Different species of animals and models of ischemia may promote postischemic inflammatory changes
by means of different combinations of adhesion molecules. Thus, a specific antibody may be effective in
reducing ischemic cell damage in our model and possibly not in another. in addition, the effectiveness of the
antibody may be dose dependent, as we observed in
our present study.
A normal range of circulating WBCs and PMNs was
maintained after anti-CD11 b antibody administration.
This may have important clinical implications, as this
antibody specifically inhibits the cytotoxic effect of leukocytes to the tissue, and no global immunosuppression is suspected. However, in the absence of data on
leukocyte adhesion, chemotaxis, oxygen-based free
radical production, and phagocytosis, we can not confirm the absence of immunosuppression. We did not
measure peripheral WBC and PMN numbers in the
ischemic animals administered lB6c or control antibody in our study. However, in a separate study of
lB6c (2 mgikg) administration 1 hour after reperfusion, a normal range of PMNs was observed in animals
subjected to occlusion of the MCA (data not shown).
Thus, our experiment suggests that the anti-CD1 Ib
antibody ( 1B6c) reduces the ischemic lesion specilirally by blocking the PMN membrane receptors.
In conclusion, administration of the monoclonal antibody directed against the CD1 l b integrin significantly reduces the functional deficit and ischemic injury after stroke in a dose-dependent way. Neutrophil
adhesion may play an important role in ischemic cell
damage after cerebral ischemia and inhibition of adhesion-dependent, neutrophil-mediated inflammatory
injury with antibody may reduce ischemic cell damage.
Our data suggest that inhibition of adhesion may be
useful in treating brain after transient focal cerebral
ischemia.
This work wils supported by National Institute of Neurological Disorders and Stroke grants NS23393 and NS29463.
The authors wish to thank Patricia Ruffin and Denice Janus for their
help with the manuscript preparation; Drs Julio H. Garcia at Henry
Ford Hospital, C. W. Smith at Baylor Medicine, Houston, and D. P.
Witt at Repligen for their helpful discussion; K. Sokolowski at Repligen and Lisa Petritoni, HTL (ASCP), at Henry Ford Hospital for
technical assistance; and Repligen for providing the antibody.
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