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*
Section of Atherosclerosis, Department of Medicine,
Center for Comparative Medicine,
Speros P. Martel Laboratory of Leukocyte Biology, Department of Pediatrics, and
Section of Infectious Disease, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 subunit of the
CD11/CD18 integrins, leading to a severe or total deficiency of the
CD11/CD18 integrins from the leukocyte surface, including CD11a/CD18
(LFA-1, 
L2), CD11b/CD18 (Mac-1, complement
receptor 3 (CR3), M2), CD11c/CD18 (p150, 95,
X2), and CD11d/CD18
(D2) (1, 2, 3). Clinically, LAD I is
manifested by leukocytosis, spontaneous infections, impaired wound
healing, and early mortality (4). The CD11/CD18 integrins have been shown to be involved in the pathogenesis of many inflammatory diseases (5), including myocardial ischemia-reperfusion injury (6) and restenosis following coronary angioplasty (7, 8). Selective pharmacological inhibition of specific CD11/CD18 integrins may provide therapeutic benefit without causing the broad defects in host defense seen with complete absence of CD18.
Mice with genetic absence of CD18 develop spontaneous skin ulcerations and also have leukocytosis and impaired T cell function, thus serving as a useful model to study LAD I (9). Global mortality observed in these animals following i.p. inoculation with Streptococcus pneumoniae was greatly increased compared with wild type (WT).
Numerous studies have been performed both in vitro and in vivo to examine the role of Mac-1 in neutrophil adhesion and transmigration (10), with less focus until recently on LFA-1 (11). Mice with targeted disruption of LFA-1 have a peripheral leukocytosis due to increased neutrophils similar to but not as severe as that noted for mice deficient in CD18 (12); additionally, ex vivo studies of stimulated LFA-1- and Mac-1-deficient neutrophils have suggested that both LFA-1 and Mac-1 have a role in adhesion to either endothelial cells or ICAM-1, but that adhesion through LFA-1 overshadows the contribution from Mac-1.
Unlike mice deficient in CD18, mice deficient in LFA-1 and Mac-1 appear healthy, with normal growth and development compared with WT littermates. Additionally, these mice have a low incidence of spontaneous infection, similar to WT mice, when housed in microisolator cages. However, in contrast to CD18 deficiency, relative roles of individual CD11 integrins in host defense against systemic bacterial infection remain virtually undefined. To better define the roles of these integrins in host defense in vivo, mice with targeted deletions in LFA-1 and Mac-1 were challenged i.p. with S. pneumoniae.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 12-week-old mice genetically deficient in LFA-1 or Mac-1 and WT controls were used for all experiments. LFA-1-deficient (12) and Mac-1-deficient (11) mutants were developed using targeted homologous recombination, as described previously, and were backcrossed for at least six generations to a C57BL/6J background (Harlan Sprague-Dawley, Indianapolis, IN). WT C57BL/6J mice were purchased commercially (Harlan Sprague-Dawley). All animals were housed in sterile microisolator cages and had no evidence of spontaneous infections. Serial serologies from sentinel animals in the colony were consistently negative for common murine viral pathogens and mycoplasma. Once inoculated, mice were placed in separate cages under an isolation hood. Prior approval was obtained from the Animal Protocol Review Committee at Baylor College of Medicine.
Bacteria
S. pneumoniae Colvin (serotype 6), isolated from
cerebrospinal fluid of a child with meningitis and unilateral severe
hearing loss at Texas Children’s Hospital (13), was
frozen at -80°C in defibrinated horse blood. Virulence was ensured
by intermittent recovery from bacteremic animals. For each experiment,
an aliquot was grown overnight on a blood agar plate. Several loopfuls
of this culture were then inoculated into 10 ml of 2% laked horse
blood broth and incubated for 12 h. Pellets were obtained by
centrifugation at 10,000 x g for 10 min. Pellets were
washed once in PBS and resuspended to a concentration of 
1 x
108 CFU/ml (estimated by
OD600 = 0.13), then diluted 10-fold to 1–10
x 107. The true concentration was determined by
culture.
Survival
Baseline weights, white blood cell counts, and quantitative blood cultures were obtained before inoculation. Mice were inoculated i.p. with a single 0.1-ml dose of S. pneumoniae (1–10 x 106 CFU). Blood was obtained by tail vein nick for leukocyte count and blood culture (10 µl each) on a daily basis. The primary endpoint was survival. Secondary endpoints included leukocyte counts and bacteremia.
Leukocyte counts and culture
Blood (10 µl) was obtained on a daily basis by tail vein nick for peripheral leukocyte count and blood culture. Counts were performed using an electronic particle counter (Coulter Counter ZM; Coulter, Miami, FL). Blood was streaked onto trypticase soy agar plates containing 5% sheep blood and colonies counted the following day. Plates growing greater than 300 CFU were labeled as "too numerous to count."
Peritoneal neutrophil counts
A subset of mice was sacrificed 8 h following i.p. inoculation of S. pneumoniae to assess neutrophil emigration into the peritoneal cavity. Eight hours following inoculation, blood was collected for leukocyte counts (Coulter Counter ZM) and blood smears for leukocyte differentials. The peritoneal cavity was then exposed and lavaged with sterile PBS. Recovered fluid was analyzed for total leukocyte counts. Cytospin preparations were stained with Neat Stain (Midlantic Biomedical, Paulsboro, NJ) for differential counts. A total of 300 cells were counted on each slide. Results are expressed as total cell numbers and percentages of neutrophils.
Quantitative organ culture
Animals deficient in LFA-1 and Mac-1 along with WT controls were inoculated i.p. with S. pneumoniae, as described above. At 2 and 6 h following inoculation, animals were killed by injection of sodium pentobarbital. Peritoneal lavage was performed using 5 ml cold sterile PBS, followed by removal of the liver and spleen, which were then weighed. The spleen and a portion of the right lobe of the liver were homogenized into 1 ml sterile PBS with a tissue grinder. Aliquots of these suspensions were then serially diluted in sterile water (to lyse neutrophils) and plated on 5% blood agar plates. Colonies on all plates were counted the following day. Data are expressed as the log CFU recovered from lavage fluid or from whole liver or spleen.
Histopathology
A subset of animals was sacrificed for histopathology. Age- and sex-matched LFA-1-deficient, Mac-1-deficient, and WT control animals were sacrificed 24 and 72 h following inoculation (n = 3 each for both time points), and LFA-1-deficient and WT mice were sacrificed 96 h following inoculation (n = 3 each for both time points). Animals were exsanguinated to obtain blood for complete blood counts, including automated and manual leukocyte differentials, and for serum chemistries, which included blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, and lactate dehydrogenase. Before exposing the peritoneal cavity, peritoneal lavage was performed with PBS. Lavage fluid was cultured, and total cells were counted electronically (Technicon H-1; Technicon, Tarrytown, New York); cytospin preparations were also made of the peritoneal fluid and stained with Diff-Quik (VWR Scientific Products, Philadelphia, PA) for differential count. Bone marrow was collected by irrigating femoral canals with PBS; total cell counts and cytospin preparations were performed similarly to the peritoneal lavage fluid. Organs were examined histologically by hematoxylin and eosin (H&E) staining and Gram staining (MacCallum-Goodpasture Tissue Gram stain; Ref. 14) for the presence of inflammation, abscess formation, necrosis, and bacteria.
Statistical analysis
Differences in total mortality were determined by
2 analysis. Kaplan-Meier curves were used to
show survival over time, and differences between curves were analyzed
using a log-rank test. Daily leukocyte counts were analyzed by two-way
ANOVA and Student’s two-tailed t test when appropriate.
Differences between total blood and peritoneal leukocyte and neutrophil
counts, as well as quantitative culture data, were examined by
two-tailed t test. Values are presented as mean ± SD.
Results were considered significant for p values <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 34 Mac-1-deficient mice were inoculated and observed
over a 7-day period, during which time increased mortality was observed
in Mac-1-deficient animals. A total of 17 of 34 deaths occurred in
Mac-1-deficient mice compared with 6 of 25 WT deaths
(p < 0.01). The majority of deaths in
Mac-1-deficient mice occurred within the first 48 h following
inoculation (12 of 17) (Fig. 1
a). In contrast, none of the
WT mice died in the first 48 h. After 48 h, the death rate
was similar between Mac-1-deficient mice (5 of 17) and WT (6 of 25).
Kaplan-Meier survival curves were significantly different within the
first 48 h (Fig. 1a, p = 0.03). A total
of 17 LFA-1-deficient mice were inoculated and compared with 35 WT
controls. Because no mortality occurred for at least 72 h
following inoculation, LFA-1-deficient mice were followed a total of 10
days for mortality. A total of 15 of 17 LFA-1-deficient mice died
compared with 13 of 35 WT mice (p < 0.01).
Kaplan-Meier survival curves were also significantly different between
LFA-1-deficient and WT mice (Fig. 1b, p =
0.05). To test the observation that mortality in Mac-1-deficient mice
appeared to be enhanced at early time points compared with both
LFA-1-deficient and WT mice, 22 mice were inoculated in the same
experiment (8 Mac-1-/-, 8
LFA-1-/-, and 6 WT) to compare directly early
mortality between mice deficient in either Mac-1 or LFA-1. The
mortality in Mac-1-deficient mice was 37.5% (3 of 8) by 72 h,
significantly greater than the 12.5% (1 of 8) in LFA-1-deficient mice,
and no deaths were observed in WT mice (Table I).
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Increased numbers of Mac-1-deficient animals were bacteremic
compared with WT controls. At 24 h, 21 of 27 Mac-1-deficient
animals still alive were bacteremic compared with 15 of 25 WT
(p = 0.02). No difference in total numbers of
bacteremic animals was observed between LFA-1-deficient and WT mice.
Animals in each group were sacrificed at 2 and 6 h following i.p.
inoculation to examine by quantitative culture whether bacterial load
was altered in the peritoneum, liver, or spleen. In Mac-1-deficient
mice, significantly increased numbers of S. pneumoniae were
recovered from spleens at 2 h (p = 0.01,
Fig. 2a), and from both livers
(p = 0.001) and spleens
(p = 0.002) by 6 h (Fig. 2b)
following inoculation. In LFA-1-deficient animals, significant
differences were not observed at 2 h (Fig. 2c), but
significantly increased numbers of S. pneumoniae were
recovered from spleens (p = 0.008) and livers
(p = 0.04) by 6 h (Fig. 2d)
following inoculation. No difference in numbers of organisms recovered
from peritoneal lavage fluid was observed in either group at 2 or
6 h following inoculation.
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At baseline, total leukocyte counts in Mac-1-deficient animals
were similar to WT controls (Fig. 3a). In contrast, baseline
total leukocyte counts in LFA-1-deficient animals were significantly
elevated (Fig. 3b); this elevation has been shown to be
primarily due to neutrophils (4). After an initial fall in
total leukocyte counts at 24 h following inoculation (observed in
all groups, but most striking in LFA-1-deficient mice), peak leukocyte
counts consistently occurred by 48 h after inoculation with
S. pneumoniae. Although peak leukocyte counts in
Mac-1-deficient animals were significantly elevated above those in WT,
the difference was not as marked as in LFA-1-deficient animals.
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To address whether differences in neutrophil emigration into the
peritoneal cavity might account in part for observed differences in
mortality, peritoneal lavages were performed in all groups of animals
following inoculation with S. pneumoniae. Separate kinetics
experiments performed in WT mice over several time points
(t = 0, 1, 2.5, 4, 7, 8, 12, 20, and 24 h)
showed that the maximum neutrophil emigration in response to S.
pneumoniae, 55% neutrophils (with nearly all the remaining
cells being macrophages), occurred by 8 h after inoculation (data
not shown). Therefore, 8 h following inoculation was chosen as a
time point to study neutrophil emigration into the peritoneal cavity.
Lavages contaminated with blood were excluded from analysis, as even a
small amount of peripheral blood could greatly affect results.
The percentage of neutrophils recovered from lavages of LFA-1-deficient
mice was significantly reduced compared with controls (Table II), but the total was not different. The
efficiency of neutrophil influx into the peritoneal cavity was examined
by calculating the ratio of peritoneal neutrophils to peripheral blood
neutrophils. As a ratio of peripheral leukocyte count, neutrophil
emigration into the peritoneal cavities of LFA-1-deficient mice was
12.5 ± 8.8% compared with 74.3 ± 86.3% in WT
(p = 0.1). The neutrophil emigration
ratio in Mac-1-deficient mice was 544.5 ± 301.7, which was
significantly greater than in WT (p <
0.05).
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Histopathology
Necropsies of all groups of animals (LFA-1 deficient, Mac-1
deficient, and WT) were performed at 24 and 72 h after
inoculation. Necropsies of LFA-1-deficient and WT mice were also
performed at 96 h (Table III).
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At 72 h after inoculation, one of three Mac-1-deficient animals
had suppurative meningoencephalitis, and one of three had suppurative
otitis media. At the same time point, three of three LFA-1-deficient
animals had suppurative meningitis or meningoencephalitis (Fig. 4, a–c) and otitis interna
and/or otitis media (Fig. 5, a
and b). Tissue Gram stains confirmed the presence of
Gram-positive diplococci within areas of meningitis, encephalitis (Fig. 4d), and otitis (Fig. 5c). In addition, three of
three LFA-1-deficient animals had marked myeloid hyperplasia in the
bone marrow (Fig. 5, a and d). By comparison,
zero of three WT animals had meningitis or meningoencephalitis, and one
of three had mild suppurative otitis media.
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At 72 and 96 h after inoculation, all groups of animals examined (Mac-1-/-, LFA-1-/-, WT) had suppurative serositis, involving mesentery, cranial mediastinum, and/or inguinal or scrotal fat, and few animals had microabscesses in these areas. The presence of Gram-positive diplococci in these lesions was confirmed by tissue Gram stain. Mild inflammatory changes of the epicardium of the right auricle were a consistent feature at these time points.
Serum chemistry evaluations were performed in all animals at each time point examined (and additionally in Mac-1-deficient animals at 18 and 36 h), and were not significantly different in any group (data not shown), with the exception of a mild elevation in alanine aminotransferase in Mac-1-deficient animals at 36 h (30 U/L vs 19.7 U/L, p = 0.019) that may correspond with hepatic necrosis observed histologically at 24 h after inoculation, and an elevation of total protein in LFA-1-deficient animals at 96 h (8 g/dl vs 6 g/dl, p = 0.046).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2) integrins have been
shown to be important in the host response to i.p. infection with
S. pneumoniae, in that CD18-deficient mutant animals have
greatly increased mortality (9). These same animals tend
to reproduce the LAD I phenotype, in that they have increased
spontaneous infections and early mortality over littermates
(9). We wished to determine relative roles for LFA-1 and
Mac-1 in host defense against i.p. infection with S.
pneumoniae as well as the unique and overlapping contributions of
LFA-1 and Mac-1 in developing the leukocytosis, increased bacteremia,
and increased mortality to systemic bacterial infection observed in
both CD18-deficient mice and LAD I. We also wished to study relative
contributions by LFA-1 and Mac-1 to neutrophil emigration into the
peritoneal cavity in response to challenge with S.
pneumoniae. We have made the novel observation that a deficiency of either Mac-1 or LFA-1 increases mortality following i.p. inoculation of S. pneumoniae, with an increase in early (first 48 h) mortality in Mac-1-deficient mice and an increase in late (>72 h) mortality in LFA-1-deficient mice. The experimental results from blood and organ cultures suggest that the increased early mortality in Mac-1-deficient mice was secondary to overwhelming sepsis. A greater number of Mac-1-deficient animals were bacteremic by 24 h compared with controls, and increased numbers of S. pneumoniae were recovered from livers at 6 h and spleens at 2 and 6 h following inoculation. Histologic findings of intravascular bacteria, bacteria in tissues, hypocellularity of the marrow, and features of lymphoid depletion, necrosis, and apoptosis in the splenic white pulp were also suggestive of overwhelming sepsis.
In animals without previous immunization, the alternative pathway of complement provides the primary host defense against pneumococcal infection (15). Increased S. pneumoniae bacteremia, decreased clearance, and increased early mortality have been shown to occur after depletion of complement in nonimmune animals. That Mac-1 serves as a complement receptor was demonstrated through a series of experiments first demonstrating selective inhibition of human CR3 by anti-Mac-1 mAb M1/70 (16), followed by evidence of Mac-1 as a receptor for iC3b (17), and finally, by the inhibition of Mac-1 binding to C3-coated erythrocytes with the use of recombinant synthetic peptides spanning the A-domain of Mac-1 (18). Furthermore, leukocytes isolated directly from patients with LAD I have been shown to have impaired protein kinase C-dependent phagocytosis of opsonized sheep erythrocytes (a Mac-1-dependent process) (19). Inhibition of Mac-1 by mAb OKM10 on human neutrophils completely blocked phagocytosis of S. pneumoniae in nonimmune serum and reduced phagocytosis by 50–80% in pooled human serum, suggesting the iC3b/CR3 interaction to be the primary trigger for phagocytosis of iC3b-bearing pneumococci and for stimulation of intracellular bactericidal processes (20). Following opsonization, types 6A and 14 S. pneumoniae bear only iC3b (21). Finally, in contrast to neutrophils isolated from WT mice, neutrophils from Mac-1-deficient mice did not release chemiluminescence in response to opsonized zymosan, suggesting defective iC3b-mediated phagocytosis (11).
Following splenectomy, increased amounts of Ab are required by remaining macrophages of the reticuloendothelial system to mediate efficient intravascular clearance of opsonized particles (22). Increased host susceptibility to S. pneumoniae and early death following splenectomy in both mice and humans are well documented (23, 24, 25, 26, 27). Following splenectomy, >50% of mice died within 48 h of challenge with S. pneumoniae type 6, whereas most deaths in mice without splenectomy occurred after 72 h (26). Furthermore, a great role for the spleen in reticuloendothelial clearance of organisms has been demonstrated for more highly virulent strains of pneumococci, and splenectomy greatly enhances host susceptibility to these strains, as the liver is unable to compensate for the loss of splenic clearance function (28). By 45 min after i.v. injection, 55–75% of radiolabeled S. pneumoniae can be localized in the liver and spleen, even in animals with marked complement deficiencies (29), suggesting that the mechanism of localization of pneumococci to the spleen is not complement dependent. Mice deficient in Mac-1 had increased numbers of pneumococci cultured from their spleens at 2 h, and from both the spleens and livers at 6 h. These data suggest that localization of pneumococci to the spleen and liver is not dependent on Mac-1. It may be that the increased number of bacteria is due to a Mac-1-dependent defect in phagocytosis or intracellular killing of pneumococci by leukocytes.
Although Mac-1-deficient animals have elevated peak leukocyte counts, the difference compared with WT is not as striking as that observed between LFA-1-deficient animals and WT. We examined neutrophil influx into the peritoneal cavity to determine whether a deficiency of Mac-1 might inhibit the ability of neutrophils to migrate into the peritoneum in response to the stimulus of S. pneumoniae. Both the absolute neutrophil count and the emigration ratio of neutrophils into the peritoneum divided by peripheral neutrophil count were increased severalfold in Mac-1-deficient mice.
We and others have previously observed that neutrophils in
Mac-1-deficient mice migrate normally in the peritoneum in response to
thioglycolate (11, 30), and that leukocyte influx in a
s.c. air pouch in response to TNF- was increased in Mac-1-deficient
mice (12). Reduced apoptosis could account for some of the
increase in the number of neutrophils in peritoneal lavage in
Mac-1-deficient mice after S. pneumoniae. At the very least,
defective neutrophil emigration does not appear to contribute to the
early deaths observed in Mac-1-deficient mice.
Phagocytosis of opsonized particles by human neutrophils rapidly
induced apoptosis that could be blocked with Mac-1 Abs
(31), and apoptosis of human neutrophils within 4 and
8 h of stimulation by TNF- occurred in response to
cross-linking with Ab to Mac-1 (32). However, no evidence
of apoptosis in murine neutrophils, as evidenced by DNA laddering, was
found after 4 h in a TNF--stimulated air pouch model
(12) or in thioglycolate-induced peritonitis at 4 h
(31).
There was no significant difference in the number of mast cells in the peritoneal lavage at either 4 or 8 h after S. pneumoniae infection between WT mice and mice deficient in Mac-1. Although these results are in contrast to the reduced number of mast cells observed after cecal ligation and puncture in Mac-1-deficient mice (33), the increased early mortality observed in Mac-1-deficient mice with S. pneumoniae in this study was very similar to the time course of increased mortality in Mac-1-deficient mice after cecal ligation and puncture, a model in which host resistance has been shown to be dependent on complement (34). In summary, defective emigration of either neutrophils or mast cells into the peritoneal cavity does not appear to contribute to the early mortality in Mac-1-deficient mice.
In contrast to mice deficient in Mac-1, mice deficient in LFA-1 had
increased late mortality after 72 h, associated with late
complications of pneumococcal disease (i.e., meningitis and
meningoencephalitis) along with an increased incidence of otitis media.
The percentage of neutrophils emigrating into the peritoneal cavity
following inoculation of S. pneumoniae was significantly
reduced compared with WT animals, and the absolute number of
neutrophils in the peritoneum tended to be reduced compared with WT
mice (1.2 ± 0.6 x 106 vs 2.8 ±
2.3 x 106, p = 0.1).
Leukocyte accumulation in response to thioglycolate has been shown to
be reduced by >50% in LFA-1-deficient mice (35), and
neutrophil influx into s.c. air pouches after TNF- was reduced by
67% in LFA-1-deficient mice (12). That neutrophil
emigration is not completely abolished in the absence of LFA-1 or CD18
is not surprising. S. pneumoniae-stimulated macrophages
induce neutrophils to emigrate by a CD18-independent mechanism of
adherence (36). Impaired neutrophil emigration to sites of
infection in other organs and tissues may be a mechanism contributing
to delayed mortality in LFA-1-deficient mice and increased incidence of
otitis and meningitis. The original case report of LAD I describes a
boy with a history of recurrent otitis media in addition to multiple
skin abscesses, perirectal abscess, and three other episodes of
pneumonia (37), and it is possible that increased
susceptibility to recurrent otitis might be a phenotypic trait in
humans with a deficiency of LFA-1. Increased mortality associated with
impaired leukocyte emigration following pneumococcal challenge is not
specific to CD11/CD18 integrins. Progressive mortality over a 10-day
observation period was also observed following i.p. challenge with
S. pneumoniae in E-, P-, and E/P-selectin-deficient mice
(38). In that study, E/P-selectin double knockouts also
had an increased incidence of meningitis. Taken together, these
findings suggest that defects in leukocyte adhesion and migration lead
to increased complications and late mortality with S.
pneumoniae.
Increased numbers of bacteria were recovered from spleens and livers of LFA-1-deficient animals. The absence of LFA-1 may reduce both neutrophil migration and bacterial phagocytosis, because binding of LFA-1 to ICAM-1 on endothelial cells is required for full phagocytic function to occur (39). TCR cross-linking has been shown, through outside-in signaling, to increase transiently the strength of adhesion between LFA-1 and ICAM (40); absence of this interaction may impair development of an adaptive immune response, and one might speculate that this could also contribute to late mortality.
Overall, these findings suggest that both LFA-1 and Mac-1 play important but distinct roles in innate host defense against S. pneumoniae. Whether similar results would be obtained with alternate routes of inoculum, different strains of S. pneumoniae, or a different organism requires further study. These studies in mice with targeted deletion of Mac-1 and LFA-1 also suggest that even though pharmacological inhibition of either Mac-1 and LFA-1 in humans may cause less of a global defect in the inflammatory response than inhibition of CD18, complete inhibition of either LFA-1 or Mac-1 may enhance susceptibility to infection in humans.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christie M. Ballantyne, Baylor College of Medicine, 6565 Fannin, Mail Stop A-601, Houston, TX 77030. E-mail address: cmb{at}bcm.tmc.edu
3 Abbreviations used in this paper: LAD I, leukocyte adhesion deficiency syndrome type I; CR3, complement receptor 3; H&E, hematoxylin and eosin; WT, wild type.
Received for publication May 31, 2000. Accepted for publication April 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc. Natl. Acad. Sci. USA 95:10134.2 integrins in inflammation. J. I. Gallin, and R. Snyderman, eds. Inflammation: Basic Principles and Clinical Correlates 569. Lippincott Williams & Wilkins, Philadelphia.
2 integrin CR3 (CD11b/CD18). Proc. Natl. Acad. Sci. USA 91:10680.2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity 5:653.[Medline]
2 integrins (CD11/CD18) promote apoptosis of human neutrophils. FASEB J. 11:1177.[Abstract]
2 integrin-binding potentiates neutrophil phagocytosis. Nat. Med. 5:231.[Medline]
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T. Kadono, G. M. Venturi, D. A. Steeber, and T. F. Tedder Leukocyte Rolling Velocities and Migration Are Optimized by Cooperative L-Selectin and Intercellular Adhesion Molecule-1 Functions J. Immunol., October 15, 2002; 169(8): 4542 - 4550. [Abstract] [Full Text] [PDF]
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