© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effect of Immune Deficiency on Lipoproteins and Atherosclerosis in Male Apolipoprotein E–Deficient Mice
From the Department of Pathology, University of Chicago, Chicago, Ill.
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Abstract |
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Abstract—To determine whether T cells and B cells influence lipid metabolism and atherosclerosis, we crossed apolipoprotein E–deficient (apoE°) mice with recombination activating gene 2–deficient (RAG2°) mice. Total plasma cholesterol levels were
20% higher in male apoE° mice
compared with the apoE°RAG2° mice at 8 weeks of age, and plasma
triglyceride levels were 2.5-fold higher in the apoE°
mice even when plasma cholesterol levels were similar. Male
mice with plasma cholesterol levels between 400 and 600
mg/dL at 8 weeks of age were euthanized at 27 and 40 weeks of age. The
aortic root lesion area in the apoE°RAG2° mice, compared with that
in the immune-competent apoE° mice, was 81% and 57% smaller at 27
and 40 weeks of age, respectively. In contrast, there was no difference
in the size of the brachiocephalic trunk lesions. Similar results were
obtained with mice euthanized at 40 weeks of age that had 8-week
cholesterol levels between 300 and 399 mg/dL. In
apoE°RAG2° mice, aortic root atherosclerosis was
more profoundly suppressed at lower cholesterol levels.
Thus, T and B cells and their products differentially influence the
development of atherosclerosis at different sites. We
also demonstrate a profound effect of the immune system on plasma lipid
homeostasis.
Key Words: atherosclerosis • apolipoprotein E • immune deficiency • T cells • lipoproteins
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Introduction |
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There is strong circumstantial evidence indicating that the immune response participates in the evolution of atherosclerosis in humans and experimental animals. Many components involved in this response have been detected in atherosclerotic vessels (see review1 ). T cells are present in human2 and murine3 atherosclerotic lesions. Atherosclerotic plaques of apoE-deficient (apoE°) mice contain T cells reactive with oxidized lipoproteins and heat shock proteins.4 ApoE° mice on a chow diet develop complex lesions throughout the vascular tree, and this occurrence is accelerated by a Western diet.5 6 These mice have been crossed with recombination activating gene (RAG)1–deficient (RAG1°) and RAG2–deficient (RAG2°) mice. Both of these RAG proteins are necessary for recombination of the T-cell receptor and immunoglobulin genes; thus, RAG° mice lack mature T and B cells. ApoE°RAG1° mice fed a chow diet for 16 weeks showed a 2-fold reduction in aortic root atherosclerosis.7 The male apoE°RAG1° mice also exhibited modest reductions in plasma cholesterol levels. On the other hand, the extent of atherosclerosis in apoE° mice with either RAG1 or RAG2 deficiency fed a Western diet was similar to that found in immune-competent apoE° mice.7 8
The role of B cells in the development of atherosclerosis is less clear. Antibodies to oxidized lipoproteins9 and to heat shock protein 6510 have been detected in the plasma of subjects with atherosclerotic cardiovascular disease. High titers of circulating autoantibodies to oxidized lipoproteins have also been detected in apoE° mice.11 Recently, Zhou and Hansson12 demonstrated the presence of CD22+ B cells and IgM in the aortic root lesions of apoE° mice. They also detected cytokines that influence B-cell differentiation.
Most studies of murine genetic atherosclerosis have focused on fatty streak formation in the aortic root rather than the complex lesions in other sites in the vascular tree. In the present study, we focus on male apoE°RAG2° mice fed a chow diet for 7 to 10 months. We attempted to normalize total plasma cholesterol between the immune-competent and -incompetent mice, and we studied their plasma lipids and lipoproteins. Importantly, we have examined atherosclerosis in 2 standard sites: the aortic root and the brachiocephalic trunk (innominate artery). Despite our best efforts, we noted significant differences in the plasma lipids and lipoproteins between the 2 experimental groups. Also, RAG2 deficiency influences the evolution of atherosclerosis differently in the 2 vascular sites. These results suggest that immune mechanisms have varying effects on the development of atherosclerosis depending on the vascular location and also that they profoundly influence plasma lipid levels.
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Methods |
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Mice
ApoE° mice13 and RAG2° mice,14 backcrossed with C57BL/6 mice for 3 and 4 generations, respectively, were used to generate apoE°RAG2° double-knockout mice. ApoE deficiency was determined by Western blotting, and RAG2 deficiency was determined by flow cytometry of Ficoll-purified lymphocytes by using FITC-labeled anti-CD4 and anti-CD8 antibodies (PharMingen). The mice were housed in a specific pathogen-free environment in a temperature-controlled room with a 12-hour light-dark cycle and fed a standard rodent diet (Purina Mills) with sulfamethoxazole+ trimethoprim (Bactrim) added to the water. All procedures performed on the mice were in accordance with the National Institutes of Health and institutional guidelines.
Analysis of Atherosclerotic
Lesions
Male animals were divided into 2 groups on the basis
of their 8-week fasting plasma cholesterol levels. The high
cholesterol group had plasma cholesterol levels
between 400 and 600 mg/dL, and the low cholesterol group
had plasma cholesterol levels between 300 and 399 mg/dL. At
27 and 40 weeks of age, anesthetized mice were exsanguinated
via the retro-orbital sinus and perfused at
physiological pressure via the left ventricle of
the heart with an outflow in the right atrium with PBS for 15 minutes,
followed by a 20-minute perfusion with 4%
paraformaldehyde and 5% sucrose in PBS. Aortas used
for immunohistochemistry were perfused with PBS alone. The upper half
of the heart and the proximal aorta including the brachiocephalic
trunk, left carotid, and left subclavian were embedded in OCT compound
(Sakura Finetek) and frozen in dry
ice/2-methylbutane.
The frozen tissue was serially sectioned into 10-µm sections from the brachiocephalic trunk through the aortic root. Every 10th section was stained with hematoxylin and eosin, with the neighboring sections stained with oil red O and Harris’ hematoxylin and counterstained with fast green, or with Gomori’s trichrome acid fuchsin (GTAF). Lesion area was quantified by using digitally captured oil red O–stained sections in the brachiocephalic trunk 350 µm distal from the point at which the brachiocephalic trunk enters the aortic arch and in the aortic root at the site of the appearance of the coronary artery. We expressed the size of the lesion in the brachiocephalic trunk as a percentage of the total lumen area, because this would reduce distortions that might occur if the aorta was sectioned at an angle.15 In preliminary studies, we averaged the lesion area in 4 sections separated by 100 µm for the brachiocephalic trunk, and we determined that the average did not significantly differ from the measurements at this standard site. Atherosclerosis was quantified by use of OpenLab Software, version 1.7.6. For immunohistochemistry involving T cells, the slides were incubated overnight at 4°C with purified anti-CD4 rat IgG (GK1.5, 1 µg/mL), rinsed, and incubated with secondary rat anti-IgG (10 µg/mL). The antigen-antibody binding was detected by an avidin-biotinylated horseradish peroxidase system (Vector Laboratories) with diaminobenzidine (DAB, Vector Laboratories) and counterstained with hematoxylin.
Lipid and Lipoprotein Analysis
Plasma lipid levels were determined as previously
described.16 Plasma obtained
at the time of euthanasia (150 to 250 µL) was fractionated on tandem
Superose 6 fast protein liquid chromatography (FPLC)
columns in 200 mmol/L sodium phosphate (pH 7.4), 50 mmol/L
NaCl, 0.03% EDTA, and 0.02% sodium azide, and 400-µL fractions were
collected. The amount of cholesterol in the even-numbered
fractions was determined and expressed as micrograms
cholesterol per milliliter of plasma. The area under the
lipoprotein peaks was quantified by computer digitizer (SigmaScan,
Scientific Measurement Systems, Jandel Scientific) and expressed as
percentage of total area.
Statistical Analysis
Measurements are expressed as mean±SEM. Results were
analyzed by 1-way ANOVA or (when multiple comparisons were made
between groups) by the Bonferroni/Dunn method with the use of StatView
5.0.1 software. The significance level was set at
P<0.05.
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Results |
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Characterization of ApoE°RAG2° Mice
The apoE°RAG2° mice that we generated were viable and healthy when housed in a specific pathogen-free facility. No apparent differences were observed in longevity and fertility in these mice compared with the immune-competent apoE° mice. However, the adult apoE°RAG2° mice were
17% smaller in weight than the
apoE° mice at 27 weeks (35.4±0.9 versus 29.0±1.0 g for apoE° and
apoE°RAG2° mice, respectively; n=14 each) and at 40 weeks
(34.2±1.0 versus 29.0±1.6 g for apoE° [n=24] and apoE°RAG2°
[n=27] mice, respectively;
P<0.001 at both
ages).
We determined plasma lipid levels in all male mice at 8
weeks of age (see Figure
I, which can be accessed online at
http://atvb.ahajournals.org). The majority (55%) of the apoE° mice
had 8-week plasma cholesterol levels between 400 and 600
mg/dL, whereas only 21% of the apoE°RAG2° mice had
cholesterol levels in this range. The
cholesterol levels of the majority (80%) of the
apoE°RAG2° mice were <400 mg/dL. The mean plasma
cholesterol level for the apoE° mice (438±5 mg/dL) was
20% higher than that for the apoE°RAG2° mice (349±4 mg/dL,
P<0.001; n>400). Differences
in plasma triglyceride levels were even more striking. The
average plasma triglyceride levels were 192±82 mg/dL in
the apoE° mice and 74±26 mg/dL in the apoE°RAG2° mice
(P<0.001).
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The distribution of cholesterol in the various
lipoprotein fractions after FPLC fractionation of the plasma of apoE°
and apoE°RAG2° mice is shown in
Figure 1
. Consistent with the higher plasma
triglyceride levels, a greater percentage of the total
plasma cholesterol was found in the VLDL fractions of the
apoE° mice (60±2% versus 51±2% for apoE° versus apoE°RAG2°
mice, respectively). On the other hand, the apoE°RAG2° mice had
more of their total cholesterol in the IDL/LDL fractions
(43±2% versus 35±2% for apoE°RAG2° versus apoE° mice,
respectively). The apoE°RAG2° mice also had slightly greater
amounts of HDL (6.6±0.6% versus 4.4±0.4% for apoE°RAG2° versus
apoE° mice, respectively).
The composition of lipoproteins obtained from 20-week-old
animals with comparable total plasma cholesterol levels was
determined (see Table I, which can be accessed online at
http://atvb.ahajournals.org). Even when plasma cholesterol
and phospholipid levels were comparable, triglyceride
levels were still 30% lower in the apoE°RAG2° mice (166 versus
56 mg/dL for apoE° versus apoE°RAG2° mice, respectively). The
triglyceride content of the VLDL and the IDL/LDL fractions
was 2.5- to 3-fold lower in the apoE°RAG2° mice. There was no
difference in the lipid composition of the HDL particles or in the
apolipoprotein content of the lipoproteins (data not shown). These
results suggest that T and/or B cells or their products have
profound influences on plasma lipids and
lipoproteins.
Analysis of
Atherosclerosis
Because differences in plasma cholesterol
levels between the 2 experimental groups could confound the
analysis of the effect of T and B cells on
atherosclerosis, atherosclerosis was
examined in male mice with 8-week cholesterol levels
between 400 and 600 mg/dL (high cholesterol group) and
between 300 and 399 mg/dL (low cholesterol group). The mean
plasma cholesterol level at 8 weeks for the apoE° mice in
the high cholesterol group was 473±9 mg/dL, and the level
for the apoE°RAG2° mice was 444±8 mg/dL (see Table II, which can
be accessed online at http://atvb.ahajournals.org). This
represents a 6% difference and is barely significantly
different (P=0.024). As
expected, plasma triglyceride levels were 3-fold higher in
the apoE° mice than in the apoE°RAG2° mice
(P<0.0001). Similar results
were obtained for the animals in the low cholesterol
group.
The mice were maintained on a chow diet and euthanized at 27 or 40 weeks of age. Although plasma cholesterol levels in all animals were between 57% and 76% higher at the time of euthanasia compared with the values at 8 weeks, they were not significantly different between the immune-competent and -incompetent mice at 40 weeks of age in either plasma cholesterol group (see online Table II). However, there was a significant difference between the immune-competent and -incompetent mice at 27 weeks of age in the high cholesterol group.
Atherosclerosis was examined at 2 sites
within the vascular tree: in the aortic root just after the appearance
of the coronary artery and in the brachiocephalic trunk 350
µm distal to the branch from the aorta
(Figure 2). This latter site is well below the branching of
the right carotid artery, and it consistently contained
lesions. In both arterial sites, the lesions were complex,
containing foam cells, smooth muscle cells, cholesterol
clefts, and amorphous necrotic gruel. Fibrous caps of varying
thickness, collagenous bands, areas of cartilaginous dysplasia, and, in
some cases, frank calcification were also observed. Most of these
features have been seen in human and murine
atherosclerosis. In the aortic root, foam cells were
predominantly located subendothelially, with a
matrix-rich region deeper in the lesions. Clusters of foam cells were
often seen in the shoulders of the lesions in both groups of animals.
Almost invariably below this lesion was an expansion of 1 or 2 inner
medial lamellae, which often contained fine lipid droplets on oil red O
staining, as well as an increase in collagen as depicted by the GTAF
stain. Occasionally, a suggestion of chondrocyte transformation was
seen. These expanded medial lamellae appeared to be an early
atherogenic change, inasmuch as they were often seen in the same
location when the intimal lesion was quite small. There was no
difference between the immune-competent and -incompetent mice with
respect to these medial changes. Our brachiocephalic trunk lesions are
similar to those reported by Rosenfeld et
al,17 except that we saw no
hemorrhage within the lesions.
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As shown in
Figure 3A, the aortic root lesion area increased in the high
cholesterol group of animals between 27 and 40 weeks in
apoE° and apoE°RAG2° mice. However, the lesion in the
apoE°RAG2° mice was 81% smaller than that in the apoE° mice at
27 weeks (P=0.0013) and 57%
smaller at 40 weeks
(P<0.0001). Similar
quantitative differences were obtained when the amount of lesion was
expressed as a percentage of the aortic root area, indicating that
these differences are not due to the smaller size of the apoE°RAG2°
mice. In contrast, there was no significant difference in the amount of
atherosclerosis in the brachiocephalic trunk in the 27-
and 40-week-old animals
(Figure 3B). Immunohistochemical analysis of lesions
in apoE° mice
(Figure 2) demonstrated that CD4+ T cells are present in
the aortic root and the brachiocephalic trunk. We noted a tendency for
the lumen area of the brachiocephalic trunk to increase with lesion
size. The lesion size and cross-sectional area of the brachiocephalic
trunk were positively correlated
(r2=0.5461),
suggesting an adaptation of the artery to the presence of a significant
lesion.
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P<0.005 for apoE° versus apoE°RAG2°; 
P<0.05 for 40-week-old apoE°RAG2° mice with high versus low initial cholesterol levels. B, Percentage of the lumen of the brachiocephalic trunk occupied by atherosclerotic lesion. Numbers of animals are as follows: for animals with high initial plasma cholesterol euthanized at 27 weeks, n=14 apoE° mice and n=14 apoE°RAG2° mice; for animals euthanized at 40 weeks of age, n=17 apoE° mice and n=15 apoE°RAG2° mice; for animals with low initial plasma cholesterol, n=7 apoE° mice and n=12 apoE°RAG2° mice.Similar results were obtained in animals in the low cholesterol group. In animals euthanized at 40 weeks, the aortic root lesions of apoE°RAG2° mice in the low cholesterol group had significantly less atherosclerosis than did the lesions of the apoE°RAG2° mice in the high cholesterol group. The size of the lesion in the apoE° mice was insensitive to the initial plasma cholesterol level, as was the extent of atherosclerosis in the brachiocephalic trunk of both genotypes.
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Discussion |
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In the present study, we have made 4 significant observations. First, a deficiency in B and T cells influences lipoprotein metabolism. Despite an attempt to normalize for plasma cholesterol levels, there remained subtle differences in the plasma lipid and lipoprotein profile between immune-competent and immune-incompetent apoE° mice. Second, and most significant to the present study, we observed site-specific differences in the response of the arterial wall to the combination of the genetic hyperlipidemia of apoE deficiency and immune incompetence. Although aortic root atherosclerosis was reduced in the immune-incompetent mice, this was not the case for atherosclerosis in the brachiocephalic trunk (innominate artery). For the first time, these 2 sites were studied in the same animals. Third, extending the results of previous investigators,7 8 the difference between aortic root atherosclerosis in the immune-competent and -incompetent mice seemed to be greatest at lower initial plasma cholesterol level. Fourth, we observed an adaptation of the brachiocephalic trunk to the presence of an atherosclerotic lesion.
ApoE°RAG2° mice screened at 8 weeks of age have lower plasma cholesterol levels than do immune-competent apoE° mice. To minimize the confounding influence of lipoprotein differences on vessel wall responses, we selected for study male mice who exhibited 8-week cholesterol levels within the interval of 400 to 600 mg/dL. The majority of the apoE° mice fall within this interval, but <30% of the apoE° RAG2° mice fall within this interval. Despite this selection, the mean cholesterol levels of this subpopulation of apoE°RAG2° mice at 8 and 27 weeks were modestly lower than those of the apoE° mice, but at 40 weeks, their total plasma cholesterol levels were very similar. Despite the relatively close match in total plasma cholesterol, plasma triglycerides were always significantly lower (by 50% to 67%) in the apoE°RAG2° mice. This is attributable to 2 factors: (1) VLDL and IDL/LDL had a much lower triglyceride content in apoE°RAG2° mice than in apoE° mice, and (2) the apoE°RAG2° mice had a lower proportion of VLDL and a higher proportion of IDL/LDL than did the apoE° mice. There was no correlation between the size of the atherosclerotic lesions and plasma cholesterol, triglyceride, or HDL cholesterol levels when values for individual animals were plotted.
The role of the immune system and its products on plasma
lipid and lipoprotein metabolism has received limited
attention. In a previous
report,7 male apoE°RAG1°
mice, compared with than apoE° mice, had 30% lower serum
cholesterol levels. The effect of the RAG2 deficiency on
lipoprotein responses is not unique to the apoE° background, inasmuch
as LDL receptor–deficient mice crossed with RAG2-deficient mice showed
a markedly attenuated response to a Western diet (authors’
unpublished data, 2000). Lower serum cholesterol has also
been noted in nude
mice.18
The lipoprotein and plasma lipid differences in the RAG2°
mice are presumed to be attributable to an altered spectrum of
cytokines of T-cell and monocyte origin that influence
lipoprotein production and metabolism and to
catabolism by lipoprotein lipase (eg, tumor necrosis factor-
,
interleukin [IL]-1, IL-6, monocyte/macrophage
colony–stimulating factor, interferon [IFN]-, and
IFN-
19 ). A reduction in
IFN-, a Th1 cytokine, in the apoE°RAG2° mice could lead
to increased lipolysis of triglycerides by lipoprotein
lipase.20 21
However, the heparin-releasable lipase activity in the apoE°RAG2°
mice (119±33 mU/mL) was not significantly different from that in the
apoE° mice (159±26 mU/mL; G. Gupta, C. Reardon, G. Getz, unpublished
data, 2000). The lipoprotein phenotype in the
apoE°RAG2° mice is distinct from that reported in
apoE°IFN-R° mice, which are produced with a cross of apoE°
mice and IFN- receptor–deficient (IFN-R°)
mice.22 Although we do
see an increase in IDL/LDL relative to VLDL in the apoE°RAG2° mice,
the change in our mice is much less pronounced than was the change in
the apoE°IFN-R° mice. Also, we have not seen an increase in
plasma phospholipid or apoA-IV
levels.22 There is probably a
less profound deficiency in IFN- signaling in our mice than is the
case for IFN-R° mice. Additionally an imbalance of other
cytokines in our immune-incompetent mice probably contributes
to the lipoprotein phenotype that we observe.
The fact that there is no difference in brachiocephalic trunk lesions in the apoE° mice may reflect the immunomodulatory role of apoE.23 In contrast, the size of the aortic root lesions was much smaller in the immune-incompetent mice than in the apoE° mice. The aortic root and the brachiocephalic trunk are exposed to similar levels and types of lipoproteins, and T cells are found in the lesions at both sites. In one previous study of immune deficiency and atherosclerosis, aortic root analysis was used, with results similar to those reported in the present study.7 A second study used whole-aorta analysis and noted no difference, similar to the results with the brachiocephalic trunk.8 Thus, aortic root atherosclerosis may not always be reflective of changes in atherosclerosis in other regions of the vascular tree; therefore, generalizations about atherogenesis based exclusively on aortic root atherosclerosis may be open to question. This and a report involving probucol administration24 are the first 2 examples of a variation of atherosclerosis by arterial site studied in the same animal.
Others have reported a reduction of aortic root atherosclerosis in chow-fed immune-incompetent apoE° mice but not in those fed a Western diet.7 8 These observations as well as our own suggest that high plasma and tissue cholesterol levels may overshadow the influence of immune deficiency, the effect of which appears to be more evident at low plasma cholesterol levels. For some arterial sites, immune cells may play a more important role at normal or modestly elevated cholesterol levels, a situation pertinent to most human atherosclerosis.
It is clear from our results and those of others7 8 18 22 25 that the participation of mature T cells is not obligatory for the development of even complex atherosclerosis. T cells have the capacity to modulate the activity of other cells involved in atherogenesis.1 26 For example, activation of macrophages by T cells could also be effected by oxidized lipoproteins.
Global immune deficiency could result in the elimination of
proatherogenic and antiatherogenic influences, so that its impact on
atherosclerosis will depend on the balance between
these opposing influences. The balance between the cross-regulatory
cytokines (eg, IFN- versus
IL-427 or IL-12 versus
IL-1028 ) may differ in the 2
aortic sites studied in the present study. The complexity of the
role of the immune system is revealed by the fact that induction of
neonatal tolerance to oxidized
lipoprotein29 in apoE° mice
reduces atherosclerosis, as does immunization of LDL
receptor–deficient mice with homologous malondialdehyde-modified
LDL.30
In the mouse as in humans, hemodynamic influences affect the localization of atherosclerotic lesions. The lesion is invariably found on the outer wall of the brachiocephalic trunk and on the lesser curvature of the aortic arch. Of special interest is the observation that in all of our mice, the brachiocephalic trunk expands to accommodate the developing atherosclerotic plaque, as has been observed in the human coronary arteries.31 A similar arterial remodeling was noted in the peripheral arteries of apoE° male mice.32
At the time of euthanasia, compared with the apoE° mice, the apoE°RAG2° mice were lower in body weight. We have no obvious explanation for this observation. Bacterial and viral pathogens were not detected in the sentinel animals in the barrier facility. A full autopsy on 2 immune-competent and 2 immune-incompetent mice also detected no evidence of infection. Although lipid oxidation is stimulated by the acute-phase reaction,33 small amounts of the acute-phase serum amyloid A protein were observed in the plasma of only some animals, and its presence did not correlate with lipoprotein levels, weight, atherosclerosis, or immune status.
In summary, immune incompetence has complex effects on lipoprotein metabolism and atherosclerosis in 2 different sites in apoE° mice. Immune deficiency had a profound effect on the development of aortic root atherosclerosis but not on brachiocephalic trunk atherosclerosis. Whether this difference is due to direct influence of the immune cells on the artery wall or to their effect on plasma lipids is not clear. The observations reported in the present study offer the opportunity for further analysis of the subtle different mechanisms of atherogenesis at various arterial sites exposed to the same systemic and plasma environment. Further study is required to dissect the precise role of T and B cells in lipoprotein metabolism and atherosclerosis.
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Acknowledgments |
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This research was supported by National Institutes of Health grants HL-15062, HL-56827, and DK-26678. We gratefully acknowledge the helpful suggestions of Dr Draga Vesselinovich and the assistance of Amanda Myers in data analysis and preparation of the manuscript.
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Footnotes |
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Reprint requests to Dr Catherine A. Reardon, University of Chicago, Department of Pathology MC 1089, 5841 S Maryland Ave, Chicago, IL 60637.
Received January 24, 2001; accepted February 16, 2001.
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