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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 932-939
Dysregulated Myelopoiesis in Mice Lacking Jak3
By
William J. Grossman,
James W. Verbsky,
Liping Yang,
Leslie J. Berg,
Larry E. Fields,
David D. Chaplin, and
Lee Ratner
From the Divisions of Molecular Microbiology and Cardiology, the
Departments of Pathology and Medicine, Washington University School of
Medicine, St Louis, MO; Howard Hughes Medical Institute, Washington
University School of Medicine, St Louis, MO; and the Department
of Molecular and Cellular Biology, Harvard University, Cambridge,
MA.
 |
ABSTRACT |
Jak3 is a cytoplasmic tyrosine kinase that associates with the
common chain of the interleukin-2 (IL-2) receptor and is involved in
the function of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15.
Mice deficient in Jak3 have few T and B cells, and no natural killer
cells. Herein we show that the myeloid lineages in these mice are also
affected by the loss of Jak3. Mice lacking Jak3 exhibit splenomegaly by
4 months of age. Peripheral blood smears show an increase in the number
of neutrophils and cells of the monocytic lineage. Flow cytometry of
splenocytes and peripheral blood show a significant increase in
Fc RII/III(FcR)/Mac-1, FcR/Gr-1, and FcR/F4/80
double-positive cells in  / and +/ mice compared to wild-type
mice, consistent with an expansion of cells of the myeloid lineages. In
addition, as the mice age, F4/80 and CD3 positive mononuclear cells
infiltrate the kidneys, lungs, and liver of these mice. When
Jak3/ mice are crossed with a transgenic mouse expressing Jak3 in
the T and NK cell compartments, the splenomegaly and myeloid expansion
are accentuated. These data correlate with the constitutive activation
of T cells in the periphery as the transgenic cells lose their
expression of Jak3 with age. However, when Jak3/ mice are crossed
with RAG-1-deficient animals, no splenomegaly or myeloid expansion is
apparent. These results indicate that the loss of Jak3 in the T-cell
compartment drives the expansion of the myeloid lineages.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HEMATOPOIESIS is controlled by a variety
of cytokines, many of which signal through receptors that belong to the
hematopoietic receptor superfamily.1,2 This family of
receptors lacks intrinsic enzymatic activity, but instead uses members
of the Janus kinase (Jak) family of tyrosine kinases to activate and
transmit a biological signal upon ligand binding. The Jak family of
proteins consists of 4 known cytoplasmic tyrosine kinases (Jak1, Jak2,
Jak3, and Tyk2) that are constitutively associated with the cytoplasmic domain of the receptors of this family. Upon ligand binding and oligomerization of receptor components, the associated Jaks are brought
together, leading to transphosphorylation and activation. Upon
activation, the Jaks phosphorylate tyrosine residues in the cytoplasmic
domains of the receptors, leading to recruitment of src homology 2 (SH2) containing proteins to the phosphorylated receptors, such as
members of the signal transducers and activators of transcription
(Stat) family. The Jaks phosphorylate and activate these associated
proteins, leading to downstream signals, such as transcriptional
activation by the Stat proteins.1,2
Recently, Jak3 has been deleted by gene targeting in mice by several
investigators.3-6 Jak3 associates with the common chain of
the interleukin-2 (IL-2) receptor (IL2Rc), and is
involved in the signal transduction of cytokine receptors that share
this subunit, which include IL-2, -4, -7, -9, and -15.1,2
Mice deficient in Jak3 exhibited a severe combined immunodeficiency (SCID) phenotype, similar to the phenotype observed in human patients with Jak3 deletions or mutations.7-10 The thymi of knockout
mice contained approximately 0.5% to 10% of the normal number of
cells. Despite the very low number of thymocytes, the CD4 and CD8
staining pattern in the thymus is relatively normal. The cellularity of the bone marrow was also similar between normal and knockout animals. However, there was a block in B-cell development at the pre-B stage in
the bone marrow, with a decrease in both
CD45R+/CD43 and
CD45R+/IgM+ cells. The spleens were
consistently smaller in young knockout animals, although total cell
numbers steadily increased with age. The CD4/CD8 staining patterns in
the spleen were relatively normal, but there was a large reduction in
CD45R+/IgM+ cells in the spleen. Though
immature B lymphocytes and mature T lymphocytes were present in the
spleen, thymus, and lymph nodes, the cells functional responses were
impaired. Responses of lymphocytes to LPS, PMA, ionomycin, concanavalin
A, IL-2, IL-7, anti-CD3, and anti-CD28 alone or in combination were
severely reduced or absent. In addition, there appears to be few or no
natural killer cells or / T cells in the Jak3 knockout
animals.4
In contrast to the dramatic defects in lymphocyte maturation observed
in young Jak3 knockout animals, the myeloid lineages showed no apparent
defects early in development. Blood smears showed normal numbers of
monocytes and neutrophils, and spleens stained with Mac-1 appeared
normal. Thus, although Jak3 is crucial for lymphoid development, it
appeared dispensable or redundant for myeloid development. This was of
interest because monocytes express Jak3 upon cytokine stimulation and
respond to the cytokines whose receptors use the IL-2Rc
chain.11-15 Herein we describe defects in myelopoiesis in
the Jak3 knockout animals that develop as the mice age. These defects
include the development of severe splenomegaly, a significant increase
in myeloid/premonocytic cells in the peripheral blood, spleen, and bone
marrow, and invasion of peripheral organs with mononuclear cells. In
addition, we show that this phenotype is accentuated when the
development of Jak3-deficient T cells is rescued with the transgenic
expression of Jak3 in the T-cell compartment. Furthermore, mice
deficient in both Jak3 and RAG-1 do not exhibit splenomegaly and
myelopoiesis, suggesting that Jak3-deficient T cells drive the
expansion of the myeloid lineages, leading to splenomegaly and
infiltration of organs with mononuclear cells.
| |
MATERIALS AND METHODS |
Animals.
The Jak3 knockout mice, and transgenic mice expressing Jak3 under the
control of the proximal Lck promoter used in these studies, have been
described previously.3,16 RAG-1-deficient mice were obtained from the Jackson Laboratory (Bar Harbor, ME). All
mice were bred and kept in pathogen-free housing in accordance with Washington University School of Medicine animal care guidelines. Mice
represented in this study were tested for common mouse pathogens and
were deemed negative by pathology, culture, and polymerase chain
reaction (PCR) analysis.
Tissue histology and peripheral blood analysis.
Tissues were fixed in 10% neutral buffered formalin (Sigma, St Louis,
MO), embedded in paraffin (Baxter, McGaw Park, IL), and stained with
hematoxylin/eosin. Peripheral blood analysis was performed on a Baker
9000 Coulter Counter (Serono Laboratories, Randolph, MA). Peripheral
blood smears were stained with Wright-Geisma (Fisher, Pittsburgh, PA),
and differential blood counts were reported as the mean cell count per
100 nucleated cells examined.
Cell preparation and flow cytometry analysis.
Splenocyte suspensions were prepared using frosted glass slides.
Approximately 1 mL of total blood was obtained from each mouse by
cardiac puncture after lethal anesthetic administration. Bone marrow
cells were obtained from the femur and tibia of each mouse using
22-gauge needles and sterile phosphate-buffered saline (PBS). All cell
samples (1 × 106 cells) were first incubated with 5 µg of R-phycoerythrin- or fluorescein isothiocyanate-conjugated Fc
receptor (FcRII/III; PharMingen, San Diego, CA) antibody for 30 minutes at 4°C, and then counterstained for 30 minutes at 4°C
with R-phycoerythrin or fluorescein isothiocyanate-conjugated
antibodies to the following surface markers: CD3 , CD4, CD8 chain,
TCR  /, CD90.2 (Thy1.2), Ly-6A/E (Sca-1), CD25 (IL-2R chain),
H2Kk, Ly-6G (Gr-1), PK136 (NK1.1), (Mac-3), CD45R (B220),
CD11b (Mac-1), L-selectin (PharMingen), and F4/80 (a gift from D. Link,
Washington University School of Medicine). Samples were analyzed on a
FACScan (Becton Dickinson, San Jose, CA) after acquisition
of 20,000 to 50,000 total cells per sample. All
fluorescence-activated cell sorting (FACS) scans depicted are
representative results of 3 to 5 mice analyzed from each genotype group.
Immunohistochemistry.
Tissues were embedded in Tissue Freezing Media (Fisher), and 10-µm
sections were cut, fixed in cold acetone, and air dried. Sections were
incubated in blocking buffer consisting of PBS, 2% goat serum, and 1%
mouse serum for 20 minutes. Sections were blocked with a commercial
biotin blocking kit (Vector, Burlingame, CA), then incubated for 1 hour
at room temperature with biotinylated antibodies directed against CD3,
Mac-1, and B220 (PharMingen) and F4/80 (Caltag, South San Francisco,
CA) at dilutions of 1:25, 1:50, 1:50, and 1:50, respectively. Sections
were washed for 15 minutes in PBS, then incubated with
streptavadin/horseradish peroxidase (ABC reagent; Vector) for 30 minutes, washed for 15 minutes in PBS, developed with a
diaminobenzidine substrate kit (Pierce, Rockford, IL), and
counterstained with methyl green (Vector).
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RESULTS |
Upon further analysis of the Jak3 knockout mice (/), we
observed that all mice 5 months or older exhibited severe splenomegaly (Fig 1A). Splenomegaly
developed in knockout animals as early as 4 months of age, but not in
heterozygous or wild-type littermates up to 12 months of age (data not
shown). The general architecture of the spleen was severely disrupted
in the / mice. The white pulp, with its characteristic
lymphoid sheath surrounding a central artery, was replaced by a
collection of large cells with euchromatic nuclei (Fig 1B).
Immunohistochemistry showed that these cells stained positive for CD3
(data not shown). In addition, numerous megakaryocytes were apparent.
Further histological examination of homozygous mice showed widespread
organ infiltration of the lungs, kidneys, and liver with mononuclear
cells (Fig 1C through E). Immunohistochemical staining of the tissues
identified both F4/80- and CD3-positive cells in the infiltrates
(Fig 2A and B).
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| Fig 1.
Gross and microscopic
examination of Jak3/ mice. (A) Anatomy of spleens from wild-type
(top), +/ (middle), and / (bottom) mice. (B) Hematoxylin and
eosin (H & E) stain of spleen. Open arrow denotes expanded
population of cells surrounding central artery. Closed arrow denotes
lymphocytes scattered amongst red pulp (original magnification [OM] × 360). (C) H & E stain of Jak3/ liver, showing portal
infiltrates (OM × 360). (D) H & E stain of lung. Closed arrow denotes
infiltrate around large vessels (OM × 360). (E) H & E stain of
kidney. Open arrow identifies large vessel infiltrates. Closed arrow
denotes emigrating lymphocytes (OM × 720). (F through I) Wright stain
of peripheral blood, showing large cells of myelo/premonocytic lineage
(OM × 1,080). (J and K) Wright stain of bone marrow smear (OM × 1,080).
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| Fig 2.
Immunohistochemistry of cellular infiltrates. (A)
Immunostaining of liver infiltrates with anti-CD3 antibody. Closed
arrows identify positive staining cells in each infiltrate (OM × 720). (B) Immunostaining of liver infiltrates with anti-F4/80 antibody.
Closed arrows identify positive staining cells in each infiltrate (OM × 720). Sections shown in (A) and (B) are serial sections.
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Peripheral blood and bone marrow smears obtained from Jak3
/ mice are shown in Fig 1F through K. There was an
increase in myeloid progenitors and a slight decrease in erythroid
progenitors in the bone marrow. Heterozygous and knockout mice
exhibited significant neutrophilia, with higher numbers of both
segmented and band neutrophils, and lymphopenia when compared with
wild-type animals. Mature monocyte numbers were relatively similar in
all 3 groups. Cells classified as myeloid/premonocytic were greatly
increased in knockout animals, and slightly increased in the
heterozygous mice (Table 1).
To further characterize the immature myeloid cells in the periphery of
heterozygous and homozygous mice, whole-blood suspensions from 6- to
12-month-old mice were analyzed by flow cytometry for specific surface
marker expression. As shown in Fig 3A,
knockout and heterozygous mice showed a decrease in lymphocytes (gate
R6, Fig 3A) compared with wild-type mice. There was a profound increase in large, granular cells in the peripheral blood from knockout and
heterozygous animals compared with wild type, as evident by an increase
in both side and forward scatter (cells outside of gate R6, Fig 3A).
This large, granular cell population stained negative for the following
markers: CD4, CD8, CD3, NK1.1, Mac-3, B220, Sca-1, CD25, TCR
/, Thy 1.2, and CD90 (data not shown). When stained with
antibodies against FcR, Mac-1, F4/80, and Gr-1, Jak3+/ and
/ mice showed an increase in FcR/Mac-1 double-positive cells, and a shift from FcRhi/Gr-1med to
FcRmed/Gr-1hi-positive cells when compared
with wild-type mice. When stained with FcR and F4/80, there was an
increase in FcR/F4/80 double-positive cells in /
animals compared with +/ and +/+ mice. The forward and side
scatter profiles of the peripheral blood of / mice separated these large granular cells into two distint populations (Fig
3B). One population showed greater granularity (SSC), a higher Gr-1
staining profile, and did not stain for F4/80 (gate R4), while the
second population showed lower granularity, a lower Gr-1 staining
profile, and positive staining for F4/80 (gate R5, Fig 3B). This
indicates that cells of the R4 and R5 gates are of neutrophilic and
monocytic lineages, respectively. When splenocytes from
Jak3/ and Jak3+/ mice were analyzed, a similar
phenotype was observed (data not shown). Finally, bone marrow from
Jak3/ mice showed an increase of FcR/Mac-1 (61.5%),
FcR/Gr-1 (69.6%), and c-Kit (11.3%) double-positive cells when
compared with wild-type animals (46.9%, 66.4%, and 8.2%,
respectively). In addition, there was a decrease in FcR/Sca-1
double-positive cells in the homozygous animals compared with wild-type
controls (3.8% v 8.8% respectively, data not shown).
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| Fig 3.
Flow cytometric analysis of cell-surface markers on
wild-type, Jak3/+, and Jak3/ mice. (A) Dot plots of
peripheral blood leukocytes (PBLs) depicting FSC and SSC scatter, R1
gates live cells from dead cells, and the R6 gate denotes the normal
lymphocyte population. Density plots of PBLs stained with antibodies
against FcRII/III (vertical axis) versus Mac-1, Gr-1, and F4/80
(horizontal axes). (B) Dot plots of PBLs from Jak3/ mice gating
on large, granular cells (gate R4) and large, less granular cells (gate
R5). Density plots of Jak3/ PBLs show FcRII/III, Gr-1, and
F4/80 staining patterns of R4 and R5 populations.
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To investigate the cause of the myeloid expansion, Jak3/
mice were bred with mice expressing Jak3 under the control of the proximal Lck promoter. These transgenic mice show normal early development of T cells and NK cells, but as the lymphocytes lose the
expression of Jak3 with age in the periphery, they revert to the Jak3
deficient phenotype.16 When we examined transgenic Jak3/ and Jak3+/ mice after 12 weeks of age,
significant splenomegaly was apparent, with spleen sizes 2 to 3 times
as large as age-matched Jak3/ mice (data not shown). The
lymphocytes in these mice had been developmentally restored, as shown
by normal CD4 and CD8 flow cytometry profiles in the spleen and thymus
(data not shown). When splenocytes from these mice were analyzed by
flow cytometry for myeloid markers, it was apparent that
Jak3/ transgenic animals showed an expansion of large,
granular cells, similar to that seen in Jak3/ mice
(Fig 4A, FSC and SSC). These mice also
exhibited an increase of FcR/Mac-1 and FcR/F4/80 double-positive
cells, and a shift from FcRhi/Gr-1med- to
FcRmed/Gr-1hi-positive cells as compared
with transgenic Jak3+/ littermates. We further characterized the
CD4-positive lymphocytes from these transgenic Jak3/
animals to determine if there was any evidence of activation.
CD4-positive cells from transgenic Jak3/ animals expressed very little L-selectin compared with transgenic Jak3+/ mice, indicating that these cells exhibited an activated phenotype (Fig
4B). This is more clearly shown when CD4-positive cells are gated and
analyzed for L-selectin expression (Fig 4B, histogram) To further
investigate this phenotype, Jak3/ mice were crossed with
RAG-1-deficient animals. When 5-month-old Jak3/RAG-1-deficient mice
were examined, no splenomegaly was apparent, and FACS profiles of the
spleens of these mice were comparable to mice deficient in RAG-1 alone
(data not shown).
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| Fig 4.
Flow cytometric analysis of cell-surface markers on
transgenic (T) Jak3/+ and Jak3/ mice. Jak3/ mice were
crossed with a transgenic mouse expressing Jak3 under the control of
the proximal Lck promoter, and splenocytes from transgenic Jak3+/
and Jak3/ animals were analyzed as depicted in Fig 3. (A) Density
plots of splenocytes depicting FSC and SSC scatter. Density plots of
splenocytes stained with antibodies against FcRII/III (vertical
axis) versus Mac-1, Gr-1, and F4/80 (horizontal axes). (B) Density
plots of splenocytes from transgenic Jak3+/ and Jak3/ mice
stained with antibodies against CD4 (vertical axis) and L-selectin
(horizontal axis). Notice the lack of L-selectin high CD4-positive
cells in the transgenic Jak3/ animals. When CD4 cells are gated
and analyzed for L-selectin expression, a shift of L-selectin high,
CD4-positive cells in the Jak3+/ mice to L-selectin low,
CD4-positive cells in the Jak3/ mice is apparent.
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DISCUSSION |
Here we describe a phenotype in the Jak3 knockout mice consistent with
dysregulated hematopoiesis of the granulocyte and monocyte lineages.
There was an increase in large, granular cells in the peripheral blood,
spleen, and bone marrow which stained positive for the myeloid markers
FcRII/III, Mac-1, Gr-1, and F4/80, but did not stain for any
lymphoid markers. Histological examination and flow cytometry of these
cells suggests that both monocytic and neutrophilic lineages have
expanded. This phenotype is not readily apparent at birth, but becomes
apparent as the mice age. By 4 months of age the mice have severe
splenomegaly, and by 5 months of age they have increased numbers of
immature neutrophils and monocytes in the peripheral blood. Consistent
with these findings, the first report of these knockout mice showed an
increase of Mac-1-positive cells in the bone marrow and spleen of
these mice as early as 4 weeks of age.3
There are several possible explanation to account for this phenotype.
First, it is possible that other cellular components, such as natural
killer (NK) cells, lacking in the Jak3/ mice might be
necessary to control myelopoiesis. SCID and RAG knockout mice, which
are deficient in T and B cells, do not exhibit myeloid expansion. These
mice, however, do have NK cells. Previous reports have suggested that
NK cells and their products may play a role in controlling
hematopoiesis.17-19 Mice deficient in both Jak3 and RAG-1,
however, do not exhibit splenomegaly or altered myelopoiesis, suggesting that the loss of NK cells is not the causative agent. Secondly, the myeloid lineages themselves may require signals by
cytokines whose receptors use Jak3 to negatively regulate their proliferation and expansion, and there is evidence for such a role for
IL-7 and IL-4.20-24 Also, it is possible that the loss of
Jak3 in the stromal cells of the bone marrow and spleen may be
responsible for this phenotype, in that the loss of Jak3 in these
stromal cells may affect colony-stimulating factor or other growth-factor production. In support of this, we have shown previously that endothelial cells can be induced to express Jak3,25
and IL-4 has been shown to affect granulocyte-macrophage
colony-stimulating factor production by endothelial
cells.26 Finally, it is possible that the activated T cells
that develop in the Jak3/ animals drive the myeloid
expansion. Recent evidence suggests that the expression of Jak3 is
required for deletion of autoreactive T cells.16 Our
findings support this notion that the Jak3-deficient T cells are the
causative agent. When Jak3-deficient animals are crossed with
RAG-1-deficient animals, no evidence of splenomegaly or myeloid
expansion is detected. Furthermore, when peripheral T-cell numbers are
increased by the transgenic expression of Jak3, the splenomegaly and
myeloid expansion is significantly more severe. This correlates with
the loss of the transgenic expression of Jak3 in the peripheral T
cells, and their reversion to a Jak3-deficient, activated phenotype.
Because the Jak3/ transgenic animals have normal levels
of Jak3 in the T cells of the thymus, these results suggest that the
peripheral expression of Jak3 is critical for maintaining T cells in an
unactivated state and preventing myeloid expansion. Furthermore, these
studies indicate that B cells are not involved, because B-cell numbers
are not increased in the Jak3/ transgenic animals.
Because the deletion of Jak3 disrupts signaling through the receptors
for IL-2, IL-4, IL-7, IL-9, and IL-15, it is difficult to determine
which cytokine or cytokines are responsible for this phenotype. Recent
studies have suggested that a similar phenotype is observed in mice
which are unable to respond to IL-2. IL-2R-deficient mice develop
normally for the first 3 to 4 weeks, but then develop a polyclonal
expansion of T and B cells with autoimmunity and inflammatory bowel
disease, which is believed to occur due to a defect in
activation-induced cell death.27 IL-2R knockout animals
exhibit a similar autoimmune syndrome.28 Interestingly, these animals develop a similar myeloproliferative disorder, with infiltrating myeloid cells in the liver, and large numbers of granulocytic and myeloid cells in the spleen. This phenotype was apparent at 4 weeks of age, and increased as the mice aged. Although necessary, we cannot say for certain if Jak3-deficient T cells are
sufficient for this phenotype. It is possible that the autoreactive T
cells initiate the myeloproliferative phenotype, while Jak3 expression
in the myeloid compartment is required to halt this response. In
support of this, depletion of T cells in IL-2R knockout mice with
antibody against CD4 did not correct the myeloproliferative disorder,
while it did completely reverse the B-cell abnormalities observed in
the IL-2R knockout animals. Also, Jak3 is expressed at very low
levels in resting monocytes, but is induced 12 to 24 hours after
treatment with interferon-, lipopolysaccharide, and
IL-2.11 The delayed, inducible expression of Jak3 may be involved in downregulating a myeloproliferative signal, and the inability to express Jak3 in the myeloid compartment may allow for this
myeloproliferative signal to go unchecked.
The finding that Jak3-deficient T cells are capable of affecting
myelopoiesis is surprising, because Jak3-deficient T cells are unable
to proliferate or secrete cytokines under any conditions tested.3,5,16 However, these cells are not entirely
nonfunctional because we provide strong evidence here that these cells
are capable of inducing significant expansion of the myeloid lineages.
Further studies are needed to clarify how these cells promote this
phenotype, as well as to investigate the function of Jak3 in the
myeloid compartment.
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ACKNOWLEDGMENT |
We are indebted to Daniel C. Thomis for his original work on the Jak3
knockout and transgenic mice. We also thank Dr Marie LaRegina, Niecey
Hinkle, and Paula Klender at the Division of Comparative Medicine
(Washington University) for their help in peripheral blood
analysis, and Dan Link and Tim Ley for thoughtful discussion and
critical review of this manuscript.
| |
FOOTNOTES |
Submitted August 25, 1998; accepted March 31, 1999.
W.J.G. and J.W.V. contributed equally to this work.
Supported by Grants No. CA63417 (L.R.), 5T32HL07088 (W.J.G.), and
MG44909 (L.E.F.) from the Public Health Service, by the American Cancer Society (L.J.B.) and the Life Sciences Research Foundation/Smith Kline Beecham Pharmaceuticals (D.D.C.), and by a
National Institutes of Health Medical Scientist Training Program grant
(to W.J.G. and J.W.V.). D.D.C. is an investigator of the Howard Hughes
Medical Institute.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Lee Ratner, MD, PhD, Washington University
School of Medicine, Box 8069, 660 S Euclid Ave, St Louis, MO 63110;
e-mail: lratner{at}imgate.wustl.edu.
| |
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INTRODUCTION