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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1097-1103
RAPID COMMUNICATION
Defective Expression of Granulocyte-Macrophage Colony-Stimulating
Factor/Interleukin-3/Interleukin-5 Receptor Common  Chain in
Children With Acute Myeloid Leukemia Associated With Respiratory
Failure
By
Uta Dirksen,
Uwe Hattenhorst,
Peter Schneider,
Horst Schroten,
Ulrich Göbel,
Alfred Böcking,
Klaus-Michael Müller,
Richard Murray, and
Stefan Burdach
From the Department of Pediatric Hematology/Oncology and the
Department of General Pediatrics and Pulmonology, Children's Hospital
Medical Center and the Institute for Cytopathology and the Department
of Internal Medicine Hematology/Oncology, and the Center for BioMedical
Research (BMFZ), Heinrich-Heine-University, Düsseldorf, Germany;
Children's Hospital Medical Center, Martin-Luther University, Halle,
Germany; The Institute for Pathology, Ruhr University, Bochum,
Germany; and The DNAX Research Institute, Palo Alto, CA.
 |
ABSTRACT |
Deficiency of the granulocyte-macrophage colony-stimulating factor
(GM-CSF)/interleukin-3 (IL-3)/IL-5 receptors common  chain (c) is
a cause of fatal respiratory failure. c deficiency manifests as
pulmonary alveolar proteinosis (PAP). PAP has heterogenous etiologies
that may be genetic or aquired. Some cases of PAP have been reported to
be associated with hematologic malignancies such as acute myeloid
leukemia (AML). In mice, the PAP phenotype was generated
by targeted deletion of the gene for c and can be treated by
transplantation of wild-type bone marrow into c  / mice. Thus,
our findings in c / mice provide evidence for a causal relationship between the lung disease and the hematopoietic system. We
describe here expression defects of c or c plus GM-CSF receptor  chain (GM-CSFR ) in 3 pediatric patients with AML and PAP
symptoms. All of the patients' leukemic cells failed to express normal
levels of c. The leukemic cells of patients no. 2 and 3 additionally lacked the expression of GM-CSFR , as shown by flow cytometry. Strikingly reduced or absent function of c was demonstrated in clonogenic progenitor assays with absent colony-forming unit (CFU) growth after GM-CSF or IL-3 stimulation. The response to growth factors
acting via a growth factor receptor distinct from the GM-CSF/IL-3/IL-5
system (recombinant human granulocyte colony-stimulating factor
[rhG-CSF]) was normal. After antileukemic treatment, the pulmonary symptoms resolved and c or c plus GM-CSFR
expression was normal. Our findings provide evidence that a defect in
the expression of c or c plus GM-CSFR on AML blasts can be
associated with respiratory failure in patients with AML.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
PATIENTS WITH MYELOID leukemias can
present with severe pulmonary symptoms. Those pulmonary affections may
be interpreted as interstitial pneumonia, infiltration of the lung with
leukemic cells, or as a disease of an unknown cause. Single cases have been reported to be associated with pulmonary alveolar proteinosis (PAP).1-3 PAP is a rare disease histopathologically
diagnosed by an accumulation of proteinaceous, periodic acid Schiff
(PAS) stain-positive material in the alveolar space. Additionally, the diagnostic value of broncheo alveolar lavage fluid (BAL) has been shown
for adults4,5 and pediatric patients.6 The BAL
fluid contains large quantities of serum proteins and
glyceroproteins.7 Furthermore, elevated amounts of
surfactant proteins (SP) have been found in adults and some pediatric
patients.8,9
In children, the disease has been described less frequently than in
adults and imposes as a heterogeneous disorder that can be associated
with different diseases. Whereas most pediatric cases remain
idiopathic, a well-defined group of some congenital PAP patients has
been found to be associated with the hereditary SP-B
deficiency.10,11 Other cases have been reported in patients with lysinuric protein intolerance,12
immunodeficiencies,13 or hematological disorders such as
acute myeloid leukemia (AML) or chronic myeloid leukemia
(CML).1-3 However, with the exception of the
SP-B-deficient patients, the etiology and pathophysiological mechanisms in pediatric PAP are unknown. Recently, we described an
expression defect of common chain (c) in pediatric patients with
PAP and in 1 patient with severe lung disease suspected to be
PAP.14,15
In mice, PAP has been shown to be associated with a deletion of the
granulocyte-macrophage colony-stimulating factor (GM-CSF) gene16,17 or with a deficiency of the GM-CSF/interleukin-3 (IL-3)/IL-5 receptor c chain.18 The lung patholgy in
both types of mutant mice shows significant similarities to human
PAP.16-18
The receptors for human GM-CSF, IL-3, and IL-5 are composed of two
subunits.19,20 The respective private chain mediates the specific binding, whereas c is required to confer high-affinity binding21 and is essential for signal
transduction.22
We now describe our findings on expression deficiencies and functional
absence of the c chain and/or the GM-CSFR chain in bone
marrow (BM), peripheral blood (PB), and/or broncheo alveolar lavage fluid myeloblasts of 3 pediatric AML patients associated with
signs of compromised respiratory function. Two of them have been
diagnosed for PAP. One patient has had noninfectious severe respiratory
failure of unknown causes suspected to be PAP.
| |
MATERIALS AND METHODS |
Flow cytometry analysis.
Surface receptor expression on cells from patients, control AML
patients, and healthy controls was assessed in whole blood samples. For
indirect flow cytometry, the following unconjugated monoclonal
antibodies (MoAbs) were used: the c-specific MoAb (CDw131) S-16, the
GM-CSF receptor chain MoAbs (CD116) S-16 (and S-50; not shown), and
the IL-3 receptor chain MoAb (CDw123) S-12 (all Santa Cruz
Biotechnology, Santa Cruz, CA). The receptor antibodies recognize
extracellular domains of c and GM-CSFR , respectively. Receptor
antibodies were developed with a fluorochrome-conjugated secondary
goat-antimouse antibody (Coulter, Krefeld, Germany). For cell type
distribution and diagnosis of AML (data are included in the case
reports), the following fluorochrome-conjugated antibodies were used:
CD3 (Leu 4), CD4 (Leu 7), CD14 (Leu M3), CD15 (Leu M1), CD20 (Leu 16),
CD33 (Leu M9), CD34 (HPCA2), CD45 (HLe-1), HLA-DR (L243), CD56 and (Leu
19) (Becton Dickinson, Heidelberg, Germany); CD7 (IOT7), CD11b (IOM1b),
CD14 (IOM2), and CD117 (17F11) (Immunotech, Krefeld, Germany); and
fluorochrome-conjugated isotype-matched control antibodies (Dianova,
Hamburg, Germany). Cell staining and analysis by FACScan (Becton
Dickinson) was performed according to standing laboratory procedure as
we have previously described.15 Briefly, for indirect
staining, cells were incubated with the first antibody for 15 to 30 minutes at room temperature (RT) according to manufacturer's
guidelines, washed twice with phosphate-buffered saline (PBS), and were
stained for 30 minutes with the fluorochrome-conjugated secondary
antibody. For direct staining, fluorochrome-conjugated antibodies were
incubated for 10 minutes at RT. After washing with PBS, both indirectly
and directly stained samples were incubated with the FACS lysing
solution according to the manufacturer's procedure (Becton Dickinson).
In BM and PB, the receptor expression was analyzed in the myeloid gate
(CD34+ and CD33+). Fluorescence intensity is
expressed as the percentage of positive cells.
Progenitor clonogenic assays.
Patients', control AML patients', and controls' BM mononuclear cells
(BMMNCs) or PB mononuclear cells (PBMNCs) were separated by
Ficoll-Hypaque density gradient, washed twice with PBS, and cultured at
a concentration of 1.5 × 105 cells/mL culture medium
in 24-well culture clusters (Costar, Cambridge, MA). The culture medium
consisted of 30% fetal calf serum (FCS; Sigma, Deisenhofen, Germany),
1% 2-mercaptoethanol (Sigma), 1% penicilline-streptomycin solution
(GIBCO, Eggenstein, Germany), 1% L-glutamin, 10% bovine serum
albumine (Behring, Marburg, Germany) with sodium bicarbonate, 0.5 U
recombinant human erythropoietin (rhEPO), 40% methylcellulose, and 500 to 5,000 U of rhIL-3 (Behring), rhGM-CSF (Leucomax; Sandoz,
Nürnberg, Germany), and granulocyte colony-stimulating factor
(G-CSF; Neupogen; Amgen/Roche, München, Germany). After 14 days
of culture at 37°C, 5% CO2, 100% humidified atmosphere, the colony-forming units (>50 cells/colony) of
granulocytes and macrophages were determined by inverse microscopy.
Cytopathological analysis.
BAL samples were collected from patients no. 1 and 2. They were
examined by light microscopy after cytocentrifugation and staining by
May-Grünwald-Giemsa, PAS, and Ziehl.
Electron microscopy analysis.
Electron microscopy was performed in glutaraldhyde-fixed BAL samples
according to standard procedures.
| |
CASE REPORTS |
Patient no. 1, a boy, was admitted to the hospital at the age of 1 month because of severe respiratory distress and generalized swelling
of lymph nodes (Table 1).
Despite pulmonary symptoms, the first x-ray showed no severe pulmonary
changes. His high leukocyte count was suspicious for a hematological
malignancy. A BM harvest was performed, leading to the diagnosis of AML
French-American-British (FAB) classification M4. Immunophenotyping of
the PB cells showed 91% myeloblasts expressing CD33, CD34, CD11b,
CD15, and they were negative for CD14 and HLA-DR. Because of the high
leukocyte count (129,000 cells/µL), the patient underwent an exchange
transfusion before the start of chemotherapy. The antileukemic
treatment was combined with a high-dose antibiotic and antimycotic
therapy. During the first course of chemotherapy, the respiratory
symptoms got worse and the patient required exogenous oxygenation. The x-ray showed perihilar infiltrates and increased interstitial markings.
After a short-lasting improvement, his respiratory condition got worse,
necessitating intubation and mechanical ventilation. Under a combined
therapy with antibiotics, antimycotics, exchange transfusion, and
lavages through the tubes, with 5 mL NaCl in each lung three times a
day, the symptoms got better. Within 3 weeks of therapy, he became
oxygen-independent. He was scheduled for myeloablative therapy and
unrelated cord blood transplantation. Before transplantation, the
patient received high-dose chemotherapy, which was well tolerated. At
day +42, autologous reconstitution was diagnosed by analysis of
chimerism. Three months after the graft failure, he relapsed under
maintenance therapy initially with 20% M4 myeloblasts in the BM
aspirate. The blast count increased up to 70% within 10 days. He again
developed tachypnoea. Two weeks after relapse, the patient underwent a
myeloablative therapy and an allogeneic BM transplantation (BMT). After
BMT, he suffered from recurrent severe infections. At day +75, he
became septicemic with progress to death at day +90. Within the
septicemia, he developed renal, liver, and respiratory failure. At day
+87, the breathing became periodic and required exogenous oxygenation.
The septicemia condition deteriorated with progression to death.
Patient no. 2, a girl, was diagnosed for AML (FAB, unclassified) at the
age of 132 months with 95% myelocytic blasts expressing CD34, CD33,
CD11b, CD56, CD13 (21%), and c-kit (23%); they were negative for CD7,
HLA-DR. The absolute leukocyte count at diagnosis was 143,000/µL.
At the time of diagnosis, she presented with dyspnea and a
nonproductive cough. The x-ray showed a bilateral pleural effusion but
no pulmonary changes. Because of the instable pulmonary condition, she
was treated with a modified BFM AML 93 protocol with split chemotherapy
course including longer intervals. Within a few days, the pulmonary
symptoms got worse and she presented with increasing shortness of
breath. This time the chest x-ray showed marked infiltrates of the
right middle and lower lobe. Despite high-dose antibiotic and
antimycotic therapy, her general condition deteriorated with increasing
dyspnea and oxygen dependency. The x-ray now showed bilateral
infiltrates. A diagnostic BAL was performed and she required mechanical
ventilation.
Alternating therapeutic lavage of each lung gave a short-lasting
improvement in oxygenation, but no long-lasting demonstrable changes in
pulmonary mechanics. Because her blasts were increasing up to 65% in
the BM, the antileukemic treatment was intensified. Under this regimen,
the pulmonary symptoms got better. However, her blast count persisted
at approximately 25%. She developed septicemia and a capillary leakage
syndrom with progression to death 4 months after diagnosis. At that
time, the pulmonary symptoms were minor and she had no clinical
evidence for PAP. A BAL was not performed and the parents refused to
have an autopsy performed.
Patient no. 3, a girl, has been diagnosed for AML M5 at the age of 9 months. At time of diagnosis, she presented with severe pulmonary
symptoms. She presented with myeloid skin infiltrates and 50% myeloid
blasts in her BM aspirate expressing CD33, CD34, CD56, CD11b, CD11c,
CD4, and CD15; they were negative for HLA-DR. Her leukocyte count was
3,900/µL. Right after the beginning of the first course of
chemotherapy, her pulmonary symptoms got worse and she developed
dyspnea and orthopnea. This time the x-ray showed bilateral perihilar
infiltrates and increased interstitial markings. Under a combined
therapy of antibiotics and chemotherapy, her pulmonary situation slowly
improved. Because she showed a persistence of her myeloblasts (5%)
after 6 months of therapy, she underwent a myeloablative chemotherapy
and unrelated BMT. At present, she is alive 5 years after
BMT. She is in good clinical condition and had no clinical
or radiological PAP symptoms ever since.
We examined 17 control patients with myeloid leukemias, 3 pediatric
patients (1 M0, 2 M2, and 1 refractory anemia with blast excess
[RAEB]), and 14 adults (3 M1, 2 M2, 6 M4, and 3 M5). Furthermore, we
examined 3 age-matched healthy controls. None of them has had clinical
or radiological PAP or PAP-like symptoms (see Table 3B).
| |
RESULTS |
Diagnosis of alveolar proteinosis in pediatric AML patients.
The cytopathologic analysis of the lavage of patients no. 1 and 2 showed a PAS-positive amorphous, granular material. The material
contained some enlarged alveolar macrophages and showed vacuolization
of their cytoplasma. The amount of extracellular proteinaceous material
was strikingly augmented. A count of BAL cells was not performed,
because it has been shown to be of no prognostic value23
(Fig 1A).
View larger version (120K):
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| Fig 1.
The figure is taken from cytospin material of broncheo
alveolar lavage fluid from patient no. 2. The accumulation of the
proteinaceous material is depicted by arrows.
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Electron microscopy was performed in BAL samples of patients no. 1 and
2 demonstrating enlarged alveolar macrophages containing lamellar
bodies and multilamellar bodies with electron dense central regions.
Furthermore, large amounts of surfactant were found in the surrounding
of the macrophages. These findings indicate either an maldigestion or
an overproduction of the surfactant material and have been described in
PAP4,6 (data not shown).
Quantification of surfactant proteins.
The testing for surfactant apoproteins A (SP-A) and SP-B has recently
been established as being of diagnostic value. Quantification of
surfactant proteins was performed as described
previously.24,25 SP-B was readily detected in both
patients; thus, the hereditary SP-B deficiency as a possible underlying
cause of PAP in children was excluded.11 However, both
patients had elevated levels of total protein and SP-A and detectable
levels of SP-B, proving that the proteinaceous PAS-positive material
seen after cytocentrifugation were proteins and surfactant
(Table 2).
Before the first course of chemotherapy, the expression of c and the
private chain of the GM-CSF receptor and the private chain of
the human IL-3 receptor was analyzed by flow cytometry. The data are
obtained by analysis of the respective receptor expression in the gate
representing the myeloid cells. Analysis was performed in PB and pooled
BAL fluid from patient no. 1 and in BM and pooled BAL fluid cells from
patients no. 2 and 3. All patients' cells showed a strikingly reduced
expression of c on their myeloid blasts in all samples (<1%).
GM-CSFR was readily detected in cells from patient no. 1 (90%),
but was not detectable in cells from patients no. 2 (<1%) and 3 (<1%), whereas IL-3R- was detectable in each patients' sample
(25% in patient no. 1, 39% in patient no. 2, and 27% in patient no.
3). All data were obtained in comparison to healthy controls and to 16 AML controls and 1 RAEB control without PAP symptoms
(Table 3B).
Thus, pulmonary symptoms in the AML patients were found to be
associated with c or c plus GM-CSFR deficiency on patients' myeloid cells (Table 3A). Remarkably, in BAL fluid from patients no. 1 and 2, the alveolar macrophages did not express mature markers (CD14+ and CD15+) but expressed early myeloid
markers (CD34+, CD33+), indicating that the
alveolar macrophages in these patients might be descendating from the
leukemic clone.
Expression of the GM-CSF/IL-3/IL-5 receptor common chain, the
GM-CSF receptor chain (GM-CSFR ), and the IL-3R chain (IL-3R
) after therapy.
After elimination of the leukemic clone by high-dose chemotherapy
(ChTx), c was readily detected on cells from patient no. 1. At the
time of the relapse, the leukemic cells failed to express c, whereas
c was detectable on the remaining mature myeloid cells. After
myeloablative therapy (ChTx) and total body irradiation (TBI), c was
found to be expressed on the myeloid cells.
Patient no. 2 did not get into remission after the first split course
of ChTx with 60% remaining blasts. After intensified ChTx, the cell
count of the leukemic blasts remained stable at around 20%, and
roughly 80% nonleukemic c+/GM-CSFR +
cells were detectable in the myeloid population.
After myeloablative ChTx, TBI, and allogeneic BMT, cells from patient
no. 3 expressed c and GM-CSFR (Table
4).
Clonogenic progenitor growth in the presence of c-dependent and
c-independent stimuli.
Hematopoietic progenitor cloning assays were performed to examine the
response of the c and c plus GM-CSFR chain-deficient MNCs to
growth factors dependent on the GM-CSF/IL-3/IL-5 receptor system, such
as GM-CSF and IL-3 to G-CSF as a growth factor that acts independently
of the GM-CSF/IL-3/IL-5 receptors system. PB or BM cells from the
c-deficient AML patients did not respond to GM-CSF and IL-3 when
compared with controls. However, normal multilineage colonies were
formed in response to a stimulus that acts independently of the c
receptor, such as G-CSF. The data obtained by progenitor cloning assays
prove the functional absence of c. There was no significant
difference between the patient lacking c only (c) and the
patients lacking both c and GM-CSFR (c plus GM-CSFR
; Table 5).
| |
DISCUSSION |
Respiratory failure is a severe complication in patients with myeloid
leukemias. The pulmonary affections can be interpreted as pneumonia, as
infiltration of the lung with myeloid cells, or as a rare lung disease
such as alveolar proteinosis (PAP). The diagnosis of PAP is based on
typical histology or cytopathology showing the accumulation of
proteinaceous material. Several theories have been advanced to explain
the association between myeloid leukemias and PAP. Some investigators
focused on PAP as a sequel of chemotherapy-induced lung
injury,2,26 altered cell immunity,3 or impaired
function of the alveolar macrophages.27,28 However, the
underlying molecular mechanism leading to this respiratory failure
remains to be determined.
In this report, we describe our investigations in 2 pediatric AML
patients with accompanying alveolar proteinosis and 1 AML patient with
severe respiratory failure suspected to be PAP. In mice, a disease
similar to human PAP has been shown to be associated with a deletion of
the GM-CSF gene16,17 or with a deficiency of
c.18 Thus, we analyzed the c expression and function
in our AML patients. All patients' myeloid blasts in BAL fluid, BM, or
PB were analyzed for the expression of c and GM-CSFR , the second
subunit of the GM-CSF receptor. In all of them we found a striking
reduction of c (c). Blasts from patients no. 2 and 3 additionally lacked the expression of GM-CSFR (GM-CSFR ) but not the IL-3 receptor chain (IL-3R). Remarkably, in the flow
cytometry analysis of BAL fluid, c myeloblasts were detected, but no mature alveolar macrophages. This finding indicates that the
leukemic clone may have displaced the mature alveolar macrophages.
All data were obtained in comparison to healthy controls and to AML
control patients without PAP.
For characterization of the functional consequences of the absence of
c or c plus GM-CSFR , we examined clonogenic growth of the
patients' hematopoietic progenitor cells in response to growth
factors. We used rhGM-CSF and rhIL-3 functioning through binding to
members of the GM-CSF/IL-3/IL-5 receptors family and the independently
effecting rhG-CSF. GM-CSF and IL-3 had almost no effect on clonogenic
growth of the patients' progenitor cells, whereas growth in response
to G-CSF was normal. The clonogenic growth in patients with a combined
deficiency of c and GM-CSFR was not different from the patient
lacking c only, indicating the specific subunit of the receptor
alone is not sufficient for the receptor function. Furthermore, the
combined deficiency of both c and GM-CSFR expression in AML
patients did not exercerbate the pulmonary disease in these patients
when compared with the patient with an isolated c expression defect.
These findings indicate that c deficiency eliminates the entire
GM-CSF/IL-3/IL-5 receptors system. This corresponds to results showing
c to be essential for signal transduction.22
Following hematopoietic reconstitution after myeloablative therapy, BM
and BAL cells from patient no. 1 beared the c receptor, and the PAP
symptoms completely resolved. When he relapsed, we again found his
leukemic clone to be c. This time he also developed tachypnoea but did not progress to severe respiratory failure. Because
the kinetic of pulmonary invasion with malignant myeloid cells is
unknown, the question of why the patient did not develop all PAP
symptoms at this time remains speculative. It has been demonstrated
that replacement of alveolar macrophages from the BM is completed
within 35 to 100 days.29 Although it is not known whether
this is true for malignant myeloid cells, we suggest that the short
time span of only a few days between relapse and myeloablative therapy
may have prevented from invasion of the lung with c
macrophages and from the development of full PAP symptoms.
After one course of chemotherapy, patient no. 2 still had 60% leukemic
cells and the pulmonary symptoms got worse; she required mechanical
ventilation. However, no focus for an infection was found, and analysis
of the BAL fluid gave strong evidence for the diagnosis of PAP. She
recieved an intensified chemotherapy protocol that was not able to
completely erradicate the blasts. However, the blast count remained
stable at around 20%, and the normal hematopoiesis recovered with 10%
mature myeloid cells (CD14+/CD15+). Whithin the
next 4 weeks, her pulmonary situation slowly improved and she was
breathing spontaneously. She died of septicemia with clinically
nonrelevant pulmonary symptoms.
After allogeneic BMT, cells from patient no. 3 beared the c and
GM-CSF receptor chain. She is in remission of her leukemia for 5 years and has had no PAP symptoms ever since.
Our data suggest that some cases of human PAP in patients with AML may
be caused by a defect of c expression on the alveolar macrophages.
The involvement of alveolar macrophages in the pathophysiology of PAP
has been suggested.27,30,31 In particular, the frequent association of PAP with hematological diseases1,3,32
immunodeficiencies13 implicates that the alteration of
macrophage function may play an important role in the pathogenesis of
PAP.23,33
Our data implicate the following model for the pathogenesis of PAP in
AML patients. Alveolar macrophages in AML may be derived from the
leukemic clone. It has been established that alveolar macrophages are
of BM origin.29 Because myeloid blasts have a growth
advantage, the blast clone may be able to replace the normal alveolar
macrophages. This has been demonstrated by our FACS analysis showing
solely the c or c plus GM-CSFR leukemic clone in the respective patients' BAL fluid before the antileukemic treatment. The c or c plus GM-CSFR
alveolar macrophages may have an impaired surfactant catabolism and
clearance of the alveolar space from surfactant, leading to PAP
symptoms. Investigations on the kinetics of the alveolar macrophages
showed a mean turnover time of 5.6 days, with 70% influx of monocytes
and a local division of 30%.34 Elimination or
marked reduction of the leukemic c or c plus
GM-CSFR clone by high-dose chemotherapy and repopulation of
the lung with an allogeneic or autologous c+ or c
plus GM-CSFR-+ clone may reverse PAP symptoms.
This study indicates that infantile PAP in AML patients can be
associated with a c or c plus GM-CSFR
expression, at least in some cases. This conclusion has been
corroborated by the following findings. PAP symptoms in the described
AML patients occurred at the time of diagnosis of the AML. In the BAL
fluid, solely c or c plus GM-CSFR
leukemic blasts were found by flow cytometry, indicating an absence of
normal alveolar macrophages. Elimination of the leukemic clone and
expansion of c+ and GM-CSFR + cells
reversed PAP symptoms. These data provide evidence that PAP in these
patients may be related to a dysfunction of alveolar macrophages due to
a deficiency in the GM-CSF/IL-3/IL-5 receptor system.
| |
FOOTNOTES |
Submitted February 24, 1998;
accepted May 22, 1998.
Supported by the Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich 503; by the Bundesministerium für
Bildung, Wissenschaft und Technologie (BMBF) Germany BEO BioRegio
311661; by the Dr. Mildred Scheel Stiftung der Deutschen Krebshilfe;
and by the Elterninitiative Kinderkrebsklinik Düsseldorf e.V.
U.D. was the recipient of the Resident Physician Merit Award of the
American Society of Hematology 1996.
Presented in part at the 38th Annual Meeting of the American Society of
Hematology, Orlando, FL. Some data presented here are part of the
thesis of U.H.
Address reprint requests to Uta Dirksen, MD, Department of
Pediatric Hematology/Oncology, Children's Hospital Medical Center, 14.82, Moorenstr. 5, D-40225 Duesseldorf, Germany; e-mail:
dirksen{at}uni-duesseldorf.de; or Stefan Burdach, MD, Children's
Hospital Medical Center, Ernst-Gruberstr. 40, 06097 Halle, Germany.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Paul Stevens and Matthias Griese for performing the
SP-B and SP-A ELISA, Dr Orthmann for helpful advice, and
Petra Genutt and Ulla Wieczoreck for technical assistance.
| |
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