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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2343-2356
By
From the Department of Medicine, Division of Hematology and Oncology,
University of Tübingen, Tübingen, Germany; Hanson Centre
for Cancer Research, Matthew Roberts Laboratory, Institute of Medical
and Veterinary Sciences, Adelaide, South Australia, Australia;
Immunotech, S.A., a Beckman-Coulter company, Marseille, France;
Department of Internal Medicine I, Division of Hematology and
Hemostaseology, University of Vienna, Vienna, Austria; and Institute of
General and Experimental Pathology, University of Vienna, Vienna,
Austria.
Basophils (Ba) and mast cells (MC) are important effector cells of
inflammatory reactions. Both cell types derive from CD34+
hematopoietic progenitors. However, little is known about the cell
subsets that become committed to and give rise to Ba and/or MC. We have
generated a monoclonal antibody (MoAb), 97A6, that specifically detects
human Ba, MC (lung, skin), and their CD34+ progenitors.
Other mature hematopoietic cells (neutrophils, eosinophils, monocytes,
lymphocytes, platelets) did not react with MoAb 97A6, and sorting of
97A6+ peripheral blood (PB) and bone marrow (BM) cells
resulted in an almost pure population (>98%) of Ba. Approximately
1% of CD34+ BM and PB cells was found to be
97A6+. Culture of sorted
CD34+97A6+ BM cells in semisolid medium
containing phytohemagglutinin-stimulated leukocyte
supernatant for 16 days (multilineage assay) resulted in the formation
of pure Ba colonies (10 of 40), Ba-eosinophil colonies (7 of 40),
Ba-macrophage colonies (3 of 40), and multilineage Ba-eosinophil-macrophage and/or neutrophil colonies (12 of 40). In
contrast, no Ba could be cultured from
CD34+97A6
BASOPHILS and mast cells are
multifunctional hematopoietic effector cells involved in allergic and
inflammatory reactions.1-4 These cells produce various
biologically active mediators which, after cell stimulation, can be
released into the extracellular space.4-7 Despite being of
similar morphology and similar biochemical and functional properties,
basophils and mast cells represent distinct cell lineages within the
hematopoietic system. In fact, basophils differ from mast cells in
their antigenic properties, their response to diverse agonists, and
their mediator content.8-10 With regard to cytokine
receptors, mature basophils express significant amounts of interleukin
(IL)-3R Basophils and mast cells originate from CD34+ progenitor
cells.15-18 An important differentiation factor for human
basophils (and eosinophils) appears to be IL-3.19 In
particular, when normal bone marrow-derived progenitor cells are
cultured in the presence of IL-3 for 14 or 16 days, a substantial
number of cultured cells are basophils and
eosinophils.18-20 Other cytokines, like granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-5 can
also promote basophil and eosinophil differentiation.21 Interestingly, neither IL-3, IL-5, or GM-CSF induce the differentiation of human mast cells in vitro.15-19 However, the
differentiation of human mast cells is inducible by stem cell factor
(SCF), the ligand of the c-kit gene product.16,18,22-25 In
addition, several codifferentiation factors (IL-6, IL-4) reportedly
influence the SCF-induced in vitro differentiation of human mast
cells.18,26
Although it is generally accepted that basophils, eosinophils, and mast
cells arise from CD34+ cells, little is known about the
phenotype and receptors that define the subsets of their precursor
cells. The distribution of cytokine receptors suggests that c-kit is
expressed early in mast cell differentiation together with other
cytokine receptors.12,25 However, the other cytokine
receptors are lost during progenitor cell maturation, whereas c-kit
expression is maintained.12 In the case of basophils, c-kit
expression apparently decreases during maturation, whereas the receptor
for IL-3 is expressed throughout the maturation process.27
So far, only a few markers that show specificity for either human
basophils or mast cells have been generated.28-33 One of these, Bsp-1, was found to react with basophils, but not with tissue
mast cells.28,29 Another marker, 2D7, specifically
recognizes a cytoplasmic antigen of basophils, but does not react with
eosinophils, neutrophils, or mast cells.30 The antibody
YB5B8 was initially described as a mast cell-specific
marker.31 In fact, this antibody did not react with other
mature myeloid cells. Later, it was found that the YB5B8-reactive
antigen is the human equivalent of c-kit and is expressed on mast cells
as well as on hematopoietic progenitors.32,33
In this report, we describe a monoclonal antibody, 97A6, which
specifically recognizes mature basophils and mast cells, but no other
mature hematopoietic and nonhematopoietic cell types. Moreover, we
provide evidence that antibody 97A6 also reacts with CD34+
basophil and mast cell progenitor cells and that the detected antigen
plays a role in basophil activation.
Immunization and Hybridoma Production
Isolation of Primary Hematopoietic Cells
Isolation of Primary Tissue Mast Cells Lung mast cells were enriched from surgical specimens of 3 patients with bronchiogenic carcinoma (lobectomy). Informed consent was obtained before surgery. Foreskin was obtained from 3 children undergoing circumcision. Informed consent was obtained from parents in each case. Uterine tissue was obtained from 3 patients with uterine myomata after informed consent was given. Tissue mast cells were isolated following published techniques.37-40 In brief, tissue specimens were cut into small pieces and washed in Tyrode's buffer (200 mg/L KCl, 50 mg/L NaH2PO4.H2O, 8 g/L NaCl, 1 g/L glucose; Mg/Ca-free). Tissue fragments were then incubated in 2 mg/mL collagenase type II (Sebak, Suben, Austria) for 90 to 180 minutes at 37°C. After digestion, dispersed cells were recovered, washed, and examined for the presence of mast cells by toluidine blue (Sigma, München, Germany) staining. Isolated cells were cultured in RPMI 1640 plus 10% fetal bovine serum (FBS) at 37°C for at least 12 hours before experiments were conducted.Cell Lines The human mast cell line HMC-1, established from a patient suffering from mast cell leukemia,41 was kindly provided by JH Butterfield, Mayo Clinic, Rochester, MN. HMC-1 cells were cultured in Iscove's modified Dulbecco's medium (IMDM) supplemented with 10% FBS, glutamine, and antibiotics at 37°C and 5% CO2. The basophil precursor cell line KU-812, raised from a patient suffering from CML,42 was a kind gift from K Kishi, Niigata University, Niigata, Japan. The eosinophilic cell line EOL-1, established from a patient suffering from acute eosinophilic leukemia,43 was purchased from the German Collection of Microorganisms and Cell Cultures (DSM; Braunschweig, Germany). KU-812 and EOL-1 cells were cultured in RPMI 1640 medium with 10% FBS, glutamine, and antibiotics (37°C, 5% CO2). The erythro-megakaryoblastic cell line UT-734 was a kind gift from Dr Komatsu (Togichi, Japan), and was grown in RPMI 1640, supplemented with 10% FBS and 10 ng/mL recombinant human (rh) IL-3 (Behring Werke). In addition, the following cell lines were used for screening with MoAb 97A6: the tumor cell lines DU.4475, MCF-7, and T-47D (breast carcinoma); NCI-H128 and NCI-69 (small cell lung carcinoma); SK-MES, SK-LU1, Calu 1, Calu 3, and Calu 6 (lung carcinoma); HELA (cervix carcinoma); 5637 (urinary bladder carcinoma); A431 (epidermal carcinoma); IMR-32 (neuroblastoma); TE-671 (medulloblastoma); A172 and U138 (glioblastoma); and the leukemic cell lines K562 and HEL (erythroleukemia); KG-1, KG-1a, HL-60, and U937 (myeloid leukemia); HSB-2, CCRF-CEM, and Molt-4 (T-lymphoid leukemia); Daudi (Epstein-Barr virus [EBV]-transformed B-cell line); and Reh (B-lymphoid leukemia) were obtained from the American Type Culture Collection (ATCC, Rockville, MD). The cell lines MO7-e (megakaryoblastic leukemia); Nalm-1, BV-173, 207, 380, and 697 (B-lymphoid leukemia); CML-T1 (T-lymphoid leukemia); EM-2 (myeloid leukemia); and U-266 (myeloma) were purchased from the German Collection of Microorganisms and Cell Cultures. The following additional cell lines were kind gifts: MEG-O1 (megakaryoblastic leukemia) from Dr H. Saito (Nagoia, Japan),44 TF-1 (erythroleukemic leukemia) from Dr T. Kitamura (Tokyo, Japan),45 MOLM-1 (megakaryoblastic leukemia) from Dr J. Minowada (Okayama, Japan),46 and OCI/AML-4 (myeloid leukemia) from Dr E.A. McCulloch (Toronto, Canada).47Purification of PB and BM CD34+ Cells Selection of normal donor BM CD34+ cells (n = 5) from 5-10 × 107 or normal donor PB CD34+ cells (n = 3) from 1 × 109 Ficoll-Hypaque-isolated cells was performed on a magnetic activated cell sorting (MACS) column according to the instructions of the manufacturer (Miltenyi, Bergisch Gladbach, Germany). Purity of selected CD34+ cells was 96% to 99%, and the recovery was greater than 65%.Selection of Peripheral Blood Basophils Ficoll-Hypaque-selected buffy coat PB cells from healthy donors (n = 3) or Ficoll-Hypaque-separated cells from patients in chronic or accelerated phase of CML (n = 2) were enriched for basophils on a magnet using the StemSep basophil enrichment antibody cocktail (CellSystems, Remagen, Germany). Negative selection of basophils was achieved by magnetic depletion of undesired cells and was performed according to the manufacturer's guidelines (CellSystems). The purity of the selected basophils was determined by morphology. The values ranged between 89% to 98%. Alternatively, PB cells (n = 3) were labeled with MoAb 97A6-biotin, washed 3 times, and magnetically stained with anti-IgG-MACS beads (Miltenyi). The selection by MACS was conducted as described by the manufacturer. To monitor positivity for MoAb 97A6, cells were stained with streptavidin-phycoerythrin (SA-PE) plus MoAb 97A6-PE and analyzed on a FACSCalibur (Becton Dickinson, Heidelberg, Germany) flow cytometer. Approximately 99% (99% ± 0.8%) of the selected cells were 97A6+ basophils, as determined by flow cytometry and morphology.Basophil Progenitor Cell Assays Liquid suspension culture. 5 × 105 CD34+ PB cells (n = 3) were incubated at 37°C in serum-free IMDM medium48 supplemented with 1% bovine serum albumin (BSA), 700 µg/mL holo-transferrin, 40 µg/mL human low density proteins, and 10 µg/mL insulin (Sigma, München, Germany). For the generation of basophils, cells were stimulated in the presence of 100 ng/mL IL-3 (Behring Werke) for 14 days. Half-medium changes were performed twice weekly. Colony assay (multilineage assay).
Duplicate cultures containing either 103 MACS-selected
CD34+ BM cells, 103 fluorescence-activated cell
sorting (FACS)-sorted CD34+97A6+
cells, or 103 CD34+97A6 Mast Cell Progenitor Assay Duplicate cultures of 103 MACS-selected CD34+, 103 FACS-sorted CD34+97A6+, and 103 CD34+97A6 BM cells were
incubated in 24-well plates (Greiner) in serum-free IMDM
medium48 supplemented with 1% BSA, 700 µg/mL
holo-transferrin, 40 µg/mL human low density proteins, and 10 µg/mL
insulin, 100 ng/mL SCF (PreproTech, Frankfurt, Germany), and 10 ng/mL
IL-6 (PreproTech), for 35 days at 37°C in a humidified atmosphere
(5% CO2). After 14 and 28 days of culture, the medium was
replaced by serum-free IMDM medium supplemented with 100 ng/mL SCF.
After 35 days of culture, the resulting cells were analyzed for
morphology and tryptase content. For morphological analysis,
cytocentrifuge preparations were stained with
May-Grünwald-Giemsa. Tryptase content was determined by a
fluoro-immuno-enzyme (FIA; Pharmacia, Uppsala, Sweden) assay as
described.49,50 The detection limit of this assay was found
to be 1 ng/mL; no cross-reactivity with histamine, heparin, or other
known growth factors was found.49,50
Histamine Release Experiments Histamine release experiments were performed as described51 using primary basophils (3 healthy donors) and primary tissue mast cells (lung, foreskin, and uterus, each 3 donors). Cell suspensions were adjusted to final concentrations of 0.5 to 1.5 × 106/mL. Basophils (immediately after isolation) and mast cells (after at least 12 hours in culture) were incubated with varying concentrations (0.01, 0.1, 1.0, and 10 µg/mL) of MoAb 97A6 or anti-IgE MoAb E-124-2-8/D 2 (Immunotech, Marseille, France) in
histamine release buffer (HRB, Immunotech; 20 mmol/L
1,4-piperazinediethanesulfonic acid [PIPES], 1 g/L
glucose, 1 mmol/L CaCl2) or with buffer (HRB) alone for 45 minutes at 37°C. Mast cells were incubated with myeloma IgE (derived from the cell line U266) for 3 hours at 4°C before the challenge with anti-IgE. After incubation with agonists, cells were
centrifuged at 4°C, and cell-free supernatants were recovered by
aspiration. Liberated histamine in supernatants was measured by
radioimmunoassay (Immunotech). Total histamine in cell suspensions was
quantified after cell lysis in distilled water and freeze thawing.
Histamine release was expressed as percentage of total histamine.
Immunofluorescence Analysis Indirect staining of cell lines.
Cells from growing cell lines were washed in FACS buffer (Hanks
supplemented with 1% BSA and 0.01% NaN3) before
incubation with 20% human AB serum for 10 minutes at 4°C to
prevent unspecific binding of mouse antibodies. Cells were then
incubated with 10 µg/mL of the primary antibody (MoAb 97A6) for 30 minutes on ice. After washing 3 times, cells were stained with the
F(ab)'2 fragment of a fluorescein isothiocyanate
(FITC)-conjugated goat-antimouse antiserum (Dunn, Asbach, Germany) for
30 minutes at 4°C. After washing, cells were suspended in FACS
buffer and analyzed on a FACSCalibur flow cytometer. In selected
experiments, 97A6 antigen expression was analyzed on HMC-1 and KU-812
cells incubated for 4 or 12 hours with the following cytokines before
staining with MoAb 97A6 (100 ng/mL): recombinant human IL-2, IL-4,
IL-5, IL-7 (Genzyme, Cambridge, MA); IL-9, IL-10, IL-13, SCF
(PreproTech, Rocky Hill, NJ); IL-3, IL-8 (Sandoz, Vienna, Austria); and
IL-1 Two-color staining of BM and PB cells. Unseparated BM and PB cells or MACS-selected PB CD34+ cells cultured for 14 days in the presence of IL-3 and collected after defined time intervals were labeled with 97A6-PE and FITC-conjugated antibodies against CD10 (W8E7), CD26 (L272), CD34 (8G12), CD44 (L178), CD61 (RUU-PL7F12), CD71 (L01.1), HLA-DR (L243) (Becton Dickinson), CD13 (SJ1D1), CD16 (3G8), CD33 (D3HL60.251), CD38 (T16), CD41 (P2) (Immunotech, Krefeld, Germany), CD117 (9B9) (Hölzel Diagnostics, Cologne, Germany), IgE (polyclonal) (BioSource, Ratingen, Germany), CD55 (1A10) and CD59 (p282(H19)) (PharMingen, Hamburg, Germany) for 30 minutes on ice and washed twice. Alternatively, BM cells were labeled with anti-CD123-PE (7G3; PharMingen) and MoAb 97A6-biotin, washed, and stained with streptavidin-FITC (SA-FITC; DAKO, Krefeld, Germany) for 15 minutes on ice. In other approaches, BM cells were labeled with 97A6-PE (IgG1) and the CD164-specific antibody 103B2/9E10 (IgG3),52,53 the CD81-specific antibody JS-64 (IgG2a; Immunotech), or the CDw17-specific antibody MEM74 (IgM; BioSource), and stained with the F(ab)'2 fragments of FITC-conjugated isotype-specific goat antimouse antisera (Medac, Hamburg, Germany). After washing twice, cells were analyzed on a flow cytometer. Three-color staining.
Unseparated BM and PB cells were stained with anti-CD34-PerCP
(HPCA-2-PerCP; Becton Dickinson), 97A6-PE, and FITC-conjugated antibodies or nonconjugated antibodies stained with
anti-isotype-specific secondary antibodies as described for 2-color
staining of BM and PB cells. To determine Fc
Double staining of basophils and mast cells with toluidine blue and immunofluorescence. Expression of cell surface antigens on basophils (n = 3) and tissue mast cells (lung, n = 3; foreskin, n = 3; uterus, n = 3) was analyzed by combined toluidine blue/immunofluorescence staining as described.38,54-56 In brief, cells were preincubated in AB serum for 30 minutes, washed, incubated with MoAb for 30 minutes (4°C), washed, and then exposed to second-step fluorescein-labeled goat F(ab')2 IgG antimouse antibody for 30 minutes (4°C). Cells were then fixed in 0.025% glutaraldehyde for 1 minute, washed, and incubated with toluidine blue (0.0125%) for 8 to 12 minutes. After washing, cells were examined under bright-field and fluorescence-light (fluorescence microscope; Olympus, Vienna, Austria). At least 20 cells were analyzed in each sample. In selected experiments, expression of 97A6 on c-kit+ tissue mast cells was analyzed by 2-color immunostaining using a PE-conjugated anti-c-kit MoAb.32 Cell Sorting Cell sorting was performed on a FACSVantage cytometer (Becton Dickinson) equipped with an air-cooled argon laser. FITC and PE fluorochromes were excited at 488 nm, and emission of FITC was detected through a 530-nm band pass filter, and PE through a 570-nm band pass filter. Instrument alignment and compensation of FITC versus PE signals were accomplished using a mixture of Calibrite beads (Becton Dickinson). The following fractions were sorted into tubes containing 50 µL of phosphate-buffered saline (PBS) supplemented with 40% BSA: the IgE+97A6+ fraction of unseparated BM cells stained with anti-IgE and 97A6-PE, the CD34+97A6+ and CD34+97A6 fractions of MACS-selected
CD34+ BM stained with anti-CD34-FITC and 97A6-PE, and the
97A6+ fractions of cultured CD34+ cells
stimulated with IL-3 and stained with anti-CD34-FITC and 97A6-PE. For
morphological analysis, sorted cells were cytocentrifuged onto
glass slides and stained with May-Grünwald-Giemsa. For
liquid culture experiments or cultures of hematopoietic progenitors
in methylcellulose, defined numbers of sorted cells were put into dishes or plates.
MoAb 97A6-Mediated Modulation of 97A6 Reactive Antigen Expression UT-7 cells were incubated in PBS for 2 hours at 37°C, either with a control antibody or with 5 µg/mL of MoAb 97A6. After washing with ice-cold PBS in the presence of NaN3, cells were labeled either with a control antibody or with MoAb 97A6, and stained with a PE-conjugated secondary antibody. Modulation of antigen expression (downregulation or upregulation) was determined as described.57Activation of Basophils by Acarids and IgE Receptor Cross-Linking One hundred microliters of heparinized blood from normal donors (n = 3) or from donors with allergy against acarids (n = 2) was incubated with serial dilutions of either anti-IgE antibody (clone E124-2-8/D2, mouse IgG1; Immunotech) or acarids allergen extract
(Dermatophagoïdes farinae + D pteronissynus;
reactivity index 10; Stallergenes, Anthony, France) for 15 minutes at
37°C. To stop the Ca2+-dependent reaction, the cells
were washed with PBS/20 mmol/L EDTA and resuspended in 100 µL
PBS/BSA. The cells were then incubated with 20 µL MoAb 97A6-PE (25 µg/mL) for 15 minutes at room temperature. After washing and red
blood cell lysis with IOTest lysing reagent (Immunotech #0486), the
cells were resuspended in PBS/BSA and analyzed on a FACSCalibur flow
cytometer. Modulation of 97A6 antigen was evaluated as change in the
mean fluorescence intensity of cells gated on the 97A6+ population.
Immunoprecipitation of the Cell Surface Molecule(s) Detected by MoAb 97A6 Immunoprecipitates and gel electrophoresis were performed as described.58 In brief, KU-812 cells were surface-labeled with 125I-iodine by the lactoperoxidase method and lysed with NP-40. Immunoprecipitation was performed with preformed complexes of 97A6 antibody immobilized on Sepharose beads conjugated with a secondary antibody. As a control, immunoprecipitation was performed with beads in the absence of the 97A6 antibody. Apparent molecular weights were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)59 after boiling the samples in SDS under reducing conditions in the presence of 2-mercaptoethanol and under nonreducing conditions, followed by separation on 5% to 15% polyacrylamide gels using 14C-methylated marker proteins.
Antibody 97A6 Specifically Recognizes PB and BM Basophils In an attempt to generate antibodies specific for rare hematopoietic cells, we produced the antibody (MoAb) 97A6 and found that the detected surface antigen is expressed on PB basophils, but not on other blood cells. To confirm the specific reaction of MoAb 97A6 with basophils, MACS-separated 97A6+ PB cells (99% pure) were stained with May-Grünwald-Giemsa for morphological analysis. Figure 1A shows the presence of a pure basophil population as identified by their typical metachromatic granules. Using a commercially available kit for basophil enrichment (StemSep; Cell Systems, Remagen, Germany), the isolated cells were found to display a very similar morphology (Fig 1B).
MoAb 97A6 Recognizes Tissue Mast Cells
Functional Studies With MoAb 97A6 and Modulation of 97A6
Reactive Antigen
In Vitro Culture of CD34+ PB Cells in the
Presence of IL-3
In Vitro Culture of CD34+ Cells in the Presence of SCF
Colony Assays for Hematopoietic Progenitor Cells
Phenotypic Characterization of
CD34
Immunochemical Characterization of Cell Surface Proteins Detected by
MoAb 97A6
In the present study, the generation of a monoclonal antibody, 97A6,
recognizing a cell surface structure on basophils, mast cells, and
their progenitors, is described. This novel marker seems to be specific
for basophils and mast cells in that (a) no other mature hematopoietic
cells (eosinophils, neutrophils, monocytes) are recognized by the
reagent; (b) only the basophil cell line KU-812, the mast cell line
HMC-1, and a few megakaryocytic cell lines, but not other cell lines,
appear to express the 97A6 reactive antigen; and (c) isolated
CD34+97A6+ cells give rise to basophils and
mast cells in appropriate cultures.
The authors thank Heike Letzkus for her excellent help in the
generation of antibody 97A6 and for FACS analysis, Minoo Ghannadan and
Gerit-Holger Schernthaner for excellent technical assistance, Anke
Marxer for MACS and FACS sorting and cell preparation, and Doris
Schweigert for photography.
Submitted March 3, 1999; accepted June 4, 1999.
Supported by the Deutsche Forschungsgemeinschaft (SFB 510, project A1),
by a grant from the Federal Ministry of Education and Research and the
Interdisciplinary Clinical Research Center (project II A1), and the
Fonds zur Förderung der Wissenschaftlichen Forschung in
Österreich, FWF, grant # P12517.
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 Hans-Jörg Bühring, PhD, Klinik
für Innere Medizin, Abteilung II, FACS-Labor,
Otfried-Müller-Str.10, 72076 Tübingen, Germany; e-mail:
hjbuehri{at}med.uni-tuebingen.de.
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TOP
ABSTRACT
INTRODUCTION
(CD123), but not c-kit (CD117), whereas tissue
mast cells express high levels of CD117, but not CD123.
, IL-6, IL-11, IL-12, IL-15, IL-16, IL-17, and IL-18
(R&D, Minneapolis, MN).
) or from donors with
allergy against acarids (
) were stimulated with serial dilutions of
either anti-IgE antibody or acarids allergen extracts for 15 minutes at
37°C. After washing, the cells were stained with MoAb 97A6-PE and
analyzed on a FACSCalibur flow cytometer. The mean fluorescence
intensities of cells gated on the 97A6+ population are
plotted against the concentrations of the stimulating agents.
in the case of CD34+97A6+ cultures
