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Varying Expression Levels of Colony Stimulating Factor Receptors in Disease States and Different Leukocytes

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Varying Expression Levels of Colony Stimulating Factor Receptors in Disease States and Different Leukocytes EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 32, No. 4, 210-215, December 2000 Varying expression levels of colony stimulating factor receptors in disease states and different leukocytes Kyo Young Lee1, Byung-Gyu Suh2, CSFs, more receptors were blocked in children than Jong Wan Kim2, Wonbae Lee2, So-Young Kim2, in adults (G-CSF P = 0.024, GM-CSF P = 0.006). These Young-Yoo Kim2, Jehoon Lee1, Jihyang Lim1, results indicate that the amount of CSFr in leukocyte 1 1 varies in different types of leukocyte, and changes Myungshin Kim , Chang Suk Kang and according to the patients’ condition even in the 1,3 Kyungja Han same type of leukocyte, and the CSFrs of children bind to CSFs more than those of adults. 1 Department of Clinical Pathology, St. Mary’s Hospital, Youngdeungpogu Youidodong 62, Catholic University, Keywords: Granulocyte-colony stimulating factor, gran- Medical College, Seoul 150-713, Korea ulocyte macrophage-colony stimulating factor, G-CSF 2 Department of Pediatrics, Catholic University Medical College, receptor, GM-CSF receptor, leukocyte Seoul 150-713, Korea 3 Corresponding author: Tel, +82-2-3779-1297; Fax, +82-2-783-6648; E-mail, [email protected] Introduction Accepted 29 November 2000 Granulocyte-colony stimulating factor (G-CSF) and gra- nulocyte macrophage CSF (GM-CSF) are the principal Abbreviations: G-CSF, granulocyte colony stimulating factor; GM- hematopoietic growth factors regulating the production, CSF, granulocyte macrophage colony stimulating factor; CSFr, differentiation and function of granulocytes(Anderlini et receptor for colony stimulating factor al., 1996). To shorten the neutropenic period and the time of engraftment after bone marrow transplantation, CSFs are frequently used in many patients. These Abstract CSFs induce granulocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase, and Administration of G-CSF may not always respond in are mediated through interactions with its receptors rise of neutrophil counts in different patient popula- (Iqbal et al., 2000). Primitive progenitor cells express tion. In order to understand a possible inter-relation- GM-CSFr (Lund-Johansen et al., 1999) and G-CSFrs are ship between the G-CSF and GM-CSF induced also detected in blast cells of patients with acute leukocyte responses and expression levels of re- myeloid leukemia and acute lymphoblastic leukemia ceptors for G-CSF (G-CSFr) and GM-CSF (GM-CSFr), (Shinzo et al., 1997). Although administering G-CSF to the levels of each receptor and CSF were measured a healthy donor does not cause any delayed adverse in patients with basophilia (8), eosinophilia (14) and reaction except a mild bone pain (Sakamaki et al., bacterial infection showing neutrophilia (12) in com- 1995), in some cases, it can cause a transient increase parison with normal healthy adults (12) and children in blasts mimicking acute leukemia and progressing (14). G-CSFr was expressed in neutrophils in the myelodysplastic syndrome (Meyerson et al., 1999). A largest amount followed by monocytes, but GM- few patients do not respond to normal response show- CSFr was expressed more in monocytes than neu- ing a rapid increase of neutrophil count after admini- trophils. Lymphocytes and basophils did not ex- stration of G-CSF and mutation in CSFr gene (McLemore press G-CSFr or GM-CSFr. The amount of GM-CSFr et al., 1998) have been implicated as a cause. Diagnosis in neutrophils was present less in patients with of G-CSF responders from the non-responders is es- infection than normal control (P = 0.031). The neu- sential prior to CSF treatment. Expression of receptors trophils expressed more G-CSFr than GM-CSFr. The for G-CSF (G-CSFr) increases with differentiation in quantity of G-CSFr in eosinophil showed marked myeloid cells (Shinzo et al., 1995) and the level of high interval change, higher in acute stage. The plasma plasma G-CSF correlates with the late engraftment after concentrations of G-CSF in patients with infection allogeneic bone marrow transplantation (BMT) (Busch were much higher than normal adults or children et al., 1998). But the relationship between the ex- (117.95 ± 181.16 pg/ml, P < 0.05). Binding assay with pression level of these receptors and the plasma CSF excess amount of CSFs could discriminate the pati- concentration has not been studied. G-CSF and GM- ent who did not show any response to G-CSF or GM- CSF administration to patients induce neutrophilia within CSF administration. After incubation with excess several hours, but their effects on other types of CSFr vary in leukocytes 211 leukocyte are unknown (Tajiri et al., 1997; Sun et al., CD9 (Figure 3) (Wardlaw et al., 1995). 1999). Levels of these receptors in different types of Markers were set using isotypic control sera, so that leukocytes were measured and correlated with plasma less than 1% of cells stained positively. Results were concentrations of CSFs in children, adults and the recorded as the geometric mean of gated cells. The patients with infection. And also we have developed a mean number of bound PE molecule per cell was calcu- new simple binding assay to predict the recovery of lated using QuantiBRITE and QuantiQuest program. neutrophil after CSF administration. Quantitative determination of G-CSF and GM-CSF concentrations in plasma Materials and Methods EDTA-anticoagulated plasma was separated immediate- ly after collection of venous blood, and stored in -70oC Materials freezer until analysis. For the quantitative determination EDTA-anticoagulated peripheral blood samples of nor- of G-CSF and GM-CSF concentrations in plasma, im- mal healthy adults (12), children under age of 12 (14), munoassay kits (R & D Systems, MN, USA) were used patients with basophilia (8) and eosinophilia (14), and according to the manufacturer’s instructions. patients with bacterial infection showing neutrophilia (12) were analyzed. Seven out of 8 patients showing baso- Binding assay of CSFs to CSFrs philia and 2 out of 14 patients showing eosinophilia The binding sites of CSFr to anti-CSFr (Serotec) were were diagnosed as chronic myelogenous leukemia. The blocked by binding of CSF in the preliminary study. To remaining patient with basophilia had breast carcinoma estimate the functional binding sites of CSFrs, the leuko- and 10 remaining patients with eosinophilia showed cytes were incubated with excess amounts of CSFs for reactive eosinophilia. All samples were analyzed within 1 h at 37oC. After wash with PBS three times, flow 4 h after collection and maintained at room temper- cytometric estimation of CSFrs using monoclonal anti- ature (18 to 20oC) before analysis. bodies was performed as described above. G-CSF For comparative fluorescence quantification, phycoe- (Neutrogen, Choong Wae Pharm, Korea) was added in rythrin (PE) conjugated fluorescence quantification kit a concentration of 0.5 µg/106 cells and GM-CSF (Leuko- (QuantiBRITE, Becton Dickinson, San Diego, CA) and gen, LG Pham, Korea) was added in a concentration of QuantiQuest program were used. PE conjugated anti- 2 µg/106 cells. The differences of the mean number of CSF receptors were purchased from Serotec (UK) and bound PE molecule per cell before and after incubation other monoclonal antibodies, PerCP conjugated anti- in excess amount of CSFs were calculated. CD19, FITC conjugated anti-CD22 and FITC conjugat- ed anti-CD9, and isotypic control were purchased from Statistics Becton-Dickinson (San Diego, CA). All the statistical data were analyzed using the Chi- square test and Mann-Whitney U test. To evaluate the Quantitative analysis of G-CSFr and GM-CSFr correlation between the amount of CSFr and plasma Immunofluorescence studies were performed using whole CSF concentration, the Pearson correlation coefficient blood. All samples were stained with anti-G-CSFr, anti- and P value were calculated. The significance was GM-CSFr and with the negative isotypic control anti- evaluated using Wilcoxon Signed Ranks test using bodies. The samples showing basophilia were stained SPSS software. with anti-CD19, anti-CD22 and anti-CSFrs simultane- ously. And the samples showing eosinophilia were stained with anti-CD9 and anti-CSFrs simultaneously. Results Then the erythrocytes were lysed by incubation in the lysing solution (Becton Dickinson) and the sediments Quantity of G-CSFr and GM-CSFr were washed in PBS. Fluorescence was analyzed by G-CSFr was expressed in neutrophils in the largest flow cytometry (FACSCalibur, Becton Dickinson) using quantity followed by monocytes in all cases (Table 1). CELLQuest software. Quality control of the flow cyto- Lymphocytes and basophils did not express G-CSFr meter was carried out twice a week using CaliBRITETM (Figure 1, 2). No significant difference in the quantity of beads (Becton Dickinson) and Autocomp software month- G-CSFr was found between adults and children or bet- ly. Basophils were identified in the lymphocyte gate by ween normal and patients with infection (P > 0.05). their positive staining for FITC-conjugated CD22 monitor- GM-CSFr was expressed more in monocytes than ed in FL1 (log scale), and their negative staining with neutrophils, but no significant difference was noted bet- PerCP-conjugated CD19 monitored in FL3 (log scale) ween eosinophils and neutrophils (P = 0.546) or bet- (Figure 2) (Han et al., 1999). Eosinophils were iden- ween eosinophils and monocytes (P = 0.236). Lympho- tified in the neutrophil gate by their strong expression of cytes and basophils did not express GM-CSFr (Figure 212 Exp. Mol. Med. Vol. 32(4), 210-215, 2000 Table 1. Quantities of receptor molecules for colony stimulating factors in different types of leukocytes in adults, children and patients with infection (number of bound PE molecules per cell) Receptor Group Neutrophils Monocytes Lymphocytes G-CSFr adult (n=12) 1551 ± 671 655 ± 183 55 ± 27 children (n=14) 1872 ± 373 914 ± 311 53 ± 30 infection (n=12) 1259 ± 768 GM-CSFr adult (n=12) 742 ± 224 3129 ± 1011 49 ± 32 children (n=14) 831 ± 55 3288 ± 852 42 ± 29 infection (n=12) 571 ± 436 1, 2).
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