REVIEW Functional Features of Neutrophils Induced by G-CSF and GM-CSF Treatment: Differential Effects and Clinical Implications

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REVIEW Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications K Spiekermann1,2, J Roesler3, A Emmendoerffer2, J Elsner4 and K Welte5

1Department of Hematology and Oncology, University of Go¨ttingen; 2Department of Immunobiology, Fraunhofer Institute ITA, Hannover; 3Department of Pediatrics, Carl-Gustav-Carus Klinik, University of Dresden; 4Department of Dermatology; and 5Department of Pediatrics, Medical School Hannover, Germany

G-CSF and GM-CSF are hematopoietic growth factors required cytokines which has clinical implications and can provide for proliferation and differentiation of hematopoietic precur- explanations for side-effects. sors. G-CSF is now widely used to overcome neutropenias of The administration of G-CSF at doses recommended (1– various origins. Beside the absolute number, the functional ␮ capacity of neutrophils at sites of inflammation is of major 20 g/kg per day; higher doses may be required in patients importance in host defense. This review summarizes major with severe congenital neutropenia (SCN)) was well tolerated. functional and phenotypical features of neutrophils induced by However, adverse effects probably related to neutrophil-activ- G-CSF treatment in patients with acquired and congenital neu- ating activity of G-CSF, eg leukocytoclastic vasculitis,31–33 tropenias. Furthermore, we focus on the differential effect of have been described in some patients during treatment with G-CSF and GM-CSF on neutrophil function in vitro and in vivo. ␮ Some of the altered abilities of cytokine-induced neutrophils G-CSF (see below). Doses of 0.3–10 g/kg GM-CSF per day are important to understand side-effects of G-CSF therapy. were usually tolerated although side-effects were more fre- Keywords: neutrophils; granulocyte colony-stimulating factor; quently observed than during treatment with G-CSF; at higher granulocyte–macrophage colony-stimulating factor; side-effects; doses (Ͼ20 ␮g/kg) side-effects such as fluid retention, pleural neutropenia and pericardial inflammation and effusions limited the clinical use of GM-CSF.1

Background Differential effects of G-CSF and GM-CSF on neutrophils in Hematopoeitic growth factors are a group of glycoproteins vitro that regulate the proliferation and differentiation of hematopoietic precursor cells.1–4 Granulocyte colony-stimulating factor G-CSF and GM-CSF are chemoattractants for neutrophils34,35 (G-CSF) and granulocyte–macrophage colony-stimulating fac- and could prime these cells for an enhanced respiratory burst tor (GM-CSF) are myeloid-predominant growth factors which activity after stimulation with several agents.26,36–40 Both cyto- have been purified to homogeneity, and their genes have been kines enhanced the antibody-dependent cellular cytotoxicity cloned.5–9 G-CSF is now widely used to overcome con- (ADCC),26,39–44 adherence,25,45–48 phagocytosis24,26,39,43,49–52 genital10–14 and acquired neutropenias15–22 of different origin, and killing24,49,52,53 of microorganisms of neutrophils (Table thereby reducing the risk of infections in these patients. 1). The chemotactic activity was reduced in G-CSF54 and GM- Neutrophils play an important role in first-line defense and CSF55–57 pretreated neutrophils. In addition, G-CSF and GM- it is generally accepted that the number of peripheral blood CSF could alter the expression of neutrophil surface proteins. neutrophils and the duration of neutropenia is closely related GM-CSF could rapidly upregulate the surface expression of to the risk of infection.23 The functional capacity of neutro- the CD11b26,27,45–47,58,59 and downregulate the LAM-1 phils is also of major clinical importance. This is dramatically expression48,59 while more conflicting results have been seen in patients with congenital or acquired functional phago- reported on the influence of G-CSF on these mol- cyte disorders showing a high susceptibility to infections. ecules25,27,48,59,60 (see Table 1). The CD35 expression Several studies have shown that G-CSF and GM-CSF can increased after stimulation with GM-CSF, but not with G- influence the phenotype and function of mature neutrophils CSF.27,61 GM-CSF was more potent in enhancing some neutro- in vitro.24–27 However, the most important effect of these cyto- phil functions, eg priming for an enhanced respiratory burst kines in therapeutical dosages in vivo is to stimulate prolifer- activity62 and the signal transduction mechanisms required for ation and differentiation of hematopoietic precursors. Further- priming were different in G-CSF- and GM-CSF-stimulated more, high doses of systemically administered G-CSF and cells.63 Apoptosis of mature neutrophils was delayed by G- GM-CSF may act on tissues other than the bone marrow, eg CSF64,65 and GM-CSF.65,66 endothelial cells28 or induce secondary cytokine release29,30 It is important to stress that the functional in vitro and ex and might influence neutrophil phenotype and function vivo studies of neutrophils were primarily performed on cells indirectly. Therefore, assessment of neutrophil function ex in suspension. However, physiologic stimuli like fMLP and IL- vivo is important to understand the in vivo effects of these 1 have a much higher potency to trigger the respiratory burst activity in neutrophils adherent to endothelium or artificial surfaces.67 Furthermore, stimulation of adherent, but not sus- pended neutrophils with G-CSF or GM-CSF could directly induce the production of ROI.68,69 This ability of G-CSF to Correspondence: K Spiekermann, Dept of Hematology/Oncology, University of Go¨ttingen, Robert-Koch-Str. 40, 37075 Go¨ttingen, activate the respiratory burst in adherent neutrophils could Germany explain the tissue damage in neutrophilic dermatoses Received 8 July 1996; accepted 11 December 1996 observed during G-CSF treatment (see below). Review K Spiekermann et al 467 Table 1 Differential effects of G-CSF and GM-CSF on neutrophil phenotype and function

In vitroa In vivob

G-CSF GM-CSF G-CSF GM-CSF

ROI production ↑(25,36,62) ↑(26,37–40,56) ↑(83,117,122) ↑(116,119–121) Chemotaxis ↓(54) ↓(55–57) ↓(70,72,91–93) n (82,97,98) ↓(94,95) n (96,98) Adherence n (48) ↑(25,90) ↑(45–48) ↑(70) ↑(46,80) Phagocytosis ↑(24,49) ↑(26,39,43,49–52) ↑(72,97,111) n (17,33) n (94) Killing ↑(24,33,49) ↑(49,52,53) n (50,51) ↑(115) n (33) ↑(116) ADCC ↑(40–42,44) ↑(26,39,40,42–44) ↑(41,71,131) ↑(114)

CD11b ↑(25,48) n (27,59) ↑(26,27,45–48,58,59) ↑(48,71,111,117) n (70,73,147) ↑(48,73,76,144) CR1 n (27) ↑(27,61) n (70) ↑(61) LAM-1 ↓(48,60) n (59) ↓(48,59) ↓(60) n (48,147) ↓(147) n (48) CD14 ↑(73,140) ↑(73,140) n (138) ↑(70,71,73) n (73) Fc␥RI (↑)(41) n (27) n (27) ↑(41,70,71,131,132) n (131) FC␥RIII ↑(27) n-↓ (27) n (59) ↓(61) ↓(70,71) n (41) ↓(61)

Increase in PMN — — 9.4 (75) 1.5 (87) production rate (× fold) Emergence time of — — ↓(1 d) (75) n (5 d) (87) labeled PMN in PB Half-life in blood — — n (8 h) (75) ↑(48 h) (87) aNeutrophils from healthy adults. bCytokine-induced neutrophils from patients with cancer, healthy adults or in some studies from primates (see text). n, normal; ↓, decreased; ↑, increased; (), not signiﬁcant; NR, not reported.

Effects of pharmacological doses of G-CSF and GM-CSF on nance of neutrophil precursors were seen in the bone marrow neutrophils in vivo after a treatment period of 28 days with G-CSF at a dose of 10 ␮g/kg.84 The GM-CSF-induced leukocytosis which White blood cell subsets and neutrophil kinetics increased in magnitude after repeated administration was due to increased numbers of eosinophilic and neutrophilic gra- Administration of pharmacological doses of G-CSF and GM-CSF nulocytes and monocytes.85–87 Bone marrow cellularity and to humans or animals resulted in a triphasic response:70–77 (1) myeloid/erythroid ratios also increased during GM-CSF ther- Market neutropenia occurring approximately 5–60 min after apy.76,85 In patients with congenital, cyclic and chronic neu- injection (depending on the mode of administration); (2) Leu- tropenias, G-CSF treatment was more effective in increasing kocytosis due to release of neutrophils (G-CSF, GM-CSF), the ANC than treatment with GM-CSF.11,15,31,32 eosinophils and monocytes (GM-CSF) from the bone marrow Kinetic studies in humans have demonstrated that the half- beginning after 3–4 h; (3) Proliferation and differentiation of life of circulating G-CSF-induced neutrophils remained nor- hematopoietic precursors in the bone marrow. mal at 8 h, whereas the production rate showed a 9.4-fold The ﬁrst decrease of the absolute neutrophil count (ANC) increase75 (Table 1). The time required for neutrophil precur- was most probably caused by an activation of neutrophils (G- sors to mature and appear in the circulation was shortened CSF, GM-CSF) and monocytes (GM-CSF) resulting in from 5 days to 1 day.75 In contrast, after treatment with GM- enhanced adherence to endothelium. This effect was also CSF the neutrophil production rate increased by only 50% observed after administration of chemotactic factors to ani- without shortening of the release time.87 The half-life of GM- mals, eg IL-878 or fMLP.79 Devereux and coworkers80 could CSF-induced neutrophils in the peripheral blood rose from 8 show that the transient leukopenia after GM-CSF adminis- to 48 h.87 tration was due to a sequestration of leukocytes within the An elevated number of immature neutrophils was found in lungs; however, this could not be shown for G-CSF.75 Studies the peripheral blood of G-CSF and GM-CSF-treated subjects investigating bone marrow samples at 4 and 12 h after admin- (‘left shift’)83,87 and neutrophils displayed an altered mor- istration of G-CSF to rats have shown a decreased number of phology with Dohle bodies, (toxic) granulation and vacuoliz- mature neutrophils in the marrow indicating that the neutro- ation83,88,89 (see below). philia occurring in this time interval was caused by a release of neutrophils from the bone marrow.74 The proliferative effect of G-CSF on granulopoiesis in a hamster model could be Adherence observed as early as 12 h after a single injection of 10 ␮g/kg and resulted in a signiﬁcant increase in bone marrow cellu- G-CSF25,90 and GM-CSF45–48 enhanced the adherence of neu- larity and the number of bone marrow progenitors.81 trophils in vitro. G-CSF treatment of patients with cancer and Repeated treatment of humans and nonhuman primates severe congenital neutropenia resulted in an increased adher- with G-CSF resulted in a stimulation of myelopoiesis and a ence of the induced neutrophils to plastic surfaces70 (Tables dose-dependent sustained neutrophilia. However, high doses 1 and 2). By administration of GM-CSF to nonhuman primates of G-CSF (30–60 ␮g/kg bodyweight) also increased the num- Yong et al46 could provide histologic evidence for an ber of monocytes and lymphocytes in the peripheral enhanced neutrophil adherence to pulmonary endothelium blood.21,82–84 Furthermore, hypercellularity and predomi- during the initial transient leukopenia which was suggested Review K Spiekermann et al 468 Table 2 Function of G-CSF-induced neutrophils from patients with congenital and acquired neutropenias

Healthy adults Cancer patients Severe congenital Cyclic neutropenia Glycogenosis Type IB MDS neutropenia

Adherence NR ↑(70) ↑(70) NR NR NR Chemotaxis ↓(70,91) n (97) ↓(70,72,93) ↓(98,107,108) ↓(110) ↓(11,14,109) n (104) n (82,98) n (16) n (13) Phagocytosis ↑(97) ↑(72,111) n (106) NR N+ (11) (↑) (104) n (33) Killing NR ↑(115) n (33) n (106) NR n (11,14,110) NR ROI PMA ↑(122) n (117) n (106,108,126) N+ (127) n (110) ↓(14) N+ (11,110) NR fMLP ↑(122) ↑(83,117) ↓(108,126) NR n (109) ↑(124) ADCC ↑(71) ↑(41,131) NR NR NR NR

N+, normal neutrophil subset; same abbreviations as in Table 1.

by radiolabeling studies in humans.80 These findings of an PMN which did not appear to have a huge influence on the enhanced neutrophil adherence in vivo are in good accord- overall ability of these cells to reach sites of inflammation in ance with the increased adherence found in vitro (Table 1) vivo. The increased adherence and altered expression of and the altered expression of the integrin CD11b. They reflect adhesion molecules induced by G-CSF and GM-CSF in vivo the activation induced by G-CSF and GM-CSF and might con- and in vitro are likely to contribute to the decrease in chemo- tribute to the decreased chemotactic activity of these neutro- tactic activity. phils (see below).

Impaired chemotaxis prior to G-CSF: In patients with mye- Chemotaxis lodysplastic syndromes (MDS) neutrophil function is often abnormal101 (eg impaired chemotaxis and phagocytosis) and Somewhat conflicting results were reported about the chemo- might contribute to the increased risk of infection. The prein- tactic motility of neutrophils induced by G-CSF and GM-CSF cubation of MDS neutrophils with G-CSF102 and GM-CSF103 (Tables 1 and 2). In this context, it is important to separate could enhance some of the impaired functions (eg production the effects of these cytokines on neutrophils in patients with of reactive oxygen intermediates (ROI), but GM-CSF further impaired neutrophil function caused by the underlying disease impaired the chemotactic response.103 Treatment of these itself and on neutrophils in patients with normal neutrophil patients with G-CSF resulted in an increased or unchanged function before treatment with G-CSF. neutrophil motility104 whereas GM-CSF further decreased the chemotactic activity.105 In some disorders severe neutropenia did not allow functional studies prior to cytokine therapy14,106 Normal chemotaxis prior to cytokine treatment: Ex vivo and therefore results obtained during treatment are difficult studies investigating neutrophils from G-CSF-treated patients to interpret. This is true for G-CSF-induced neutrophils from with cancer and healthy volunteers have shown a decreased patients with severe congenital neutropenia107,108 and glyco- migration70,72,91–93 which was related to the dose of G-CSF in genosis type IB (GSD IB)11,14,109 which have been described one study.70 During continuous intravenous infusion of GM- to show moderate to severe impairment of their chemotactic CSF, a markedly reduced neutrophil motility was found in a response towards a variety of chemoattractants in vitro. skin chamber assay.94,95 The latter finding was in good Measurement of neutrophil chemotaxis in one patient with accordance with the in vitro activity of GM-CSF as a potent GSD IB before and during treatment with G-CSF suggested an inhibitor of neutrophil chemotaxis.55,57 However, other stud- enhancement to the normal range in vitro and an increased ies showed no impairment of neutrophil migration in G-CSF- infiltration in the skin chamber assay in vivo.13 Qualitative and GM-CSF-treated subjects in vitro82,96,97 and in vivo.98 Fac- evaluation of migration in four patients with severe congenital tors that might be responsible for the variable results of neutro- neutropenia by the Rebuck-window revealed monocytic and phil chemotaxis in vivo include the use of different chemo- lymphocytic cell infiltration prior to treatment and neutrophils taxis assays, the dose of cytokine, its mode of administration at the site of abrasion during treatment with G-CSF.10 and the time interval between cytokine administration and Conflicting results were also reported about chemotactic blood collection. The ability of G-CSF-induced neutrophils to motility of G-CSF-induced neutrophils from patients with cyc- enter the mucosal surfaces of the oral cavity was assessed by lic neutropenia which has been found to be decreased in Lieschke et al99 using a mouthrinse assay in patients after bone vitro,110 but to be normal in an in vivo assay.16 Neutrophils marrow transplantation. The relationship between the ANC assessed during G-CSF treatment in one patient with chronic and the number of neutrophils recoverable from the oral cav- neutropenia showed normal accumulation in a skin ity was not altered by G-CSF treatment suggesting that G-CSF- chamber assay.17 induced neutrophils were able to leave the circulation and Taken together, the pronounced decrease of chemotactic enter tissue. The transfusion of radiolabelled leukocytes to a activity in G-CSF-treated patients with impaired neutrophil neutropenic patient with an invasive skin infection during function in in vitro tests suggests that G-CSF could not com- GM-CSF and pentoxifyllin treatment showed that these cells pletely restore the functional defects. The increased neutrophil were able to localize to the site of infection.100 counts during G-CSF treatment in some patients could explain Taken together the studies clearly indicate some decrease the enhanced accumulation in skin window assays in vivo. in the chemotactic motility of G-CSF- and GM-CSF-induced However, the evaluation of chemotaxis by different methods Review K Spiekermann et al

106,108,126 469 and the paucity of studies comparing chemotaxis before and PMA. Another study described the O2-release after during cytokine treatment limit these conclusions. PMA stimulation to be impaired in a subgroup of G-CSF- treated SCN patients127 only. Taken together, G-CSF and GM-CSF could enhance the res- Phagocytosis piratory burst activity of normal and of some defective neutrophils in vitro and in vivo. This effect was also observed in G-CSF24,49 and GM-CSF26,39,43,49–52 have been described to vivo in patients with cancer and in healthy volunteers. A more enhance neutrophil phagocytosis in vitro. The phagocytotic complex pattern was seen in patients with congenital phago- activity of neutrophils induced by G-CSF17,33,97,111 and GM- cyte disorders. However, no negative influence of G-CSF has CSF94 in vivo was normal or enhanced in most studies (Tables been observed yet and some improvements are probable. 1 and 2). Furthermore, both cytokines could correct the impaired neutrophil phagocytosis when administered to patients with myelodysplastic syndromes104,105 and chronic Surface marker expression and related functions 112 graft-versus-host disease (only G-CSF). Fc␥RI (CD 64) and ADCC: In peripheral blood cells, the high affinity receptor for monomeric IgG (Fc␥RI) is exclusively expressed on monocytes, but not on neutrophils. Bone mar- Killing row neutrophil precursors constitutively express the Fc␥RI,128 whereas mature, peripheral blood neutrophils can be induced Incubation of neutrophils from healthy donors and from can- to express this receptor by interferon-␥ in vitro27,129 and in cer patients with GM-CSF49,52,53 or G-CSF24,33,49 resulted in vivo,130 but not by G-CSF or GM-CSF27 in vitro. A strong enhanced bacterial killing. However, in some studies GM-CSF induction of the Fc␥RI on neutrophils after administration of did not affect the killing rate of normal neutrophils.50,51 G-CSF could be seen in patients with cancer,41,70,131 in The bactericidal activity of defective neutrophils from HIV- 107,110 24 49 patients with severe congenital neutropenia, cyclic neu- 1-infected patients, patients after allogeneic and autolog- 110 110 113 tropenia, glycogenosis type IB and healthy volun- ous bone marrow transplantation could be enhanced and teers.70,71,132 Kinetic studies in healthy volunteers could dem- partially corrected after in vitro incubation of neutrophils from onstrate that this upregulation was seen as early as 3–8 h after these patients with G-CSF. Similar improvements of defective a single dose of 300 ␮g G-CSF.70,71 The sequential treatment killing activity by GM-CSF were found in neutrophils from 103 of a patient suffering from cyclic neutropenia with GM-CSF patients with MDS in vitro and from patients infected with and G-CSF could clearly demonstrate that expression of the HIV114 in vivo. ␥ 11,14,110 Fc RI is a characteristic feature of neutrophils during G-CSF, Administration of G-CSF to patients with GSD IB, but not during GM-CSF therapy.131 severe congenital neutropenia106 and hairy cell leukemia33 Neutrophils constitutively express low affinity receptors for resulted in a grossly normal bacterial killing capacity of neu- multimeric IgG ((Fc␥RII and Fc␥RIII) which mediate binding and trophils, whereas an enhanced neutrophil bactericidal activity lysis of target cells coated with IgG (ADCC) as well as binding was found in G-CSF-treated cancer patients.115 The killing of and phagocytosis of immune complexes.133 G-CSF could E. coli by neutrophils increased when GM-CSF was given to 40–42,44 116 enhance ADCC of neutrophils from healthy donors, from nonhuman primates. HIV-infected patients42 and from patients with hairy cell leu- kemia33 in vitro. Studies on G-CSF-induced neutrophils from cancer patients41,131 and healthy donors71 could confirm these Production of reactive oxygen intermediates (ROI) results in vivo (Tables 1 and 2). An enhanced ADCC was also found after exposure of neutrophils from healthy volunteers to Although G-CSF or GM-CSF alone were not able to initiate a GM-CSF in vitro26,39,40,42–44 and patients infected with HIV in respiratory burst in native neutrophils, preincubation with vitro and in vivo.114 these cytokines ‘primed’ the cell for an enhanced superoxide The increased cytotoxicity of G-CSF-induced neutrophils anion production after stimulation with physiological stimuli, has been shown to be mediated by the induction of the Fc␥RI eg the chemotactic peptide fMLP.25,26,36–40,62 This effect was in cancer patients131 and in healthy volunteers71 and could be also observed after administration of G-CSF and GM-CSF to inhibited by antibodies blocking the binding site of the Fc␥RI. patients with cancer83,116–121 and to healthy volunteers122 However, the in vitro incubation of neutrophils with G-CSF (Table 1). Neutrophils from patients with myelodysplastic syn- did not induce Fc␥RI expression27 and the enhanced ADCC dromes with impaired ROI production showed an enhance- could be inhibited by antibodies blocking the function of ment of respiratory burst activity after exposure to G-CSF or ␥ 44 102,103,123,124 105,124 Fc RII. Although the mechanisms of G-CSF-enhanced neu- GM-CSF in vitro and in vivo. Similar in vitro trophil cytotoxicity are not yet clear, they appear to be inde- results have been reported for G-CSF-induced neutrophils in 49,113 pendent of oxidative metabolism. This could be demonstrated patients undergoing allogeneic or autologous BMT. The in neutrophils from patients with chronic granulomatous dis- administration of GM-CSF after BMT could correct the defec- 42 125 109 ease who have a severely impaired ability to produce ROI. tive ROI production in some patients. McCawley et al Therefore, priming for an enhanced respiratory burst activity reported an improvement of the impaired neutrophil ROI pro- cannot explain the G-CSF-induced enhanced cytotoxicity. duction from patients with GSD IB to normal levels after 4 In summary, G-CSF, but not GM-CSF induced the months of treatment with G-CSF. However, other authors expression of the Fc␥RI on neutrophils in vivo. Furthermore, found some impairment of the neutrophil ROI production G-CSF and GM-CSF were able to enhance the ADCC of neu- from these patients even during G-CSF treatment.11,14,110 trophils in vitro and in vivo. The mechanisms of the increased Assessment of respiratory burst activity of G-CSF-induced neu- ADCC in vitro and in vivo seem to be different. trophils from patients with SCN revealed a decrease of ROI production after stimulation with fMLP, but normal values after stimulation with protein kinase C activators, eg Fc␥RIII (CD16) and soluble CD16 (sCD16): Mature neu- Review K Spiekermann et al 470 trophils express high surface levels of PIG (phospha- ietic precursors with G-CSF to neutrophils in vitro.141 How- tidylinositol glycan)-anchored Fc␥RIII which bind to the Fc ever, other explanations than influencing precursors by G-CSF part of multimeric IgG. Its expression increases during differ- for the strong expression of the CD14 antigen on neutrophils entiation of neutrophils with highest levels in mature cells.134 are possible (see below). Activation of neutrophils with certain agonists (eg fMLP) resulted in shedding of the Fc␥RIII from the cell surface and ␥ 135 ␤ release of a soluble form of the receptor (sFc RIII) which CD 11b: The 2 integrin subfamily of adhesion molecules can be detected in human plasma.136 shares a common ␤-chain (CD18) and has three associated ␣- In vitro, stimulation of neutrophils with G-CSF27 or GM- subunits with it: CD11a (LFA-1), CD11b (Mo-1) and CD11c 26,59,61 ␥ 142 ␤ CSF resulted in an inconsistent effect on Fc RIII (p150,95). Neutrophils express all three 2 integrins and the expression. However, the level of CD16 antigen expression expression of the CD11b antigen can be used as a differen- 134 ␤ was markedly decreased on G-CSF-induced neutrophils from tiation marker with highest levels in mature cells. 2 inte- patients with acquired70 and congenital neutropenias107,110 as grins play an important role in the process of adhesion and well as from healthy volunteers70,71 (Tables 1 and 3). This locomotion of neutrophils142 and the surface expression of the could also be shown in GM-CSF-treated patients with CD11b antigen can be upregulated by various agonists, eg cancer.61 fMLP,143 G-CSF25,48 and GM-CSF26,27,45–48,58,59 in vitro. Several possible explanations exist for the decreased CD16 Administration of GM-CSF to patients with cancer resulted in expression which include neutrophil immaturity, effects of G- an increased expression of the CD11b antigen on neutro- CSF and GM-CSF on neutrophil precursors and shedding phils.48,73,76,144 This was also found in G-CSF-treated induced by activation (see below). The latter topic was patients48,111,117 using the mAb anti Mo-1111,117 (Tables 1 and addressed in a study of Kerst et al71 who showed that the con- 3) and in healthy volunteers.71 However, the latter results centration of soluble Fc␥RIII in the plasma of volunteers could not be confirmed by other groups using different anti- treated with a single dose of G-CSF was increased for as long body clones70,73 in neutrophils from patients after chemo- as 10 days. A maximum level of sCD16 was observed after 6 therapy, healthy volunteers and patients with congenital neu- days when neutrophil CD16 expression had already returned tropenias.107 Kinetic studies have shown that the upregulation to normal. of the CD11b antigen is a very early event with a maximum The meaning of the marked reduction of CD16 expression level of expression approximately 1 h after administration of for the functional abilities of these granulocytes has not been G-CSF.71,111,117 The enhanced CD11b expression proposed to studied yet, but initiation of respiratory burst activity of G- be closely associated with enhanced neutrophil adherence145 CSF-induced neutrophils with immune complexes binding to might help to understand the initial neutropenia after G-CSF the Fc␥RIII revealed normal results (unpublished own administration (see above). observation).

Leukocyte adhesion molecule 1 (LAM-1, L-selectin): The CD14 and sCD14: The receptor for LPS and LPS-binding LAM-1 molecule belongs to the selectin family of adhesion protein (CD14) is a PIG-anchored membrane protein and is molecules and is rapidly shed from the cell surface after incu- predominantly expressed on monocytic cells and at low levels bation of neutrophils with distinct activating agents (eg GM- on neutrophils.137 The neutrophil CD14 expression can be CSF, TNF␣) in vitro.48,59 Conflicting results have been reported upregulated by several agonists, eg IFN␥,138,139 TNF␣,140 G- on the influence of G-CSF on LAM-1 expression. Two groups CSF73,140 and GM-CSF73,140 (Table 1). Administration of G-CSF found a significant downregulation of LAM-1 by G-CSF,48,60 to patients with acquired70,73 and congenital neutropen- whereas Griffin et al59 described an unchanged expression ias107,110 and to healthy volunteers70,71 resulted in an after incubation of neutrophils with G-CSF. Interestingly, the increased expression of the CD14 antigen on neutrophils, affinity of LAM-1 for ligands (eg PPME) is markedly increased whereas GM-CSF did not alter the CD14 level.73 Kinetic stud- after short exposure of neutrophils to G-CSF.146 LAM-1 has ies could demonstrate maximal levels of expression 8–12 h been shown to play an essential role in leukocyte rolling along after a single administration of G-CSF.70,71 Concentration of endothelium, the first step of the adhesion cascade.142 An soluble CD14 was also increased in the plasma of G-CSF- increased ligand binding affinity might contribute to the treated healthy adults with a similar time pattern.71 An enhanced adherence of G-CSF-induced neutrophils in vitro increased CD14 expression on G-CSF-induced neutrophils and in vivo. was observed, too, after differentiation of CD34+ hematopo- Administration of G-CSF60 (and own unpublished

Table 3 Phenotype of G-CSF-induced neutrophils

Healthy adults Cancer patients Severe congenital Cyclic neutropenia Glycogenosis Type neutropenia IB

Fc␥RI (CD64) ↑(70,71,132) ↑(41,70,131) ↑(107,110) ↑(110) ↑(110) Fc␥RIII (CD16) ↓(70,71) ↓(70) n (41) ↓(107,110,127) ↓(110) ↓(110) CD14 ↑(70,71) ↑(70,73) ↑(107,110) n (110) ↑(110) CD11b Anti-Mo1 NR ↑(111,117) n (127) NR NR Other MAb n (70) – ↑(71) n (70,73) ↑(48) n (107,110) n (110) n (109,110) LAM-1 ↓(60) n (48) ↓(60) NR NR NR

Same abbreviations as in Table 1. Review K Spiekermann et al

147 2+ 471 observation) and GM-CSF to cancer patients resulted in a stimulation with fMLP, eg impairment of [Ca ]i mobilization, strongly diminished expression of LAM-1. However, other membrane depolarization and increase in F-Actin con- authors found an unaltered expression of the LAM-1 molecule tent.108,154 These defects in intracellular signalling might be 48,147 − during G-CSF and GM-CSF treatment (Tables 1 and 3). related to the impaired O2 production and decreased chemo- Taken together, G-CSF and GM-CSF could induce an tactic activity also found in neutrophils from these patients.108 enhanced expression of the CD11b antigen and a diminished The lack of functional studies prior to G-CSF treatment due to expression of the CD16 antigen and LAM-1 on neutrophils in severe neutropenia complicated the interpretation of the 2+ vivo. An increased expression of the CD64 and CD14 antigens results. However, assessment of F-Actin, [Ca ]i mobilization was found in G-CSF-induced neutrophils only. and membrane depolarization revealed no abnormalities in G-CSF-induced neutrophils from patients with cancer.154 Therefore, either a defect in signal transduction or the ongoing Leukocyte alkaline phosphatase activity (LAP) maturational arrest due to the underlying disease, but not G- CSF treatment are responsible for the functional impairments Leukocyte alkaline phosphatase is found in high levels in of neutrophils from patients with GSD IB and SCN. intracellular vesicles of neutrophils and is translocated to the plasma membrane after in vitro stimulation.148 The activity of LAP increases during neutrophil maturation and can be used as a marker of maturity.149 In vitro, G-CSF could induce LAP- Morphology mRNA150 and enhance LAP activity151 in neutrophils. In addition, the decreased LAP score of neutrophils from patients Administration of G-CSF to patients and healthy volunteers with chronic myelogenous leukemia and myelodysplastic syn- resulted in some morphological immaturity of the induced dromes was enhanced by G-CSF in vitro.102 neutrophils, eg Dohle bodies and toxic granu- Administration of G-CSF to healthy volunteers and cancer lation10,21,82,83,88,106,155 indicating cytoplasmatic immaturity156 patients resulted in a significant decrease of the neutrophil (Table 4). Furthermore, a decreased nuclear lobulation show- LAP score lasting from 0.5 to 4 h after injection followed by ing nuclear immaturity82,88,106 and hypogranularity88 were a strong increase reaching a peak level of 48 h after injec- present in G-CSF-induced neutrophils. Neutrophils with tion71,72,82 (Table 4). The initial decrease in the LAP score is increased diameter were identified by conventional light probably caused by a sequestration of neutrophils with higher microscopy88 and by an increased forward angle light scatter LAP activity from the bloodstream,111 whereas cells with intensity in flow cytometric studies154 in G-CSF-treated lower activity are left in the circulation. An alternative humans and rats74 (Table 4). Campbell et al155 described the explanation is the degranulation of LAP-containing secretory appearance of large, multilobulated and hypersegmented neu- vesicles due to activation of the cells. trophils (macropolycytes) after G-CSF administration which In accordance with the in vitro results the reduced LAP were shown to be tetraploid. These cells were approximately scores in a patient with MDS recovered to normal values dur- twice the size of normal neutrophils and represented mostly ing G-CSF therapy.104,152 The direct up-regulation of the LAP 3–5% of white cells. A nuclear hypersegmentation of periph- expression by G-CSF might explain that G-CSF-induced neu- eral blood neutrophils was also described in neutrophils from trophils have increased LAP activity although they show some G-CSF-treated humans88,155 and rats.74,157 The administration features of immaturity. of GM-CSF also resulted in an altered neutrophil morphology including prominent granulation and vacuolization.89 Taken together, the administration of G-CSF and GM-CSF 2+ Mobilization of [Ca ]i, membrane depolarization, F- could induce morphologic abnormalities of neutrophils, eg Actin content altered granularity and vacuolization. The hypersegmentation which can be observed in older neutrophils could be a result Neutrophils from patients with GSD IB have been shown to of delayed apoptosis seen after exposure of neutrophils to G- 2+ be impaired in their ability to mobilize [Ca ]i in response to CSF in vitro (see above). Furthermore, increased diameter and physiologic stimuli, eg fMLP.153 Treatment of these patients altered cytoplasmatic structure was observed during G-CSF with G-CSF resulted in a variable increase in the percentage treatment compatible with activation or immaturity of the of cells responding to fMLP stimulation.11,109 cells. The latter might be caused by premature release of gra- Less severe functional deficits have been found in neutro- nulocytes from the bone marrow or direct effects of G-CSF phils from patients with severe congenital neutropenia after and GM-CSF on precursors.

Table 4 LAP score and morphology of G-CSF-induced neutrophils

Healthy adults Cancer patients Severe congenital Cyclic Glycogenosis Type MDS neutropenia neutropenia IB

LAP ↑(71)a ↑(72,82) NR ↑(16) NR ↑(104,152) Diameter ↑(154) ↑(88,154) ↑(154) ↑(154) ↑(154) NR Dohle bodies/toxic granul. − (71) +(21,82,83,88,155)b + (10,106) − (16) NR + (104) Nuclear NR ↓(82,88) ↓(106) n (16) NR NR lobulation/segmentation ↑(88,155) dysmorph (10) aA transient decrease was observed 0.5 to 4 h after injection of 300 ␮g G-CSF.71 bGiant neutrophils were present.155 +, present; −, absent; same abbreviations as in Table 1. Review K Spiekermann et al 472 Possible mechanisms of G-CSF and GM-CSF action on Neutrophilic dermatoses: Sweet’s syndrome and neutrophil function in vivo bullous pyoderma gangraenosum

Sweet’s syndrome (acute febrile neutrophilic dermatosis) is Some explanations for the alterations in neutrophil phenotype characterized by pyrexia, neutrophilia, erythematous, painful and function have been suggested: (1) Activation (as indicated cutaneous plaques, dense dermal infiltrate of neutrophils and by the following findings, see above): G-CSF and GM-CSF- a prompt response to corticosteroid therapy.159,160 Approxi- induced neutrophils were primed for an enhanced respiratory mately 10–15% of published cases occur in patients with can- burst activity and showed enhanced adherence. These fea- cer. Several patients developing this syndrome during G-CSF tures could be found after exposure of neutrophils to these therapy have been described.33,161–164 In each of these cytokines in vivo and in vitro and are therefore probably patients an underlying malignant disease was present and all caused by direct action of G-CSF and GM-CSF. (2) Induction received G-CSF in recommended dosages. The duration of G- of secondary cytokine production: Enhanced levels of IL-6 and CSF therapy ranged from 0 days to 1–2 months. Fukutoku et TNF␣ were found during GM-CSF therapy of neutropenic al164 described three episodes of erythematous nodules in a patients29,30 which could in turn activate neutrophils. (3) Par- patient with aplastic anemia which could be induced by tial immaturity: Evidence arose especially from the morpho- administration of G-CSF and resolved rapidly after discontinu- logical examinations, eg Dohle bodies and toxic granulation. ing cytokine therapy. Interestingly, only doses of more than Furthermore, G-CSF and GM-CSF have been shown to act as 100 ␮g of G-CSF per day caused the skin lesions, whereas release factors for neutrophils from the bone marrow includ- 50 ␮g were tolerated without any complications. ing cells which still have some degree of immaturity. In Evidence that G-CSF might in fact be involved in the patho- addition, some phenotypical characteristics of G-CSF-induced genesis of Sweet’s syndrome is provided by one study in neutrophils were compatible with this hypothesis (eg which cytokine levels were measured during the clinical expression of Fc␥RI). (4) Effect on neutrophil precursors: This course of the disease.165 Levels of G-CSF and IL-6 were view is supported by studies showing that differentiation of extremely high during the acute phase of disease, whereas CD34+ cells with G-CSF in vitro resulted in Fc␥RI-positive levels of TNF␣, IFN␥ and IL-1␤ remained unchanged. neutrophils. G-CSF, but not GM-CSF shortened the maturation Additionally, in two patients occurrence of pyoderma gang- time of neutrophils in the bone marrow which might explain raenosum, characterized by dense neutrophilic infiltrates the differential effects of these cytokines on the Fc␥RI and without vasculitis or infection has been reported during treat- CD14 expression in vivo. ment with G-CSF.166,167 In patients with primary neutrophil functional defects, eg GSD IB, G-CSF treatment was not able to restore completely the functional capacity of the induced neutrophils. This might be responsible for the better clinical response in patients with Leukocytoclastic vasculitis and interstitial lung disease SCN compared with GSD IB, the former showing mainly a maturational arrest in the bone marrow and only a moderate neutrophil functional deficit. Leukocytoclastic vasculitis (LV) was observed in four patients receiving G-CSF therapy.31,32,168,169 In a recently published report of the Severe Chronic Neutropenia International Regis- try 3% of a total of 279 patients receiving long-term G-CSF treatment developed vasculitis.170 In contrast to patients with Adverse effects of G-CSF possibly related to neutrophil neutrophilic dermatoses during G-CSF therapy, LV occurred activation mainly in patients with nonmalignant disorders, but also in recommended dosages 6–12 days after initiation of G-CSF. In three patients32,168,169 two episodes of LV were induced by G- Adverse reactions to G-CSF include bone pain, reversible CSF, in the latter case complicated by renal involvement. abnormalities of liver function tests, elevations in serum uric Recently, several reports addressing the role of G-CSF in acid levels and increase in lactate dehydrogenase activity.1,158 increasing pulmonary toxicity in combination with chemo- After GM-CSF administration more severe side-effects were therapy were published. Three studies described an enhanced observed, eg fluid retention, pleural and pericardial effusions incidence of drug-induced pneumonia (DIP) in patients and inflammation and a characteristic first dose reaction with treated with chemotherapy for lymphoma when G-CSF was dyspnea, hypotension and tachycardia. Some of these side- given,171–173 but only one of these reports compared their effects might be due to secondary cytokine production after results with a control group of patients not receiving G-CSF.173 GM-CSF administration, eg IL-6 and TNF␣.29,30 A detailed list Pooling data from two randomized trials Bastion et al174 found of adverse effects can be found in the review of Lieschke et no increased incidence of DIP in patients with malignant lym- al.1,158 In the following we will focus on the adverse effects phoma. Boogaerts et al175 described three cases of ARDS of G-CSF because of its expanding clinical use. occurring during G-CSF treatment of eight patients with drug- In some patients neutrophilic dermatoses (Sweet’s syn- induced agranulocytosis. Injury to pulmonary alveolar epi- drome and pyoderma gangraenosum), leukocytoclastic vascu- thelial cells is a prominent feature in a variety of lung diseases, litis, interstitial pneumonia and ARDS have been observed eg the ARDS. Mechanisms involved in alveolar cell damage during G-CSF treatment. These adverse effects might be asso- include adherence of primed neutrophils via CD11b-depen- ciated with the neutrophilia and neutrophil activation induced dent pathways and subsequent killing176 as well as overpro- by G-CSF. It lowers the threshold for stimuli concentration duction of oxidative metabolites by cytotoxic drugs, eg bleo- required for initiation of respiratory burst activity or for the mycin.177 Since G-CSF has been shown to enhance some of release of neutrophil enzymes, eg elastase, and might there- these functions (see above) it might well be involved in the fore result in tissue damage. cell injury of pulmonary vascular endothelial cells. Review K Spiekermann et al 473 The role of G-CSF and GM-CSF in infectious diseases function could be partially restored by G-CSF or GM-CSF treatment. G-CSF and GM-CSF can reduce the number of infectious epi- Therapy with G-CSF was in some cases associated with the sodes in patients with chemotherapy-induced and severe con- occurrence of side-effects such as leukocytoclastic vasculitis genital neutropenia (see above) by shortening the time of neu- and neutrophilic dermatoses. G-CSF-induced and thereby tropenia and increasing the neutrophil count. Moreover, by activated neutrophils might well cause or contribute to the enhancing neutrophil function and thereby their antimicrobial tissue damage in these disorders. Although associated with activity, G-CSF and GM-CSF could enhance the ability of neu- some alterations in neutrophil phenotype and function, G-CSF trophils from neutropenic patients to fight infections. treatment of children with SCN and other neutropenic Several groups have investigated the role of these cytokines disorders has resulted in a dramatic reduction of infectious in non-neutropenic animal model of infection, eg neonatal episodes and an improvement of quality of life. and intraabdominell sepsis (reviewed in Ref. 178). In most of the studies treatment with G-CSF significantly increased the survival of these animals. However, the administration of GM- References 179 CSF to rats after the onset of sepsis decreased survival and 1 Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor enhanced the endotoxin-induced lethality in a mouse and granulocyte–macrophage colony-stimulating factor (1). 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