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      G-CSF and GM-CSF Are Different. Which One Is Better for COVID-19?

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      Acta Haematologica
      S. Karger AG

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          Abstract

          Development of molecularly cloned myeloid hematopoietic growth factors (e.g., granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) more than 30 years ago increased safety and efficacy of intensive chemotherapy and radiation therapy by reversing damage to bone marrow function, thereby decreasing infections and bleeding and shortening hospitalizations. These drugs were also used to mobilize bone marrow hematopoietic progenitor cells into the blood facilitating their use as a graft for hematopoietic cell transplants. Other proposed uses included increasing efficacy of anti-leukemia chemotherapy and treating persons exposed to high doses of acute whole-body ionizing radiation [1, 2]. Safety and efficacy of G- and GM-CSFs, typically given intravenously or subcutaneously, are well-known. Practice guidelines and consensus statements on their use are available from many medical societies and organizations including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the American Society of Hematology (ASH), and the National Comprehensive Cancer Network (NCCN). G-CSF (e.g., filgrastim and pegfilgrastim, and their biosimilars) and GM-CSF (e.g., sargramostim) are the two most common types of hematopoietic growth factors. These drugs (proteins) are sometimes thought as being interchangeable. This is wrong. Structure, receptors, receptor distribution, and biologic effects of these proteins differ substantially. Filgrastim is a 19-kDa protein produced in E. coli which is not glycosylated. In contrast, sargramostim, a mixture of three GM-CSFs with molecular weights of 19.5, 16.8, and 15.5 kDa, is a glycosylated protein produced in S. cerevisiae. Glycosylation adds stability and degradation resistance [3]. Receptors for filgrastim and sargramostim belong to the cytokine receptor super-family. The G-CSF receptor (G-CSFR; CD114) is a homo-oligo-dimer, whereas the GM-CSF receptor (GM-CSFR; CD116) is a hetero-oligo-dimer sharing a β-chain with the IL-3 and IL-5 receptors. The G-CSFR is expressed primarily on neutrophils and bone marrow precursor cells. The GM-CSFR, more widely expressed than the G-CSFR, is present on neutrophils, monocytes, eosinophils, dendritic cells, basophils, and, possibly, B-cells, whereas the G-CSFR is expressed only on neutrophils and monocytes [4]. Differences in receptor expression account for most of the biologic differences between filgrastim and sargramostim. Importantly, G-CSF is the dominant colony-stimulating factor (CSF) released from lung cells in response to pro-inflammatory cytokines [5]. G-CSF is the most widely used molecularly cloned hematopoietic growth factor (shown in Fig. 1). GM-CSF has a broader range of biologic activities than G-CSF as well as anti-bacterial, anti-fungal, and anti-viral properties via complex signaling [6]. GM-CSF has been used as an adjuvant for diverse anti-cancer therapies including immune therapy and anti-cancer vaccines [7, 8, 9]. Other uses of GM-CSF include therapy of post-transplant graft failure [10], reversal of immune paralysis (i.e., persistence of a marked compensatory anti-inflammatory innate immune response following an insult such as sepsis or trauma) [11, 12, 13, 14, 15], and treatment of lung diseases such as autoimmune pulmonary alveolar proteinosis, acute respiratory distress syndrome (ARDS), and pneumonia [11, 16]. In an uncontrolled clinical trial, Herold and colleagues [11] gave aerosolized GM-CSF (sargramostim), 125 µg for 2 doses 48 h apart to 6 subjects with moderate-to-severe community-acquired pneumonia or ventilator-associated ARDS. They reported improved oxygenation in subjects receiving GM-CSF compared with controls with a mean increase of about 40% in lung compliance [11]. GM-CSF promoted an M1 phenotype of alveolar macrophages and increased activation of alveolar mononuclear phagocytes without increasing neutrophils in the alveolar compartment. Similarly, safety of aerosolized sargramostim was reported in autoimmune pulmonary alveolar proteinosis [16]. A phase-2 Belgian, multi-center SARPAC study used aerosolized sargramostim in persons with COVID-19-related ARDS (EudraCT 2020-001254-22, NCT04326920) [17]. Preliminary data are most encouraging (unpublished observations). Hematologists and oncologists are more familiar with G-CSF than GM-CSF, and as shown in Figure 1, G-CSF accounts for >95% of the use of molecularly cloned myeloid hematopoietic growth factors. Consequently, many physicians may be more likely to use G-CSF than GM-CSF in persons with COVID-19-related ARDS. This may be a mistake based on the data we cite regarding G-CSF-induced influx of granulocytes in the lung, an effect not seen with GM-CSF. However, there are no comparative clinical data in this setting (see below). Whether aerosolized molecularly cloned hematopoietic growth factors are safe and effective in COVID-19-related ARDS and in other SARS-CoV-2-infected persons is controversial and unknown. Several reports suggest not giving molecularly cloned hematopoietic growth factors to persons undergoing conventional chemotherapy and hematopoietic cell transplantation during the SARS-CoV-2 pandemic because of concerns of increasing lung inflammation or the hypothetical risk of increasing inflammatory cytokines such as interleukin-6 (IL-6) associated with an adverse outcome [18, 19]. However, these recommendations are not evidenced-based and there are no published data reporting such events in humans. Several studies report systemic G-CSF can exacerbate lung injury in the setting of pulmonary infection. For example, Jing and colleagues [20] reported G-CSF increases lung injury in a mouse model of acute renal injury. Wang et al. [21, 22] reported blocking the G-CSF receptor in mouse models of infection and asthma reduced neutrophil infiltration and neutrophil-mediated inflammation. Tsantikos and associates [23] reported G-CSF was important in the pathogenesis of chronic obstructive pulmonary disease in some persons. Arimura and co-workers [24] described severe acute lung injury in a healthy hematopoietic cell transplant donor given G-CSF. Boujoukos and colleagues [25] reported that during the initial inflammatory response to endotoxin in humans, the alveolar space is relatively insulated from cytokine-induced effects of endotoxin including tumor necrosis factor, IL-6, and IL-8 but not G-CSF. Takatsuka et al. [26]reported five people developed ARDS whilst receiving G-CSF with chemotherapy or a hematopoietic cell transplant. These data suggest that giving G-CSF can worsen lung function by causing neutrophil infiltration. This effect is especially so in settings of inflammation such as infection and cytokine release syndrome. Because cytokine release syndrome is a feature of COVID-19-related ARDS, caution is needed. These same adverse effects on lung function are not reported in mouse models or humans receiving sargramostim in similar settings. The favorable preliminary data from the SARPAC study using aerosolized sargramostim are encouraging [17]. Several studies suggest G-CSF is likely to exacerbate lung injury in the setting of infection. Consequently, persons receiving intensive chemotherapy during the SARS-CoV-2 pandemic, especially those with COVID-19, may not be receiving G-CSF. Giving GM-CSF may be associated with less lung injury risk. Three clinical trials of GM-CSF in persons with COVID-19-related ARDS are in progress (SARPAC [EudraCT 2020-001254-22; NCT04326920], iLeukPulm [NCT04411680], and NCT04400929). In summary, although G-CSF and GM-CSF are molecularly cloned myeloid growth factors, their biology and clinical effects differ. GM-CSF has a much wider activity spectrum in animals and humans. In persons with lung infection and/or ARDS, GM-CSF may be a safer drug than G-CSF. Whether this is so can only be definitively answered in a randomized comparison trial. Unfortunately, this is unlikely to be done and we may have to rely on indirect evidence of safety and efficacy. Conflict of Interest Statement H.M.L. is a consultant to Partner Therapeutics. R.P.G. received funds from Partner Therapeutics for consulting within the past 2 years but none in relation to this publication. Funding Sources Partner Therapeutics financially supported this publication. Author Contributions H.M.L. and R.P.G. equally contributed to the entirety of this publication.

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          Most cited references24

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          Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

          Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).
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            COVID-19 outcomes in patients with hematologic disease

            To the Editor: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus of zoonotic origin that emerged in China at the end of 2019. The infection, named Coronavirus Disease 2019 (COVID-19), is now spreading worldwide. As of April 16, 2020, the virus had affected more than 2,000,000 individuals and resulted in over 125,000 deaths worldwide. Mortality can be as high as 15% in elderly patients, and/or in patients with comorbidities [1, 2]. Based on the current available data, the incubation period (time from exposure to symptom development) is estimated as between 2 and 14 days [3]. At present, there are no approved treatment options in Europe and no available vaccine. Avoiding exposure by adhering to recommended hygiene procedures, isolation of infected persons and social distancing are the only prevention strategies recommended by the WHO [4]. Risk factors for COVID-19 severity and death include older age, along with comorbidities such as diabetes, hypertension, or cardiac disease [1, 2]. In addition, data from China suggest that patients with cancer have a significantly higher incidence of severe events (including intensive care unit admission, need of assisted ventilation, death) after contracting the virus (39% versus 8% in patients without cancer) [5]. Another study reported that cancer patients appear to be twice as likely to contract infection with SARS-CoV-2 [6]. Importantly, that study suggests that hospital admission and recurrent hospital visits, inherent to cancer patients’ management, are potential risk factors for SARS-CoV-2 infection [6]. To date, very few data are available on COVID-19 outcomes in patients with hematologic diseases. Only one 47-year-old patient with a lymphoma has been included in a previous report [5], and two articles have reported on the course of COVID-19 infection in a 39-year-old patient with chronic lymphocytic leukemia [7] and in a 60-year-old patient with multiple myeloma (MM) [8]. All three patients had a favorable outcome. Nevertheless, these were relatively young, unlike the overall patient population with hematologic neoplasms which is usually aged, comorbid and highly immunosuppressed. These patients are therefore expected to be a particularly vulnerable group for COVID-19. A better characterization of those infected with the virus is important. Here we describe the demographic characteristics, coexisting conditions, imaging findings, and outcomes among patients with hematologic disease and COVID-19 infection. We included all consecutive adult patients with a hematologic disease admitted to the Hematology Department (inpatient and outpatient admissions) of the Saint-Antoine-Hospital, AP-HP, Paris, France, with laboratory-confirmed COVID-19 infection between March 9 and April 4, 2020 and with at least 10 days of follow-up. A confirmed case of COVID-19 was defined by a positive result on a real-time RT-PCR assay of a specimen collected on a nasopharyngeal swab. We reviewed medical records to collect demographic, clinical, and treatment data and outcomes of COVID-19. All laboratory tests and radiologic assessments, including plain chest radiography and computerized chest tomography, were performed at the discretion of the treating physician. COVID-19 was suspected and screened by PCR in 48 patients with a hematologic disease and the infection was identified in 25. Clinical details on hematologic and treatment history and COVID-19 infection are listed in Table 1. The median patient age was 72 (range, 40–96) years, 68% were male. The median duration of symptoms before the COVID-19 PCR assay was performed, was 4 (range, 0–22) days. None of the patients had recently traveled to a country with known transmission such as China, Iran, or Italy, but five had direct contact with a COVID-19 positive family member. Among the remaining patients, six were already hospitalized (none of them in the hematology department) at the time of viral infection symptoms’ onset due to a fall episode (n = 2), MM diagnosis (n = 3) or accidental cardiac drug overdose (n = 1). Ten patients had one or more outpatient visits to the hematology department, suggesting a possible nosocomial origin of their infection. In the remaining four patients, the origin of COVID-19 infection was unknown. Table 1 Clinical characteristics, treatments and outcomes of patients with hematological malignancies and SARS-CoV-2 infection. Patient No Age Sex BMI Hemalogical disease Hematological status Hematological treatment Ongoing corticosteroids Number of treatment lines Previous transplant Comorbidities Time between onset of symptoms and diagnosis (days) Radiologic diagnosis ARDS Invasive mechanical ventilation COVID-19 management Follow-up since first symptoms (days) Survival status 1 65 M 28.7 Myeloma Complete remission Ongoing isatuximab + DXM maintenance Yes 2 Autologous HBP 3 Positive CT Yes Yes Best supportive care 17 Dead 2 73 F 30.2 Myeloma Diagnosis None No 0 No Diabetes, HBP, stroke, obesity 4 Positive X-ray Yes Yes Best supportive care 13 Dead 3 65 M 24.3 Myeloma Complete remission Ongoing lenalidomide maintenance No 1 Autologous HBP 4 ND No No HCQ/AZT + Tociluzumab 40 Alive 4 61 M 41.5 Lymphoma (DLBCL) Complete remission None, 3 months post CAR T-cell No 4 Autologous and allogeneic Diabetes, HBP, obesity 7 Positive CT Yes Yes Best supportive care 38 Alive 5 61 F 31.6 Myeloma Partial remission Ongoing carfilzomib + lenalidomide + DXM Yes 6 Autologous Diabetes, HBP, stroke, obesity 7 Positive CT No No Lopinavir-ritonavir 34 Alive 6 45 M 45.8 PNH Partial remission Ongoing eculizumab No 1 No Obesity 4 Positive CT Yes Yes Best supportive care 32 Alive 7 40 F 26.7 ALL Complete remission None, 9 months post allo-HSCT No 1 Allogeneic No 0 Positive CT Yes Yes Best supportive care 23 Alive 8 78 M 26.3 MDS Progressive disease Best supportive care Yes 0 No Glioma, stroke 1 Positive X-ray Yes No Tociluzumab + corticosteroids 10 Dead 9 79 M 37.8 Lymphoma (hairy cell) Complete remission None, 12 years post Cladribine No 2 No HBP, obesity, CKD, MDS, MGUS 2 Positive X-ray No No Lopinavir-ritonavir 26 Alive 10 62 F 24.2 LGL leukemia Complete remission None, 18 months post cyclophosphamide No 1 No No 1 Positive CT No No Best supportive care 32 Alive 11 75 M 28.7 MDS Progressive disease Best supportive care No 0 No Diabetes, HBP 7 Positive CT Yes No Best supportive care 27 Dead 12 81 M 21.3 Myeloma Partial remission Ongoing lenalidomide + DXM Yes 1 No HBP 3 Positive CT Yes No Best supportive care 10 Dead 13 81 M 30.1 Lymphoma (Marginal zone) Progressive disease None, 14 months post rituximab + bendamustine No 1 No Diabetes, HBP, stroke, obesity, COPD 0 ND No No Best supportive care 35 Alive 14 63 M 25.0 Lymphoma (hairy cell) Complete remission None, 5 years post rituximab No 2 No HBP 5 ND No No Best supportive care 32 Alive 15 92 M 20.0 Myeloma Progressive disease Ongoing cyclophosphamide + prednisone Yes 3 No HBP 14 Positive X-ray Yes No Best supportive care 14 Dead 16 89 M 23.6 Myeloma Stable disease Ongoing lenalidomide + DXM Yes 2 No CKD 6 Positive CT Yes No Best supportive care 21 Dead 17 61 M 23.9 Myeloma Complete remission Ongoing bortezomib maintenance No 2 Autologous Cardiomyopathy 12 Positive X-ray No No Best supportive care 29 Alive 18 86 M 22.3 CLL Stable disease Wait and watch No 0 No HBP, stroke, CKD 10 Positive X-ray Yes No Lopinavir-ritonavir + corticosteroids 17 Dead 19 68 F 24.4 Myeloma Partial remission Ongoing daratumumab + lenalidomide + DXM Yes 2 No Diabetes, HBP 1 Positive CT Yes Yes Lopinavir-ritonavir + corticosteroids + tociluzumab 17 Alive 20 72 F 31.5 Myeloma Partial remission Ongoing daratumumab + lenalidomide + DXM Yes 1 No HBP, obesity 0 Positive CT No No Best supportive care 20 Alive 21 76 M 19.3 MDS Progressive disease Best supportive care No 1 No CKD, COPD 3 Positive CT No No Best supportive care 20 Alive 22 97 F 17.2 MDS Progressive disease Best supportive care No 1 No Pancreatic adenocarcinoma, CKD 2 ND Yes No Best supportive care 4 Dead 23 71 M 24.1 Lymphoma (DLBCL) Complete remission Ongoing rituximab maintenance No 2 Autologous HBP, stroke 22 Positive CT No No Anakinra 29 Alive 24 63 M 22.8 Lymphoma (Poppema) Complete remission Ongoing rituximab-CHOP Yes 1 No HBP 10 Positive X-ray No No Best supportive care 19 Alive 25 75 F 41.4 Waldenström macroglobulinemia Partial remission Ongoing rituximab + cyclophosphamide + DXM Yes 3 No HBP, obesity, epidermoid carcinoma of the anal canal 1 Positive CT No No Best supportive care 14 Alive M male, F female, BMI body mass index (kg/m2), DLBLC diffuse large B-cell lymphoma, PNH paroxysmal nocturnal hemoglobinuria, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndrome, LGL large granular lymphocyte, CLL chronic lymphoid leukemia, DXM dexamethasone, allo-HSCT allogeneic hematopoietic stem cell transplantation, HBP high blood pressure, CKD chronic kidney disease, MGUS monoclonal gammopathy of undertemined significance, COPD chronic obstructive pulmonary disease, CT computed tomography, HCQ hydroxychloroquine, AZT azithromycine. The most common symptoms at diagnosis were fever (n = 22, 89%), cough (n = 19, 79%), and shortness of breath (n = 19, 79%). The majority (n = 20, 80%) of patients had a lymphoid malignancy, including 10 with MM (40%), and only 4 (16%) had a myeloid malignancy (myelodysplastic syndrome). One patient had paroxysmal nocturnal hemoglobinuria. Patients received a median of 1 (range, 0-6) line of treatment. Fourteen patients (56%) were being treated for their underlying disease at the time of COVID-19 diagnosis, with 10 (40%) receiving corticosteroids. Seven patients had a history of hematopoietic stem cell transplantation (autologous, n = 5, allogeneic, n = 1, and both, n = 1) and one had been treated with anti-CD19 CAR T cells 3 months before. Of note, the four patients with myelodysplastic syndrome received only supportive care, one patient with MM had just been diagnosed and had not initiated therapy, and one with stage A chronic lymphoid leukemia was on a ‘wait and watch’ strategy. In addition, all patients but two (92%) had additional chronic medical conditions. In particular, 17 (68%) patients had high blood pressure, 8 (32%) were obese, and 6 (25%) had diabetes mellitus. Fourteen (56%) patients had more than one coexisting condition besides the hematologic disease. As reported elsewhere [1], lymphopenia was common at hospital admission (n = 23, 92%), with a median lymphocyte count of 760/µL (range, 150–5910). Only one patient had severe neutropenia at the time of COVID-19 diagnosis (median, 2,350/µL; range, 70–11,400). A computerized tomographic scan of the chest was performed in 14 patients and bilateral ground glass opacities were evident in all of them. A chest radiography was performed in seven additional patients and all radiographs showed bilateral pulmonary opacities. As of April 16, 2020, with a median follow-up since symptom onset of 29 days (range, 14–40), 13 of the 18 patients (52%) developed acute respiratory distress syndrome (ARDS) [9] and 6 received mechanical ventilation (Supplementary Fig. 1). It was decided not to transfer the remaining seven patients with ARDS to the intensive care unit because of their age and hematological disease history. All patients who did not develop ARDS were alive at last follow-up. Of patients with ARDS, nine died, including two who received mechanical ventilation. The Kaplan–Meier estimate of overall survival at 1 month was 60%. It is hypothesized that similarly to patients with solid malignancies, those with hematologic neoplasms are more susceptible to COVID-19 and develop severe forms. This study highlighted the following observations: patients with a hematologic malignancy harbored a higher risk of developing a severe form of COVID-19 with ARDS, requiring mechanical ventilation, compared to those in the general French population without an underlying medical condition [1]. This translated into a very high mortality (estimated as 40% at 1 month) which we can expect to be even higher with a longer follow-up. Furthermore, fewer than half of the patients were receiving active anti-neoplastic treatment before COVID-19, highlighting that vigilance must remain high in every patient given the long-term immunosuppressive effect of prior therapies. Interestingly, for the majority of the patients, a nosocomial origin was suspected, owing to their hospitalized status or to outpatient visits within the 14 previous days. We observed an overrepresentation of patients with MM in our cohort (although MM is not overrepresented in our department), suggesting that such patients are particularly vulnerable, owning to the immunosuppression associated with the disease and its treatment, in particular steroids. In fact, the detrimental effect of steroids on patient outcome has been established during previous coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) [10, 11], and a similar impact is expected in patients infected with SARS-CoV-2 [12]. Finally, we must emphasize that more than half of the patients were over 65 years of age, and 92% had at least one additional comorbidity, factors which have been associated with COVID-19 severity [1, 2], and which have possibly contributed to the seriousness of the infection and high mortality rate observed in our study. Overall, patients with hematologic malignancies appear to be a population very vulnerable to COVID-19 infection. Therefore, hematology departments should remain COVID-19 free zones dedicated solely to hematologic treatment. Furthermore, patients should strictly comply with social distancing and hospital outpatient visits should be reduced to mitigate the risk of COVID-19. Supplementary information Supplementary Figure
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              GM-CSF: An immune modulatory cytokine that can suppress autoimmunity.

              GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune-modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases such as Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune-modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance.
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                Author and article information

                Journal
                Acta Haematol
                Acta Haematol
                AHA
                Acta Haematologica
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                0001-5792
                1421-9662
                13 August 2020
                : 1-4
                Affiliations
                [1] aDepartment of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, Ohio, USA
                [2] bCentre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
                Author notes
                *Hillard M. Lazarus, Case Western Reserve University, Cleveland, OH 44106 (USA), Hillard.Lazarus@ 123456case.edu

                Dedicated to Academician Andrei Vorobiev of the Russian Federation, the 2nd human to receive GM-CSF, who died recently.

                Article
                aha-0001
                10.1159/000510352
                7490498
                32791509
                9b7222f3-09e2-4539-a6d3-72555225bd84
                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 17 July 2020
                : 20 July 2020
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                Figures: 1, References: 26, Pages: 4
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