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Nong K, Qin X, Liu Z, Wang Z, Wu Y, Zhang B, Chen W, Fang X, Liu Y, Wang X, Zhang H. Potential effects and mechanism of flavonoids extract of Callicarpa nudiflora Hook on DSS-induced colitis in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155523. [PMID: 38489893 DOI: 10.1016/j.phymed.2024.155523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 03/17/2024]
Abstract
Callicarpa nudiflora Hook (C. nudiflora) is an anti-inflammatory, antimicrobial, antioxidant, and hemostatic ethnomedicine. To date, little has been reported regarding the activity of C. nudiflora against ulcerative colitis (UC). In this study, we investigated the effect of a flavonoid extract of C. nudiflora on Dextran Sulfate Sodium (DSS)-induced ulcerative colitis in mice. Mice in the treatment group (CNLF+DSS group) and drug-only (CNLF group) groups were administered 400 mg/kg of flavonoid extract of C. nudiflora leaf (CNLF), and drinking water containing 2.5 % DSS was given to the model and treatment groups. The symptoms of colitis were detected, relevant indicators were verified, intestinal barrier function was assessed, and the contents of the cecum were analyzed for intestinal microorganisms. The results showed that CNLF significantly alleviated the clinical symptoms and histological morphology of colitis in mice, inhibited the increase in pro-inflammatory factors (TNF-α, IL-6, IL-1β, and IFN-γ), and increased the level of IL-10. The expression of NF-κB and MAPK inflammatory signal pathway-related proteins (p-p65, p-p38, p-ERK, p-JNK) was regulated. The expression of tight junction proteins (ZO-1, OCLDN, and CLDN1) was increased, while the content of D-LA, DAO, and LPS was decreased. In addition, 16S rRNA sequencing showed that CNLF restored the gut microbial composition, and increased the relative abundance of Prevotellaceae, Intestinimonas butyriciproducens, and Barnesiella_intestinihominis. In conclusion, CNLF alleviated colitis by suppressing inflammation levels, improving intestinal barrier integrity, and modulating the intestinal microbiota, and therefore has promising future applications in the treatment of UC.
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Affiliation(s)
- Keyi Nong
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Xinyun Qin
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Zhineng Liu
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Zihan Wang
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Yijia Wu
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Bin Zhang
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Wanyan Chen
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Xin Fang
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Youming Liu
- Yibin Academy of Agricultural Sciences, Yibin 644600, China
| | - Xuemei Wang
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China
| | - Haiwen Zhang
- College of Tropical Agriculture and Forestry, Hainan University, Danzhou 571737, China.
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Danne C, Skerniskyte J, Marteyn B, Sokol H. Neutrophils: from IBD to the gut microbiota. Nat Rev Gastroenterol Hepatol 2024; 21:184-197. [PMID: 38110547 DOI: 10.1038/s41575-023-00871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2023] [Indexed: 12/20/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that results from dysfunction in innate and/or adaptive immune responses. Impaired innate immunity, which leads to lack of control of an altered intestinal microbiota and to activation of the adaptive immune system, promotes a secondary inflammatory response that is responsible for tissue damage. Neutrophils are key players in innate immunity in IBD, but their roles have been neglected compared with those of other immune cells. The latest studies on neutrophils in IBD have revealed unexpected complexities, with heterogeneous populations and dual functions, both deleterious and protective, for the host. In parallel, interconnections between disease development, intestinal microbiota and neutrophils have been highlighted. Numerous IBD susceptibility genes (such as NOD2, NCF4, LRRK2, CARD9) are involved in neutrophil functions related to defence against microorganisms. Moreover, severe monogenic diseases involving dysfunctional neutrophils, including chronic granulomatous disease, are characterized by intestinal inflammation that mimics IBD and by alterations in the intestinal microbiota. This observation demonstrates the dialogue between neutrophils, gut inflammation and the microbiota. Neutrophils affect microbiota composition and function in several ways. In return, microbial factors, including metabolites, regulate neutrophil production and function directly and indirectly. It is crucial to further investigate the diverse roles played by neutrophils in host-microbiota interactions, both at steady state and in inflammatory conditions, to develop new IBD therapies. In this Review, we discuss the roles of neutrophils in IBD, in light of emerging evidence proving strong interconnections between neutrophils and the gut microbiota, especially in an inflammatory context.
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Affiliation(s)
- Camille Danne
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, Paris, France.
- Paris Center For Microbiome Medicine (PaCeMM) FHU, Paris, France.
| | - Jurate Skerniskyte
- CNRS, UPR 9002, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Architecture et Réactivité de l'ARN, Strasbourg, France
- Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Benoit Marteyn
- CNRS, UPR 9002, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Architecture et Réactivité de l'ARN, Strasbourg, France
- University of Strasbourg Institute for Advanced Study (USIAS), Strasbourg, France
- Institut Pasteur, Université de Paris, Inserm 1225 Unité de Pathogenèse des Infections Vasculaires, Paris, France
| | - Harry Sokol
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, Paris, France
- Paris Center For Microbiome Medicine (PaCeMM) FHU, Paris, France
- Université Paris-Saclay, INRAe, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
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Dougan M, Nguyen LH, Buchbinder EI, Lazarus HM. Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer. Cancers (Basel) 2024; 16:501. [PMID: 38339253 PMCID: PMC10854719 DOI: 10.3390/cancers16030501] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.
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Affiliation(s)
- Michael Dougan
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (M.D.); (E.I.B.)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
| | - Long H. Nguyen
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Elizabeth I. Buchbinder
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (M.D.); (E.I.B.)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Hillard M. Lazarus
- Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH 44106, USA
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Dharra R, Kumar Sharma A, Datta S. Emerging aspects of cytokine storm in COVID-19: The role of proinflammatory cytokines and therapeutic prospects. Cytokine 2023; 169:156287. [PMID: 37402337 PMCID: PMC10291296 DOI: 10.1016/j.cyto.2023.156287] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/24/2023] [Indexed: 07/06/2023]
Abstract
COVID-19 has claimed millions of lives during the last 3 years since initial cases were reported in Wuhan, China, in 2019. Patients with COVID-19 suffer from severe pneumonia, high fever, acute respiratory distress syndrome (ARDS), and multiple-organ dysfunction, which may also result in fatality in extreme cases. Cytokine storm (CS) is hyperactivation of the immune system, wherein the dysregulated production of proinflammatory cytokines could result in excessive immune cell infiltrations in the pulmonary tissues, resulting in tissue damage. The immune cell infiltration could also occur in other tissues and organs and result in multiple organs' dysfunction. The key cytokines implicated in the onset of disease severity include TNF-α, IFN-γ, IL-6, IL-1β, GM-CSF, and G-CSF. Controlling the CS is critical in treating COVID-19 disease. Therefore, different strategies are employed to mitigate the effects of CS. These include using monoclonal antibodies directed against soluble cytokines or the cytokine receptors, combination therapies, mesenchymal stem cell therapy, therapeutic plasma exchange, and some non-conventional treatment methods to improve patient immunity. The current review describes the role/s of critical cytokines in COVID-19-mediated CS and the respective treatment modalities.
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Affiliation(s)
- Renu Dharra
- CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India
| | - Anil Kumar Sharma
- Department of Bio-Science and Technology, M. M. Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India
| | - Sonal Datta
- Department of Bio-Science and Technology, M. M. Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India.
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Zhang X, Wu Y, Liu X, Lin X, Liu Y, Kang L, Ye H, Wang Z, Ma Y, Dai Z, Che D, Pi Y, Che L, Wang J, Han D. Pro-inflammatory Polarization of Macrophages Causes Intestinal Inflammation in Low-Birth-Weight Piglets and Mice. J Nutr 2023:S0022-3166(23)37559-X. [PMID: 37084872 DOI: 10.1016/j.tjnut.2023.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND Low-birth-weight (LBW) animals suffer from intestinal damage and inflammation in their early life. OBJECTIVES The aim of this study was to investigate the role of macrophages in intestinal inflammation in LBW piglets and mice. METHODS Major genes involved in intestinal barrier function such as claudin-1, zonula occludens-1 (ZO-1), occludin, and mucin 2 and inflammatory cytokines such as IL-1β, TNF-α, IL-10, and IL-13 were evaluated in 21-day-old, normal birth weight (NBW) and LBW piglets and mice. Macrophage markers such as CD16/32, CD163, and CD206 were also assessed by immunofluorescence and flow cytometry. Polarized and unpolarized macrophages were further transferred into NBW and LBW mice, followed by evaluation of intestinal permeability and inflammation. RESULTS Claudin-1 mRNA in LBW piglets as well as claudin-1, occludin, ZO-1 and mucin 2 mRNAs in LBW mice was significantly downregulated. IL-1β and TNF-α were significantly upregulated in LBW piglets (P < 0.05). LBW mice showed a reduced expression of IL-10 and IL-13 (P < 0.05), with a heightened IL-6 level (P < 0.01) in the jejunum. CD16, a marker for M1 macrophages, was significantly elevated in the jejunum of LBW piglets, whereas CD163, a marker for M2 macrophages, was significantly decreased (P < 0.05). Similarly, LBW mice had more CD11b+CD16/32+ M1 macrophages (P < 0.05) and fewer CD206+ M2 macrophages (P < 0.01) than NBW mice. Moreover, transfer of M1 macrophages exacerbated intestinal inflammation in LBW mice. Furthermore, two major glycolysis-associated genes, hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), were significantly upregulated in LBW piglets and mice (P < 0.05). CONCLUSIONS This study revealed for the first time that the intestinal macrophages are polarized towards a pro-inflammatory phenotype in LBW piglets and mice, contributing to intestinal inflammation. The findings of this study provide new options for the management of intestinal inflammation in LBW animals.
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Affiliation(s)
- Xiangyu Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yujun Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xiaoyi Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xu Lin
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yisi Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Luyuan Kang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Hao Ye
- Department of Animal Sciences, Wageningen University, Wageningen 6700 AH, Netherlands
| | - Zhenyu Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yingying Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Dongsheng Che
- College of Animal Science and Technology, Jilin Agricultural University, Jilin, 130118, China
| | - Yu Pi
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Lianqiang Che
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan 611130, China
| | - Junjun Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Dandan Han
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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Lazarus HM, Pitts K, Wang T, Lee E, Buchbinder E, Dougan M, Armstrong DG, Paine R, Ragsdale CE, Boyd T, Rock EP, Gale RP. Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders. Front Immunol 2023; 13:1069444. [PMID: 36685591 PMCID: PMC9850113 DOI: 10.3389/fimmu.2022.1069444] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/05/2022] [Indexed: 01/07/2023] Open
Abstract
Introduction Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF. Methods We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy. Results We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events. Discussion We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.
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Affiliation(s)
- Hillard M. Lazarus
- Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States
| | - Katherine Pitts
- Medical Affairs, Partner Therapeutics, Inc., Lexington, MA, United States
| | - Tisha Wang
- Division of Pulmonary, Critical Care, and Sleep Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Elinor Lee
- Division of Pulmonary, Critical Care, and Sleep Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Elizabeth Buchbinder
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
| | - Michael Dougan
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - David G. Armstrong
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Robert Paine
- Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah, Salt Lake City, UT, United States
| | | | - Timothy Boyd
- Clinical Development, Partner Therapeutics, Inc., Lexington, MA, United States
| | - Edwin P. Rock
- Clinical Development, Partner Therapeutics, Inc., Lexington, MA, United States
| | - Robert Peter Gale
- Hematology Centre, Department of Immunology and Inflammation, Imperial College, London, United Kingdom
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Chen TK, Batra JS, Michalik DE, Casillas J, Patel R, Ruiz ME, Hara H, Patel B, Kadapakkam M, Ch'Ng J, Small CB, Zagaliotis P, Ragsdale CE, Leal LO, Roilides E, Walsh TJ. Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases. Open Forum Infect Dis 2022; 9:ofac535. [PMID: 36381625 PMCID: PMC9645583 DOI: 10.1093/ofid/ofac535] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/07/2022] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). METHODS The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. RESULTS Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). CONCLUSIONS Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.
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Affiliation(s)
- Tempe K Chen
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - Jagmohan S Batra
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - David E Michalik
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - Jacqueline Casillas
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Ramesh Patel
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Maritza E Ruiz
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Harneet Hara
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Bhavita Patel
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Meena Kadapakkam
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - James Ch'Ng
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Catherine B Small
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
| | - Panagiotis Zagaliotis
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
- Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece
- Department of Pharmacology and Therapeutics, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Luis O Leal
- Partner Therapeutics, Inc., Lexington, Massachusetts, USA
| | - Emmanuel Roilides
- Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece
| | - Thomas J Walsh
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
- Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia, USA
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Mortha A, Remark R, Del Valle DM, Chuang LS, Chai Z, Alves I, Azevedo C, Gaifem J, Martin J, Petralia F, Tuballes K, Barcessat V, Tai SL, Huang HH, Laface I, Jerez YA, Boschetti G, Villaverde N, Wang MD, Korie UM, Murray J, Choung RS, Sato T, Laird RM, Plevy S, Rahman A, Torres J, Porter C, Riddle MS, Kenigsberg E, Pinho SS, Cho JH, Merad M, Colombel JF, Gnjatic S. Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn's Disease. Gastroenterology 2022; 163:659-670. [PMID: 35623454 PMCID: PMC10127946 DOI: 10.1053/j.gastro.2022.05.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. METHODS We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. RESULTS Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. CONCLUSIONS Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.
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Affiliation(s)
- Arthur Mortha
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Immunology, University of Toronto, Toronto, Canada.
| | - Romain Remark
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Innate Pharma, Marseille, France
| | - Diane Marie Del Valle
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ling-Shiang Chuang
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Zhi Chai
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Inês Alves
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal
| | - Catarina Azevedo
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal
| | - Joana Gaifem
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Jerome Martin
- Université de Nantes, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, Nantes, France; CHU Nantes, Laboratoire d'Immunologie, CIMNA, Nantes, France
| | - Francesca Petralia
- Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kevin Tuballes
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Vanessa Barcessat
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Hsin-Hui Huang
- Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ilaria Laface
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Yeray Arteaga Jerez
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gilles Boschetti
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Hépato-Gastroentérologue, Hospices Civils de Lyon, Université Claude Bernard, Lyon, France
| | - Nicole Villaverde
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mona D Wang
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Ujunwa M Korie
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Joseph Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Rok-Seon Choung
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Renee M Laird
- Naval Medical Research Center, Silver Spring, Maryland
| | | | - Adeeb Rahman
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center at Mount Sinai, New York, New York
| | - Joana Torres
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
| | - Chad Porter
- Naval Medical Research Center, Silver Spring, Maryland
| | - Mark S Riddle
- Naval Medical Research Center, Silver Spring, Maryland
| | - Ephraim Kenigsberg
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center at Mount Sinai, New York, New York
| | - Salomé S Pinho
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; School of Medicine and Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Judy H Cho
- Charles Bronfman Institute for Personalized Medicine, Department of Genetics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Miriam Merad
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center at Mount Sinai, New York, New York
| | - Jean-Frederic Colombel
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sacha Gnjatic
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center at Mount Sinai, New York, New York
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9
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Sun H, Tang C, Chung SH, Ye XQ, Makusheva Y, Han W, Kubo M, Shichino S, Ueha S, Matsushima K, Ikeo K, Asano M, Iwakura Y. Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway. Cell Rep 2022; 40:111158. [PMID: 35926458 DOI: 10.1016/j.celrep.2022.111158] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/26/2022] [Accepted: 07/13/2022] [Indexed: 11/28/2022] Open
Abstract
Dendritic cell immunoreceptor (DCIR; Clec4a2), a member of the C-type lectin receptor family, plays important roles in homeostasis of the immune and bone systems. However, the intestinal role of this molecule is unclear. Here, we show that dextran sodium sulfate (DSS)-induced colitis and azoxymethane-DSS-induced intestinal tumors are reduced in Clec4a2-/- mice independently of intestinal microbiota. STAT5 phosphorylation and expression of Csf2 and tight junction genes are enhanced, while Il17a and Cxcl2 are suppressed in the Clec4a2-/- mouse colon, which exhibits reduced infiltration of neutrophils and myeloid-derived suppressor cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) administration ameliorates DSS colitis associated with reduced Il17a and enhanced tight junction gene expression, whereas anti-GM-CSF exacerbates symptoms. Furthermore, anti-NA2, a ligand for DCIR, ameliorates colitis and prevents colorectal tumors. These observations indicate that blocking DCIR signaling ameliorates colitis and suppresses colonic tumors, suggesting DCIR as a possible target for the treatment of these diseases.
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Affiliation(s)
- Haiyang Sun
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan
| | - Ce Tang
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, Guangdong Province 510080, China
| | - Soo-Hyun Chung
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan
| | - Xiao-Qi Ye
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan
| | - Yulia Makusheva
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan
| | - Wei Han
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan
| | - Masato Kubo
- Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
| | - Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
| | - Koji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
| | - Kazuho Ikeo
- DNA Data Analysis Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan
| | - Masahide Asano
- Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoichiro Iwakura
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan.
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10
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De Gregorio V, Sgambato C, Urciuolo F, Vecchione R, Netti PA, Imparato G. Immunoresponsive microbiota-gut-on-chip reproduces barrier dysfunction, stromal reshaping and probiotics translocation under inflammation. Biomaterials 2022; 286:121573. [PMID: 35617781 DOI: 10.1016/j.biomaterials.2022.121573] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 01/21/2022] [Accepted: 05/07/2022] [Indexed: 11/25/2022]
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11
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Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.
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Affiliation(s)
- Adrian A Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia.
| | - Kevin M C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia; Australian Institute for Musculoskeletal Science, St Albans, Victoria 3021, Australia
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12
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Lazarus HM, Ragsdale CE, Gale RP, Lyman GH. Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time? Front Immunol 2021; 12:706186. [PMID: 34484202 PMCID: PMC8416151 DOI: 10.3389/fimmu.2021.706186] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. OBJECTIVE Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. METHODS AND RESULTS We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. CONCLUSIONS Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.
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Affiliation(s)
- Hillard M. Lazarus
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | | | - Robert Peter Gale
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Gary H. Lyman
- Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
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13
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Wirthgen E, Hornschuh M, Wrobel IM, Manteuffel C, Däbritz J. Mimicking of Blood Flow Results in a Distinct Functional Phenotype in Human Non-Adherent Classical Monocytes. BIOLOGY 2021; 10:biology10080748. [PMID: 34439980 PMCID: PMC8389597 DOI: 10.3390/biology10080748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/27/2021] [Accepted: 07/31/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary Monocytes are immune cells of increasing interest as cellular-based therapeutic products in inflammation-related diseases. The underlying mechanism is that isolated monocytes are modified outside the body. After re-injection, monocytes are recruited to the site of inflammation, exerting their therapeutic effect. One current challenge is that isolated monocytes rapidly lose migratory capacity during culture, limiting their therapeutic efficacy. During suspension culture, mimicking blood flow has been shown to preserve the migratory capacity. However, the effects on the inflammatory response and other functional properties have not been studied so far. Hence, the present study investigates the effect of shear flow on cytokine secretion and selected features of human blood-derived classical monocytes. Our results demonstrate that mimicking blood flow resulted in a distinct phenotype with an anti-inflammatory cytokine response and a higher migratory capacity than cultured under static conditions. These features could be particularly relevant for further developing monocyte-based products as unwanted inflammatory signaling at the injection site or peripheral blood circulation will be attenuated. Abstract Ex vivo culture conditions during the manufacturing process impact the therapeutic effect of cell-based products. Mimicking blood flow during ex vivo culture of monocytes has beneficial effects by preserving their migratory ability. However, the effects of shear flow on the inflammatory response have not been studied so far. Hence, the present study investigates the effects of shear flow on both blood-derived naïve and activated monocytes. The activation of monocytes was experimentally induced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which acts as a pro-survival and growth factor on monocytes with a potential role in inflammation. Monocytes were cultured under dynamic (=shear flow) or static conditions while preventing monocytes’ adherence by using cell-repellent surfaces to avoid adhesion-induced differentiation. After cultivation (40 h), cell size, viability, and cytokine secretion were evaluated, and the cells were further applied to functional tests on their migratory capacity, adherence, and metabolic activity. Our results demonstrate that the application of shear flow resulted in a decreased pro-inflammatory signaling concurrent with increased secretion of the anti-inflammatory cytokine IL-10 and increased migratory capacity. These features may improve the efficacy of monocyte-based therapeutic products as both the unwanted inflammatory signaling in blood circulation and the loss of migratory ability will be prevented.
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Affiliation(s)
- Elisa Wirthgen
- Mucosal Immunology Group, Department of Pediatrics, Rostock University Medical Center, 18057 Rostock, Germany; (M.H.); (J.D.)
- Correspondence: ; Tel.: +49-(0)381-494-7076
| | - Melanie Hornschuh
- Mucosal Immunology Group, Department of Pediatrics, Rostock University Medical Center, 18057 Rostock, Germany; (M.H.); (J.D.)
| | - Ida Maria Wrobel
- Department of Transfusion Medicine, Rostock University Medical Center, 18057 Rostock, Germany;
| | - Christian Manteuffel
- Institute of Behavioral Physiology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany;
| | - Jan Däbritz
- Mucosal Immunology Group, Department of Pediatrics, Rostock University Medical Center, 18057 Rostock, Germany; (M.H.); (J.D.)
- Center for Immunobiology, The Barts and the London School of Medicine and Dentistry, Blizard Institute, Barts Cancer Institute, Queen Mary University, London E1 4NS, UK
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14
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Zysset D, Montani M, Spalinger J, Schibli S, Zlobec I, Mueller C, Sokollik C. Molecular and Histological Profiling Reveals an Innate-Shaped Immune Microenvironment in Solitary Juvenile Polyps. Clin Transl Gastroenterol 2021; 12:e00361. [PMID: 34060497 PMCID: PMC8162518 DOI: 10.14309/ctg.0000000000000361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION Solitary juvenile polyps (JP) are characterized by a benign disease course with low recurrence rate but present with signs of intestinal inflammation. To better understand the underlying pathogenesis, we performed histological and molecular evaluation targeting distinct immune mechanisms. METHODS Pediatric patients with JP (n = 12), with treatment-naïve inflammatory bowel disease (IBD; [n = 41]) as inflammatory control, and non-IBD controls (n = 14) were investigated. For a comparative analysis of infiltrating immune cells, a next-generation tissue microarray of biopsies was assembled, immunostained, and scored. Targeted transcriptional profiling was performed using a customized immunology panel. RESULTS In JP, a predominant accumulation of neutrophils and eosinophils was observed. RNA expression profiles revealed increased levels of CXCL8, CXCL5, and CCL11 transcripts in JP, indicating an enhanced recruitment of neutrophils and eosinophils. Moreover, messenger RNA levels of the proinflammatory cytokine IL1b and the inflammation-amplifying receptor TREM1 were higher in JP, whereas we could not find signs of a functionally polarized Tcell response in JP when compared with IBD. DISCUSSION Patients with JP and patients with treatment-naïve IBD have distinct cell infiltrates during active disease. The ample presence of eosinophils in JP supports neutrophil accumulation, which is responsible for the elevated release of calprotectin. Intriguingly, however, we were not able to identify a functionally polarized T-cell response in JP, which indicates that during the acute onset of inflammation in JP, a potent adaptive immune memory is not established. This may explain the low reoccurrence rate of JP.
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Affiliation(s)
- Daniel Zysset
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Matteo Montani
- Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Susanne Schibli
- Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital, Inselspital, University of Bern, Switzerland
| | - Inti Zlobec
- Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Christiane Sokollik
- Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital, Inselspital, University of Bern, Switzerland
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15
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Lee KMC, Achuthan AA, Hamilton JA. GM-CSF: A Promising Target in Inflammation and Autoimmunity. Immunotargets Ther 2020; 9:225-240. [PMID: 33150139 PMCID: PMC7605919 DOI: 10.2147/itt.s262566] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 10/15/2020] [Indexed: 12/14/2022] Open
Abstract
The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly the biology of GM-CSF, raise some current issues and questions pertaining to this biology, summarize the results from preclinical models of a range of inflammatory and autoimmune disorders and list the latest clinical trials evaluating GM-CSF blockade in such disorders.
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Affiliation(s)
- Kevin M C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, 3050, Australia
| | - Adrian A Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, 3050, Australia
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, 3050, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, Melbourne, VIC, Australia
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16
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Hamilton JA. GM-CSF in inflammation. J Exp Med 2020; 217:jem.20190945. [PMID: 31611249 PMCID: PMC7037240 DOI: 10.1084/jem.20190945] [Citation(s) in RCA: 194] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/09/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
GM-CSF is a potential therapeutic target in inflammation and autoimmunity. This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis. Granulocyte–macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.
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Affiliation(s)
- John A Hamilton
- The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Australian Institute for Musculoskeletal Science, The University of Melbourne and Western Health, St Albans, Victoria, Australia
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17
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Hamo Z, Azrad M, Nitzan O, Peretz A. Characterization of the Immune Response during Infection Caused by Clostridioides difficile. Microorganisms 2019; 7:microorganisms7100435. [PMID: 31658740 PMCID: PMC6843454 DOI: 10.3390/microorganisms7100435] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/03/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023] Open
Abstract
The high risk of complications and death following Clostridioides difficile infection (CDI) requires identifying patients with severe disease and treating them accordingly. We characterized the immune response of CDI patients in relation to infection severity. Concentrations of 28 cytokines and chemokines were measured in serum samples, obtained from 54 CDI patients within a median timeframe of 24–48 h after laboratory confirmation of C. difficile infection. Demographic and clinical data were retrospectively collected from medical records. Disease severity score was determined by “Score indices for Clostridioides difficile infection severity”. Of 54 patients (mean age, 76.6 years, 61.1% female), 38 (70.4%) had mild disease and 16 (29.6%) had moderate disease. Seven cytokines were associated with a more severe CDI: granulocyte-macrophage colony-stimulating factor (p = 0.0106), interleukin (IL)-1β (p = 0.004), IL-8 (p = 0.0098), IL-12p70 (p = 0.0118), interferon-α (p = 0.0282), IL-15 (p = 0.0015), and IL-2 (p = 0.0031). Additionally, there was an increased T-helper 1 response in more severe cases of CDI. Cytokines may serve as biomarkers for early prediction of CDI severity. Better and earlier assessment of illness severity will contribute to the adjustment of medical treatment, including monitoring and follow-up.
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Affiliation(s)
- Zohar Hamo
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed 13100, Israel.
- The Clinical Microbiology Laboratory, Baruch Padeh Medical Center, Poriya 15208, Israel.
| | - Maya Azrad
- The Clinical Microbiology Laboratory, Baruch Padeh Medical Center, Poriya 15208, Israel.
| | - Orna Nitzan
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed 13100, Israel.
- Unit of Infectious Diseases, Baruch Padeh Medical Center, Poriya 15208, Israel.
| | - Avi Peretz
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed 13100, Israel.
- The Clinical Microbiology Laboratory, Baruch Padeh Medical Center, Poriya 15208, Israel.
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18
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Camara-Lemarroy CR, Silva C, Greenfield J, Liu WQ, Metz LM, Yong VW. Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity. Mult Scler 2019; 26:1340-1350. [PMID: 31317818 DOI: 10.1177/1352458519863133] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Recent evidence suggests a role for the gut-brain axis in the pathophysiology of multiple sclerosis (MS). MATERIALS AND METHODS We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. RESULTS Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood-brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad- subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. CONCLUSIONS People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut-brain axis modulates neuroinflammation in MS.
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Affiliation(s)
- Carlos R Camara-Lemarroy
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Claudia Silva
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jamie Greenfield
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Wei-Qiao Liu
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Luanne M Metz
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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19
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Vorobjova T, Tagoma A, Oras A, Alnek K, Kisand K, Talja I, Uibo O, Uibo R. Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa. J Immunol Res 2019; 2019:6179243. [PMID: 31214623 PMCID: PMC6535873 DOI: 10.1155/2019/6179243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/08/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023] Open
Abstract
Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.
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Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Aili Tagoma
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Astrid Oras
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kristi Alnek
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kalle Kisand
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Ija Talja
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Oivi Uibo
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Estonia
- Children's Clinic, Tartu University Hospital, Tartu, Estonia
| | - Raivo Uibo
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
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20
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Hu Y, Xu F, Zhang R, Legarda D, Dai J, Wang D, Li H, Zhang Y, Xue Q, Dong G, Zhang H, Lu C, Mortha A, Liu J, Cravedi P, Ting A, Li L, Qi CF, Pierce S, Merad M, Heeger P, Xiong H. Interleukin-1β-induced IRAK1 ubiquitination is required for T H-GM-CSF cell differentiation in T cell-mediated inflammation. J Autoimmun 2019; 102:50-64. [PMID: 31080014 DOI: 10.1016/j.jaut.2019.04.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/12/2019] [Accepted: 04/12/2019] [Indexed: 12/29/2022]
Abstract
Accumulating evidence suggests granulocyte macrophage-colony stimulating factor (GM-CSF) can function as an inflammatory mediator, but whether GM-CSF-producing CD4+ T cells (TH-GM-CSF) are a distinct T helper cell subset is lacking. Herein we demonstrate that interleukin (IL)-1β exclusively drives differentiation of naïve CD4+ T cells into TH-GM-CSF cells via inducing ubiquitination of IL-1 receptor-associated kinase 1 (IRAK1) and subsequent activation of the transcription factor NF-kappaB (NF-κB), independent of RAR-related orphan receptor gamma (RORγt) required for TH17 differentiation. In vivo, TH-GM-CSF cells are present in murine Citrobacter Rodentium infections and mediate colitis following adoptive transfer of CD4+ T cells into Rag1-/- mice via GM-CSF-induced macrophage activation. The TH-GM-CSF cell phenotype is stable and distinct from the TH17 genetic program, but IL-1β can convert pre-formed TH17 cells into TH-GM-CSF cells, thereby accounting for previously reported associations between IL-17 and GM-CSF. Together, our results newly identify IL-1β/NF-κB-dependent TH-GM-CSF cells as a unique T helper cell subset and highlight the importance of CD4+ T cell-derived GM-CSF induced macrophage activation as a previously undescribed T cell effector mechanism.
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Affiliation(s)
- Yuan Hu
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China
| | - Feihong Xu
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ruihua Zhang
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Diana Legarda
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jun Dai
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China
| | - Di Wang
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Heyu Li
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yao Zhang
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Qingjie Xue
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China
| | - Hui Zhang
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China
| | - Chang Lu
- Department of Biomedical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Arthur Mortha
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jianguo Liu
- Departments of Internal Medicine & Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Paolo Cravedi
- Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Adrian Ting
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Liwu Li
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Chen-Feng Qi
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Susan Pierce
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Miriam Merad
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Peter Heeger
- Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Huabao Xiong
- Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute of Immunology and Molecular Medicine, Jining Medical University, Shandong, 272067, China.
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Rolandsdotter H, Jönsson-Videsäter K, L Fagerberg U, Finkel Y, Eberhardson M. Exclusive Enteral Nutrition: Clinical Effects and Changes in Mucosal Cytokine Profile in Pediatric New Inflammatory Bowel Disease. Nutrients 2019; 11:E414. [PMID: 30781421 PMCID: PMC6412217 DOI: 10.3390/nu11020414] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 12/31/2022] Open
Abstract
Exclusive Enteral Nutrition (EEN) is the first-line treatment in children with Crohn's disease (CD) for induction of remission. However, the mode of action remains conjectural. The aim of this study was to investigate whether the effect of EEN is paralleled by changes in the mucosal cytokine profiles (MCP). Twelve children with new onset inflammatory bowel disease (IBD) received induction treatment with a polymeric EEN. We assessed clinical, endoscopic and histologic scoring before and after EEN. Twelve colonic cytokines were analyzed by Polymerase Chain Reaction (PCR) in six of the IBD patients at onset and after EEN as well as in six non-IBD control children at the diagnostic colonoscopy. Twelve children completed 6 weeks of EEN, except from one child who completed 4 weeks. At the control colonoscopy, 83% were in complete clinical remission. Changes were found in the MCPs of individual patients after EEN. In particular, children with IBD showed significantly higher values of Interleukin (IL)-12β (p = 0.008) and IL-23α (p = 0.02) compared to non-IBD controls at the diagnostic colonoscopy. Furthermore, an overall change in proinflammatory cytokines was noted in the IBD-group after treatment. Further studies are warranted to understand the role of EEN in MCP.
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Affiliation(s)
- Helena Rolandsdotter
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, 11883 Stockholm, Sweden.
- Department of Gastroenterology, Sachs' Children and Youth Hospital, Södersjukhuset, 11883 Stockholm, Sweden.
| | - Kerstin Jönsson-Videsäter
- Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, 14157 Huddinge, Sweden.
- Department of Medicine, Huddinge, Karolinska Institutet, 14157 Huddinge, Sweden.
| | - Ulrika L Fagerberg
- Department of Women's and Children's Health, Karolinska Institutet, 17177 Stockholm, Sweden.
- Center for Clinical Research, Västmanland Hospital, Uppsala University, 72189 Västerås, Sweden.
| | - Yigael Finkel
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, 11883 Stockholm, Sweden.
- Department of Gastroenterology, Sachs' Children and Youth Hospital, Södersjukhuset, 11883 Stockholm, Sweden.
| | - Michael Eberhardson
- Department of Gastroenterology, Karolinska University Hospital, 17177 Stockholm, Sweden.
- Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden.
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22
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Yu WL, Hua ZC. Evaluation of effectiveness of granulocyte-macrophage colony-stimulating factor therapy to cancer patients after chemotherapy: a meta-analysis. Oncotarget 2018; 9:28226-28239. [PMID: 29963274 PMCID: PMC6021338 DOI: 10.18632/oncotarget.24890] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 02/28/2018] [Indexed: 12/24/2022] Open
Abstract
The impact of granulocyte-macrophage colony stimulating factor (GM-CSF) on hematologic indexes and complications remains existing contradictory evidence in cancer patients after treatment of chemotherapy. Eligible studies up to March 2017 were searched and reviewed from PubMed and Wanfang databases. Totally 1043 cancer patients from 15 studies were included in our research. The result indicated that GM-CSF could significantly improve white blood cells count (SMD = 1.16, 95% CI: 0.71 – 1.61, Z = 5.03, P < 0.00001) and reduce the time to leukopenia recovery (SMD = -0.85, 95% CI: -1.16 – -0.54, Z = 5.38, P < 0.00001) in cancer patients after treatment of chemotherapy. It also could improve absolute neutrophil count (SMD = 1.11, 95% CI: 0.39 – 1.82, Z = 3.04, P = 0.002) and significantly shorten the time to neutropenia recovery (SMD = -1.47, 95% CI: -2.20 – -1.75, Z = 3.99, P < 0.0001). However, GM-CSF could not improve blood platelet (SMD = 0.46, 95% CI: -0.37 – -1.29, Z = 1.10, P = 0.27). And GM-CSF had significant connection with fever (RR = 3.44, 95% CI: 1.43 – 8.28, Z = 2.76, P = 0.006). The publication bias existed in the data of the impact of GM-CSF on blood platelet and complication. In conclusions, GM-CSF had an intimate association with some hematologic indexes and complications. Our study suggested that more hematological indexes and even more other indexes need to be observed in future studies.
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Affiliation(s)
- Wen-Liang Yu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China
| | - Zi-Chun Hua
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China.,The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.,Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, China
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23
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Liu YH, Ding Y, Gao CC, Li LS, Wang YX, Xu JD. Functional macrophages and gastrointestinal disorders. World J Gastroenterol 2018; 24:1181-1195. [PMID: 29568199 PMCID: PMC5859221 DOI: 10.3748/wjg.v24.i11.1181] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 02/12/2018] [Accepted: 02/25/2018] [Indexed: 02/06/2023] Open
Abstract
Macrophages (MΦ) differentiate from blood monocytes and participate in innate and adaptive immunity. Because of their abilities to recognize pathogens and activate bactericidal activities, MΦ are always discovered at the site of immune defense. MΦ in the intestine are unique, such that in the healthy intestine, they possess complex mechanisms to protect the gut from inflammation. In these complex mechanisms, they produce anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor-β, and inhibit the inflammatory pathways mediated by Toll-like receptors. It has been demonstrated that resident MΦ play a crucial role in maintaining intestinal homeostasis, and they can be recognized by their unique markers. Nonetheless, in the inflamed intestine, the function of MΦ will change because of environmental variation, which may be one of the mechanisms of inflammatory bowel disease (IBD). We provide further explanation about these mechanisms in our review. In addition, we review recent discoveries that MΦ may be involved in the development of gastrointestinal tumors. We will highlight the possible therapeutic targets for the management of IBD and gastrointestinal tumors, and we also discuss why more details are needed to fully understand all other effects of intestinal MΦ.
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Affiliation(s)
- Yue-Hong Liu
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Yue Ding
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Chen-Chen Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Function Platform Center, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Yue-Xiu Wang
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
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24
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Liu T, Liu F, Peng LW, Chang L, Jiang YM. The Peritoneal Macrophages in Inflammatory Diseases and Abdominal Cancers. Oncol Res 2017; 26:817-826. [PMID: 29237519 PMCID: PMC7844755 DOI: 10.3727/096504017x15130753659625] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Peritoneal macrophages (PMs) are the major cell type of peritoneal cells that participate in multiple aspects of innate and acquired immunity in the peritoneal cavity. PMs have an ability to release a large amount of proinflammatory and anti-inflammatory cytokines and therefore play a critical role in regulating the differentiation of innate immune cells and inflammatory T cells. Accumulating studies demonstrate that the immunological reactions and inflammatory responses of PMs are strongly related to the pathogenic processes of various inflammatory diseases and abdominal cancers. Consequently, the regulation of PM activation has gradually emerged as a promising target for immunotherapy, and better understanding of the distinctly biological function of PMs in individual diseases is crucial for designing specific and effective therapeutic agents. This review covers the characterization and immunological function of PMs in hosts with inflammatory diseases and abdominal cancers.
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Affiliation(s)
- Ting Liu
- Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Sichuan University, Chengdu, P.R. China
| | - Fang Liu
- Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Sichuan University, Chengdu, P.R. China
| | - Lei-Wen Peng
- Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Sichuan University, Chengdu, P.R. China
| | - Li Chang
- Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Sichuan University, Chengdu, P.R. China
| | - Yong-Mei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, and Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Sichuan University, Chengdu, P.R. China
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25
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Bilsborough J, Targan SR, Snapper SB. Therapeutic Targets in Inflammatory Bowel Disease: Current and Future. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.18] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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26
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Targeting the complex interactions between microbiota, host epithelial and immune cells in inflammatory bowel disease. Pharmacol Res 2016; 113:574-584. [PMID: 27702681 DOI: 10.1016/j.phrs.2016.09.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 09/30/2016] [Accepted: 09/30/2016] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder that includes two distinct disease categories: ulcerative colitis and Crohn's disease. Epidemiological, genetic, and experimental studies have revealed many important aspects of IBD. Genetic susceptibility, inappropriate immune responses, environmental changes, and intestinal microbiota are all associated with the development of IBD. However, the exact mechanisms of the disease and the interactions among these pathogenic factors are largely unknown. Here we introduce recent findings from experimental colitis models that investigated the interactions between host genetic susceptibility and gut microbiota. In addition, we discuss new strategies for the treatment of IBD, focusing on the complex interactions between microbiota and host epithelial and immune cells.
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27
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Shiomi A, Usui T, Mimori T. GM-CSF as a therapeutic target in autoimmune diseases. Inflamm Regen 2016; 36:8. [PMID: 29259681 PMCID: PMC5725926 DOI: 10.1186/s41232-016-0014-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 05/10/2016] [Indexed: 12/23/2022] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been known as a hematopoietic growth factor and immune modulator. Recent studies revealed that GM-CSF also had pro-inflammatory functions and contributed to the pathogenicity of Th17 cells in the development of Th17-mediated autoimmune diseases. GM-CSF inhibition in some animal models of autoimmune diseases showed significant beneficial effects. Therefore, several agents targeting GM-CSF are being developed and are expected to be a useful strategy for the treatment of autoimmune diseases. Particularly, in clinical trials for rheumatoid arthritis (RA) patients, GM-CSF inhibition showed rapid and significant efficacy with no serious side effects. This article summarizes recent findings of GM-CSF and information of clinical trials targeting GM-CSF in autoimmune diseases.
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Affiliation(s)
- Aoi Shiomi
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54-Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan
| | - Takashi Usui
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54-Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54-Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan
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28
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Utility of surrogate markers for the prediction of relapses in inflammatory bowel diseases. J Gastroenterol 2016; 51:531-47. [PMID: 26975751 DOI: 10.1007/s00535-016-1191-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/21/2016] [Indexed: 02/04/2023]
Abstract
Patients with diagnosed inflammatory bowel disease (IBD) will commonly experience a clinical relapse in spite of a prolonged therapy-induced period of clinical remission. The current methods of assessing subclinical levels of low-grade inflammation which predispose patients to relapse are not optimal when considering both cost and patient comfort. Over the past few decades, much investigation has discovered that proteins such as calprotectin that are released from inflammatory cells are capable of indicating disease activity. Along with C-reactive protein and erythrocyte sedimentation rate, calprotectin has now become part of the current methodology for assessing IBD activity. More recently, research has identified that other fecal and serum biomarkers such as lactoferrin, S100A12, GM-CSF autoantibodies, α1-antitrypsin, eosinophil-derived proteins, and cytokine concentrations have variable degrees of utility in monitoring gastrointestinal tract inflammation. In order to provide direction toward novel methods of predicting relapse in IBD, we provide an up-to-date review of these biomarkers and their potential utility in the prediction of clinical relapse, given their observed activities during various stages of clinical remission.
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29
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Jose S, Madan R. Neutrophil-mediated inflammation in the pathogenesis of Clostridium difficile infections. Anaerobe 2016; 41:85-90. [PMID: 27063896 DOI: 10.1016/j.anaerobe.2016.04.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 04/04/2016] [Indexed: 12/19/2022]
Abstract
Clostridium difficile is the most important cause of nosocomial infectious diarrhea in the western world. C. difficile infections are a major healthcare burden with approximately 500,000 new cases every year and an estimated annual cost of nearly $1 billion in the U.S. Furthermore, the infections are no longer restricted to health care facilities, and recent studies indicate spread of C. difficile infection to the community as well. The clinical spectrum of C. difficile infection ranges from asymptomatic colonization to severe diarrhea, fulminant colitis and death. This spectrum results from a complex interplay between bacterial virulence factors, the colonic microbiome and the host inflammatory response. The overall vigor of host inflammatory response is believed to be an important determinant of C. difficile disease severity, and a more robust immune response is associated with worse outcomes. Neutrophils are the primary cells that respond to C. difficile invasion and neutrophilic inflammation is the hallmark of C. difficile-associated disease. In this review, we will focus on the role of neutrophils (infiltration to infected tissue, pathogen clearance and resolution of inflammation) in the immuno-pathogenesis of C. difficile-associated disease (CDAD).
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Affiliation(s)
- Shinsmon Jose
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati, OH 45267, USA
| | - Rajat Madan
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati, OH 45267, USA.
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30
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Altered gp130 signalling ameliorates experimental colitis via myeloid cell-specific STAT3 activation and myeloid-derived suppressor cells. Sci Rep 2016; 6:20584. [PMID: 26848037 PMCID: PMC4742831 DOI: 10.1038/srep20584] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
STAT3 regulates the expansion of myeloid-derived suppressor cells (MDSCs) during
inflammation, infection and cancer. Hyperactivation of STAT3 in
gp130757F/F mice is associated with protection from experimental
colitis. This study determined mechanisms for this protection and compared this to
mice with myeloid-specific STAT3-deficiency (LysMcre/STAT3flox;
gp130757F/F LysMcre/STAT3flox). Acute and chronic
colitis was induced and colons were removed for histological, mRNA and protein
analysis. Cell populations from spleen, mesenteric lymph node and colon were
analyzed for different myeloid cell populations using flow cytometry. Functions of
MDSCs and LPS-stimulated peritoneal macrophages were further characterized by in
vitro and in vivo assays. Here we show that the resistance to
experimental colitis in gp130757F/F mice is via myeloid-cell specific
STAT3 activation, MDSC expansion and increased production of suppressive and
protective cytokines.
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31
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Abstract
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a growth factor first identified as an inducer of differentiation and proliferation of granulocytes and macrophages derived from haematopoietic progenitor cells. Later studies have shown that GM-CSF is involved in a wide range of biological processes in both innate and adaptive immunity, with its production being tightly linked to the response to danger signals. Given that the functions of GM-CSF span multiple tissues and biological processes, this cytokine has shown potential as a new and important therapeutic target in several autoimmune and inflammatory disorders - particularly in rheumatoid arthritis. Indeed, GM-CSF was one of the first cytokines detected in human synovial fluid from inflamed joints. Therapies that target GM-CSF or its receptor have been tested in preclinical studies with promising results, further supporting the potential of targeting the GM-CSF pathway. In this Review, we discuss our expanding view of the biology of GM-CSF, outline what has been learnt about GM-CSF from studies of animal models and human diseases, and summarize the results of early phase clinical trials evaluating GM-CSF antagonism in inflammatory disorders.
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Abstract
As the frontiers of immunological research expand, new insights into the pathogenesis of long poorly understood diseases, such as inflammatory bowel disease (IBD), are opening up new possible avenues for treatment. Myeloid-derived cells (i.e., monocytes, macrophages, neutrophils, and dendritic cells), long believed to be effector cells driving the initiation of inflammation, have been increasingly shown to have immunoregulatory effects previously underappreciated. Dysfunction in the immunoregulatory roles of these cells may play a part in the pathogenesis of a subset of patients with IBD. The role of myeloid-derived suppressor cells, initially described in cancer, have been shown to play an important role in the balancing of effector and regulatory T cells in inflammation as well, and their role in IBD is also explored. The potential for future cell-based therapies for IBD is enhanced by the advances being made in the understanding of the innate immune system in the intestine.
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Däbritz J. GM-CSF and the role of myeloid regulatory cells in the pathogenesis and treatment of Crohn's disease. Mol Cell Pediatr 2015; 2:12. [PMID: 26626346 PMCID: PMC4666883 DOI: 10.1186/s40348-015-0024-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/20/2015] [Indexed: 12/19/2022] Open
Abstract
Background Intestinal monocytes/macrophages sustain the intestinal immune homeostasis and might be an attractive therapeutic target for the management of inflammatory bowel disease (IBD). Granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects on intestinal inflammation and promotes signal transducer and activator of transcription 3 (STAT3)-mediated expansion of myeloid-derived suppressor cells (MDSCs). However, the full action mechanism of GM-CSF, and especially whether monocytes mediate its therapeutic effects in vivo, had not been previously elucidated. Conclusions This review article summarizes recent developments in the immunology of mucosal diseases and describes new aspects of the role of myeloid regulatory cells in IBD and the function of GM-CSF in maintaining the intestinal immune homeostasis in Crohn’s disease (CD). This review article highlights the exploration of stimulating in addition to suppressive therapies for patients with IBD and underpins that myeloid regulatory cells might become a promising novel cell-based therapeutic option.
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Affiliation(s)
- Jan Däbritz
- Present address: Department of Pediatrics, University Hospital Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany. .,Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany. .,Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, 50 Flemington Road, Parkville, VIC, 3052, Australia.
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Bhattacharya P, Thiruppathi M, Elshabrawy HA, Alharshawi K, Kumar P, Prabhakar BS. GM-CSF: An immune modulatory cytokine that can suppress autoimmunity. Cytokine 2015; 75:261-71. [PMID: 26113402 DOI: 10.1016/j.cyto.2015.05.030] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 05/22/2015] [Accepted: 05/25/2015] [Indexed: 12/12/2022]
Abstract
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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Affiliation(s)
- Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Muthusamy Thiruppathi
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Hatem A Elshabrawy
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Khaled Alharshawi
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
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Viennois E. Granulocyte-Macrophage Colony-Stimulating Factor-Activated Monocytes as an Anti-inflammatory Player in the Intestine. Cell Mol Gastroenterol Hepatol 2015; 1:354-355. [PMID: 28210687 PMCID: PMC5301284 DOI: 10.1016/j.jcmgh.2015.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Emilie Viennois
- Correspondence Address correspondence to: Emilie Viennois, PhD, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303.
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Weinhage T, Däbritz J, Brockhausen A, Wirth T, Brückner M, Belz M, Foell D, Varga G. Granulocyte Macrophage Colony-Stimulating Factor-Activated CD39 +/CD73 + Murine Monocytes Modulate Intestinal Inflammation via Induction of Regulatory T Cells. Cell Mol Gastroenterol Hepatol 2015; 1:433-449.e1. [PMID: 28210690 PMCID: PMC5301274 DOI: 10.1016/j.jcmgh.2015.04.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Granulocyte macrophage colony-stimulating factor (GM-CSF) treatment induces clinical response in patients with active Crohn's disease. To explore whether monocytes mediate GM-CSF effects in vivo, we used a mouse model of chronic colitis induced by dextran sulfate sodium (DSS). METHODS Murine bone marrow-derived monocytes were activated with GM-CSF in vitro, and gene expression, phenotype, and function of GM-CSF-activated monocytes (GMaM) were analyzed. Therapeutic effects of GMaM were assessed in a model of chronic colitis induced by repeated cycles of DSS. Monocytes were administered intravenously and their immunomodulatory functions were evaluated in vivo by clinical monitoring, histology, endoscopy, immunohistochemistry, and expression of inflammatory markers in the colon. The distribution of injected monocytes in the intestine was measured by in vivo imaging. RESULTS GMaM expressed significantly higher levels of anti-inflammatory molecules. Production of reactive oxygen species was also increased while phagocytosis and adherence were decreased. GMaM up-regulated CD39 and CD73, which allows the conversion of adenosine triphosphate into adenosine and coincided with the induction of Foxp3+ (forkhead-box-protein P3 positive) regulatory T cells (Treg) in cocultures of GMaM and naive T cells. In chronic DSS-induced colitis, adoptive transfer of GMaM led to significant clinical improvement, as demonstrated by reduced weight loss, inflammatory infiltration, ulceration, and colon shrinkage. As GMaM migrated faster and persisted longer in the inflamed intestine compared with control monocytes, their presence induced Treg generation in vivo. CONCLUSIONS GM-CSF leads to specific monocyte activation that modulates experimental colitis via mechanisms that include the induction of Treg. We demonstrate a possible mechanism of Treg induction through CD39 and CD73 expression on monocytes.
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Key Words
- ALDH, aldehyde dehydrogenase
- ATP, adenosine triphosphate
- Adaptive Immunity
- Arg1, arginase 1
- CD, Crohn’s disease
- CD39, E-NTPDase
- CD73, ecto-5′-nucleotidase
- CFSE, carboxyfluorescein succinimidyl ester
- DC, dendritic cells
- DSS, dextran sulfate sodium
- Dextran Sulfate Sodium
- Experimental Colitis
- FCS, fetal calf serum
- Foxp3, forkhead-box-protein P3
- GM-CSF
- GM-CSF, granulocyte macrophage colony-stimulating factor
- GMaM, granulocyte-macrophage colony-stimulating factor–activated monocytes
- IBD, inflammatory bowel disease
- IL, interleukin
- IL-1Ra, IL-1 receptor antagonist
- Immune Response
- Innate Immunity
- LPS, lipopolysaccharide
- MACS, magnetic-activated cell sorting
- MEICS, murine endoscopic index of colitis severity
- Monocyte
- NO, nitric oxide
- OD, optical density
- PBS, phosphate-buffered saline
- PCR, polymerase chain reaction
- RA, retinoic acid
- ROS, reactive oxygen species
- T Cell
- TNFα, tumor necrosis factor α
- Treg, regulatory T cells
- WT, wild type
- qRT-PCR, quantitative reverse-transcription polymerase chain reaction
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Affiliation(s)
- Toni Weinhage
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
- Correspondence Address correspondence to: Toni Weinhage, MSc, University Children’s Hospital Münster, Department of Pediatric Rheumatology and Immunology, Domagkstraße 3, D-48149 Münster, Germany. fax: +49 (0)251 8358104.
| | - Jan Däbritz
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
- The Royal Children’s Hospital Melbourne, Murdoch Children’s Research Institute, Gastrointestinal Research in Inflammation and Pathology, Parkville, Australia
- Interdisciplinary Centre of Clinical Research, University of Münster, Münster, Germany
- Department of Pediatrics, University of Melbourne, Melbourne Medical School, Parkville, Australia
| | - Anne Brockhausen
- Department of Translational Dermatoinfectiology, University of Münster, Münster, Germany
| | - Timo Wirth
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
| | - Markus Brückner
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
- Department of Medicine B, University Hospital Münster, Münster, Germany
| | - Michael Belz
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
- Department of Dermatology, University Hospital Münster, Münster, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
- Interdisciplinary Centre of Clinical Research, University of Münster, Münster, Germany
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster, Germany
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Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015; 2015:568543. [PMID: 25838639 PMCID: PMC4370199 DOI: 10.1155/2015/568543] [Citation(s) in RCA: 158] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/23/2015] [Indexed: 12/14/2022] Open
Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4+ T cells. Therefore, the mechanism of GM-CSF-producing CD4+ T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review.
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Hamilton JA. GM-CSF as a target in inflammatory/autoimmune disease: current evidence and future therapeutic potential. Expert Rev Clin Immunol 2015; 11:457-65. [PMID: 25748625 DOI: 10.1586/1744666x.2015.1024110] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) can be viewed as a pro-inflammatory cytokine rather than as a key regulator of steady state and systemic myelopoiesis. Key aspects of GM-CSF biology need to be clarified such as pro-survival vs activation/differentiation function, its cellular sources, its responsive cell populations, its downstream mediators/pathways, and when GM-CSF is relevant. Striking effects of GM-CSF depletion/deletion in some pre-clinical autoimmune/inflammation models have been reported. Systemic effects of administered GM-CSF are not necessarily informative about its local blockade in disease. Recent clinical RA trials, particularly Phase II trials with mavrilimumab (anti-GM-CSFRα Ab), show rapid and impressive efficacy with no significant adverse effects. Larger and longer trials targeting GM-CSF are needed and with careful monitoring of unwanted side effects. This review summarizes the most recent information on these topics.
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Affiliation(s)
- John A Hamilton
- Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia
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Däbritz J, Weinhage T, Varga G, Wirth T, Walscheid K, Brockhausen A, Schwarzmaier D, Brückner M, Ross M, Bettenworth D, Roth J, Ehrchen JM, Foell D. Reprogramming of monocytes by GM-CSF contributes to regulatory immune functions during intestinal inflammation. THE JOURNAL OF IMMUNOLOGY 2015; 194:2424-38. [PMID: 25653427 DOI: 10.4049/jimmunol.1401482] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell-induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn's disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.
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Affiliation(s)
- Jan Däbritz
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany; Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Gastrointestinal Research in Inflammation & Pathology, Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Parkville 3052, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne Medical School, Parkville 3052, Victoria, Australia;
| | - Toni Weinhage
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Timo Wirth
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Karoline Walscheid
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Anne Brockhausen
- Department of Dermatology, University Hospital Münster, Münster 48149, Germany; Institute of Immunology, University Hospital Münster, Münster 48149, Germany; and
| | - David Schwarzmaier
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Markus Brückner
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Matthias Ross
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Johannes Roth
- Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Institute of Immunology, University Hospital Münster, Münster 48149, Germany; and
| | - Jan M Ehrchen
- Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Department of Dermatology, University Hospital Münster, Münster 48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany; Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany
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Xu D, Zhao M, Song Y, Song J, Huang Y, Wang J. Novel insights in preventing Gram-negative bacterial infection in cirrhotic patients: review on the effects of GM-CSF in maintaining homeostasis of the immune system. Hepatol Int 2015; 9:28-34. [PMID: 25788376 DOI: 10.1007/s12072-014-9588-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 10/20/2014] [Indexed: 02/08/2023]
Abstract
Cirrhotic patients with dysfunctional and/or low numbers of leukocytes are often infected with bacteria, especially Gram-negative bacteria, which is characterized by producing lipopolysaccharide (LPS). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that influences the production, maturation, function, and survival of various immune cells. In this paper, we reviewed not only Toll-like receptors 4 (TLR4) signaling pathway and its immunological effect, but also the specific stimulating function and autocrine performance of GM-CSF on hematopoietic cells, as well as the recent discovery of innate response activator-B cells in protection against microbial sepsis and the direct LPS-TLR4 signaling on hematopoiesis. Thus we concluded that GM-CSF might play important roles in preventing Gram-negative bacterial infections in cirrhotic patients through maintaining immune system functions and homeostasis.
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Affiliation(s)
- Dong Xu
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
Intestinal mucosal barrier function is the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. The central element is the epithelial layer, which physically separates the lumen and the internal milieu and is in charge of vectorial transport of ions, nutrients, and other substances. The secretion of mucus-forming mucins, sIgA, and antimicrobial peptides reinforces the mucosal barrier on the extraepithelial side, while a variety of immune cells contributes to mucosal defense in the inner side. Thus, the mucosal barrier is of physical, biochemical, and immune nature. In addition, the microbiota may be viewed as part of this system because of the mutual influence occurring between the host and the luminal microorganisms. Alteration of the mucosal barrier function with accompanying increased permeability and/or bacterial translocation has been linked with a variety of conditions, including inflammatory bowel disease. Genetic and environmental factors may converge to evoke a defective function of the barrier, which in turn may lead to overt inflammation of the intestine as a result of an exacerbated immune reaction toward the microbiota. According to this hypothesis, inflammatory bowel disease may be both precipitated and treated by either stimulation or downregulation of the different elements of the mucosal barrier, with the outcome depending on timing, the cell type affected, and other factors. In this review, we cover briefly the elements of the barrier and their involvement in functional defects and the resulting phenotype.
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Systematic review: new serological markers (anti-glycan, anti-GP2, anti-GM-CSF Ab) in the prediction of IBD patient outcomes. Autoimmun Rev 2014; 14:231-45. [PMID: 25462578 DOI: 10.1016/j.autrev.2014.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 11/08/2014] [Indexed: 12/20/2022]
Abstract
Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.
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McDermott AJ, Frank CR, Falkowski NR, McDonald RA, Young VB, Huffnagle GB. Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa during Clostridium difficile infection in mice. Gut Microbes 2014; 5:476-84. [PMID: 25045999 PMCID: PMC5915364 DOI: 10.4161/gmic.29964] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Clostridium difficile infection in antibiotic-treated mice results in acute colitis characterized by severe intestinal histopathology, robust neutrophil influx, and increased expression of numerous inflammatory cytokines, including GM-CSF. We utilized a neutralizing monoclonal antibody (mAb) against GM-CSF in a murine model to study the role of GM-CSF during acute C. difficile colitis. Cefoperazone-treated mice were challenged with C. difficile (strain 630) spores. Expression of GM-CSF was significantly increased in animals challenged with C. difficile. Treatment with an anti-GM-CSF mAb did not alter C. difficile colonization levels, weight loss, or expression of IL-22 and RegIIIγ. However, expression of the inflammatory cytokines TNFα and IL-1β, as well as iNOS, was significantly reduced following anti-GM-CSF treatment. Expression of the neutrophil chemokines CXCL1 and CXCL2, but not the chemokines CCL2, CCL4, CXCL9, and CXCL10, was significantly reduced by anti-GM-CSF treatment. Consistent with a decrease in neutrophil-attractant chemokine expression, there were fewer neutrophils in histology sections and a reduction in the expression of secretory leukocyte protease inhibitor (SLPI), a tissue anti-protease that protects against damage by secreted neutrophil elastase. These data indicate that GM-CSF plays a role in the inflammatory signaling network that drives neutrophil recruitment in response to C. difficile infection but does not appear to play a role in clearance of the infection.
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Affiliation(s)
- Andrew J McDermott
- Department of Microbiology and Immunology; University of Michigan Medical School; Ann Arbor, MI USA
| | - Charles R Frank
- Division of Pulmonary and Critical Care Medicine; Department of Internal Medicine; University of Michigan Medical School; Ann Arbor, MI USA
| | - Nicole R Falkowski
- Division of Pulmonary and Critical Care Medicine; Department of Internal Medicine; University of Michigan Medical School; Ann Arbor, MI USA
| | - Roderick A McDonald
- Division of Pulmonary and Critical Care Medicine; Department of Internal Medicine; University of Michigan Medical School; Ann Arbor, MI USA
| | - Vincent B Young
- Department of Microbiology and Immunology; University of Michigan Medical School; Ann Arbor, MI USA,Division of Infectious Diseases; Department of Internal Medicine; University of Michigan Medical School; Ann Arbor, MI USA
| | - Gary B Huffnagle
- Department of Microbiology and Immunology; University of Michigan Medical School; Ann Arbor, MI USA,Division of Pulmonary and Critical Care Medicine; Department of Internal Medicine; University of Michigan Medical School; Ann Arbor, MI USA,Correspondence to: Gary B Huffnagle;
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