Granulocyte Macrophage Research Articles

Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency.

BackgroundThe role of inflammation in superficial venous reflux in varicose veins (VVs) is unknown. Computational network modeling has deduced inflammation in experimental and clinical settings. We measured immune mediators in plasma from competent and incompetent leg veins inferring the role of cellular immunity based on cytokine networks.MethodsTemperature was assessed using infrared thermography (IRT) to measure inflammation. Blood was obtained during sclerotherapy or endovenous thermal ablation for VVs. Control subjects underwent phlebotomy from saphenous and forearm veins. Vein segments were harvested during surgery. Demographics, clinical, etiology, anatomy and pathophysiology classification, venous clinical severity scores (VCSSs), and body mass index (BMI) were collected. Twenty-five mediators were measured in serum and vein segments. Means were compared using Mann-Whitney U test. Pearson correlations equaling or exceeding a threshold prompted connections among nodes, and mapped as networks. Spearman correlations were performed between interleukin (IL)-17A and both granulocyte macrophage colony stimulation factor, and IL-10 as indicators of pathogenic and nonpathogenic Th17 cell involvement.ResultsAge, BMI, and VCSSs differed significantly between groups. Temperatures were higher over diseased veins. Plasma concentrations of 20 cytokines differed between control and patient subjects (P<0.05), and most were lower in patients. C-X-C motif chemokine ligand-9 (aka monokine-induced by gamma interferon), C-X-C motif chemokine ligand 10 (aka IFNγ induced protein 10), and soluble IL-2 receptor-alpha were higher in patients, but not connected to other mediators in networks. In contrast, IL-17A, IL-12p70, and interferon gamma were the only mediators that were more highly interconnected in venous insufficiency. IL-17A and granulocyte macrophage colony stimulating factor (GM-CSF) were highly correlated in chronic venous insufficiency (CVI) but not in controls. In tissue, refluxing VVs significantly higher IL-15 expression than competent saphenous veins.ConclusionsVenous insufficiency associates with age, BMI, skin temperature, and plasma cytokines associated with interferon gamma and possibly IL-17A signaling. The vein wall may be a source of activation of cellular activation, given elevated IL-15 expression. Correlations between IL-17A and GM-CSF suggested a potential role for pathogenic Th17 cells in VVs. Differentially expressed inflammatory networks induced by venous hypertension may reflect or drive venous damage and ulceration.

Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review.

This study reports the clinical manifestations, genetics, and efficacy of treatment with the efficacy of recombinant human granulocyte macrophage colony-stimulating factor (rhGM-GSF) of a 2-year-old female patient with severe congenital neutropenia (SCN) type 7 (SCN7) caused by novel biallelic mutations in the colony-stimulating factor 3 receptor (CSF3R) gene. Genetic diagnosis of the patient was performed by whole-exome and Sanger sequencing. Expression of the CSF3R gene in the peripheral neutrophils of the patient was detected by real-time PCR and Western blotting. The patient presented with recurrent suppurative tonsillitis and decreased absolute neutrophil count <0.5 × 109/L. Novel heterozygous mutations were found to be inherited from each parent (maternal c.690delC [p.met231Cysfs*32] and paternal c.64+5G>A). The patient's neutrophils had lower CSF3R mRNA and protein levels than those of the parents. Low-dose rhGM-CSF (3 μg/kg/day once a week) prevented recurrent infection in the patient. These results demonstrate that the clinical manifestations of SCN7 with biallelic CSF3R mutations and downregulated CSF3R can be effectively treated with rhGM-CSF.

MiR-124-3p relieves allergic rhinitis by inhibiting dipeptidyl peptidase-4

MicroRNA-124-3p (miR-124-3p) and dipeptidyl peptidase-4 (DPP4) are closely related to the development of inflammation. Allergic rhinitis (AR) models in mice and HNEpC cells were established. AR progression was assessed assessing by the frequency of nasal rubbing and sneezing, hematoxylin and eosin (HE), and TUNEL staining. Tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), granulocyte–macrophage colony-stimulating factor (GM-CSF), eotaxin, and MUC5AC were assessed by enzyme-linked immunosorbent assay and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Apoptosis in HNEpC cells was assessed using flow cytometry. DPP4, activated-caspase-3, and pro-caspase-3 protein expression were evaluated by western blotting. In addition, we clarified the influence of miR-124-3p-targeted DPP4 on AR inflammation and cell injury. MiR-124-3p was downregulated in AR nasal mucosa tissue. Upregulation of miR-124-3p reduced the frequency of nasal rubbing and sneezing, pathological changes, eosinophil number, and apoptosis of nasal mucosa, TNF-α and IL-6 protein and mRNA levels in serum and HNEpC cells, and MUC5AC, eotaxin, and GM-CSF levels in HNEpC cells. Downregulation of miR-124-3p has the opposite effect. Therefore, the miR-124-3p /DPP4 axis may be an attractive target for AR therapy.

Double Recombinant Vaccinia Virus: A Candidate Drug against Human Glioblastoma.

Glioblastoma is one of the most aggressive brain tumors. Given the poor prognosis of this disease, novel methods for glioblastoma treatment are needed. Virotherapy is one of the most actively developed approaches for cancer therapy today. VV-GMCSF-Lact is a recombinant vaccinia virus with deletions of the viral thymidine kinase and growth factor genes and insertions of the granulocyte–macrophage colony-stimulating factor and oncotoxic protein lactaptin genes. The virus has high cytotoxic activity against human cancer cells of various histogenesis and antitumor efficacy against breast cancer. In this work, we show VV-GMCSF-Lact to be a promising therapeutic agent for glioblastoma treatment. VV-GMCSF-Lact effectively decreases the viability of glioblastoma cells of both immortalized and patient-derived cultures in vitro, crosses the blood–brain barrier, selectively replicates into orthotopically transplanted human glioblastoma when intravenously injected, and inhibits glioblastoma xenograft and metastasis growth when injected intratumorally.

Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.

Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis

ObjectivesThis study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of...

RETRACTED ARTICLE: Expression and preliminary characterization of the potential vaccine candidate LipL32 of leptospirosis.

Leptospirosis is a globally re-emerging infectious disease mainly for mammals. The infection is caused by the spirochete Gram-negative bacterium Leptospira interrogans, which affects animals and humans worldwide. In our previous studies, recombinant protein production has been obtained from the bacterial expression system. In this study, we have investigated the over expression of LipL32 and hGMCSF genes into yeast expression system for obtaining a high yield of recombinant protein production. Here, we described the yeast expression studies with several applications such as protein folding, fast growth, and post-translational modification. The expression studies were carried out in a novel protein expression system, the methylotrophic yeast Pichia pastoris KM71 strain. The LipL32, Green fluorescent protein (EGFP), and human granulocyte–macrophage colony-stimulating factor (hGMCSF) genes were cloned into pPIC9 yeast expression vector. The recombinant clones of pPIC9-EGFP-LipL32 and pPIC9-EGFP-hGMCSF-LipL32 were transformed into Pichia pastoris KM71 strain by electroporation. Media optimization and other physiological characters were studied for the transformed recombinant protein. The protein was then purified using a Ni–NTA column; meanwhile, the recombinant DNA constructs contain His-tag at the C- terminal end. Finally, the intracellular EGFP expression of pPIC9-EGFP-LipL32, and pPIC9-EGFP-hGMCSF-LipL32 in Pichia pastoris KM71 strain was confirmed by fluorescence microscopic analysis. Protein–protein dockings were done to study LipL32-Adjuvant (hGMCSF, hIgGFC, and hC3d) interactions. Furthermore, this docking analysis was shown better interaction between LipL32, and hGMCSF, which is also used for the enhanced vaccine potential against leptospirosis.

Impact of tribocorrosion and titanium particles release on dental implant complications - A narrative review.

Titanium particles as a product of degradation have been detected in periimplant oral tissues and it has been assumed that implants were the source of these particles. Periimplantitis sites had higher concentrations of particles in comparison to healthy implant sites. Several factors have been identified in the degradation of dental implant surface, such as mechanical wear, contact with chemical agents, and the effects of biofilm adhesion. Titanium particles silently prompt the immune-system activation and generate a pro-inflammatory response in macrophages, T lymphocytes and monocytes. During the activation, inflammatory cytokines are released including, granulocyte–macrophage colony-stimulating factor (GM-CSF), prostaglandin, and TNF-α, IL-1β, IL-6. The nanoparticles depict unique features such as high level of biological reactivity and potentially harmful compared to microparticles since they have a relatively greater surface area to volume ratio. Allergic response to titanium as a cause of implant failure has not been well documented. Evidence demonstrating biological complication due to titanium particles release includes peri-implant tissue inflammation that lead terminally to implant loss. There is a biological probability for a relation between the presence of titanium particles and ions, biological complication, and corrosion, but there is no justifiable evidence for unidirectional series of causative actions.

Myeloid-Derived Suppressor Cells Alleviate Renal Fibrosis Progression via Regulation of CCL5-CCR5 Axis.

BackgroundRenal fibrosis is inevitable in all progressive chronic kidney diseases (CKDs) and represents a serious public health problem. Immune factors contribute to the progression of renal fibrosis. Thus, it is very possible that immunosuppression cells, such as myeloid-derived suppressor cells (MDSCs), could bring benefits to renal fibrosis. Herein, this study investigated the antifibrotic and reno-protective effect of MDSCs and the possible mechanisms.MethodsMurine and cell models of unilateral ureter obstruction (UUO) renal fibrosis were used. Bone marrow-induced MDSCs and granulocyte–macrophage colony-stimulating factor (GM-CSF) were pretreated before surgery. Kidney weight, pathological injury, extracellular matrix deposition, and epithelial–mesenchymal transition progression were examined. Transforming growth factor (TGF)-β1)/Smad/Snail signaling pathway involvement was investigated through Western blotting and quantitative PCR (qPCR). Accumulation of MDSC, CD4+ T cell, regulatory T (Treg), and T helper 1 (TH1) cell accumulation, and CCL5 and CCR5 expression level in MDSCs and non-MDSCs were evaluated using flow cytometry.ResultsIn vitro- and in vivo-induced MDSCs significantly ameliorated UUO-induced tubulointerstitial fibrosis, inhibited the TGF-β1/Smad/Snail signaling pathway, and enhanced MDSC and Treg infiltration in the kidney while downregulating the TH1 cells. Both in vitro and in vivo experiments confirmed CCL5 elevation in the two MDSC-treated groups.Conclusion In vitro- and in vivo-induced MDSCs alleviated renal fibrosis similarly through promoting the CCL5–CCR5 axis interaction and TGF-β1/Smad/Snail signaling pathway inhibition. Our results indicate an alternative treatment for renal fibrosis.

Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13.

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.

1094TiP A randomized, controlled, open-label, phase II study of cemiplimab as a single agent and in combination with RP1 in patients with advanced cutaneous squamous cell carcinoma [CERPASS

Prognosis of advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains dismal. The anti-PD1 antibody cemiplimab was the first agent approved for the treatment of advanced CSCC. RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity. In preliminary study, high response rates including complete response have been observed in patients with CSCC treated with RP1 combined with nivolumab.

1093TiP An open-label, multicenter, phase I/II clinical trial of RP1 as a single agent and in combination with nivolumab in patients with solid tumors [IGNYTE

RP1 is an enhanced potency oncolytic HSV-1 which expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). Pre-clinical studies with RP1 demonstrated potent GALV-GP R-enhanced anti-tumor activity and immunogenic cell death. This phase I/II (Ph I/II) study (NCT03767348) was designed to evaluate the safety and efficacy of RP1 as single agent and in combination with nivolumab (nivo) in pts with advanced solid tumors, including pts whose disease failed prior anti-PD1/PD-L1 therapy.

GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity

ObjectiveIntrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations...

Staphylococcus aureus Protection-Related Type 3 Cell-Mediated Immune Response Elicited by Recombinant Proteins and GM-CSF DNA Vaccine.

Staphylococcus aureus mastitis remains a major challenge for dairy farming. Here, 24 mice were immunized and divided into four groups: G1: control; G2: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) DNA vaccine; G3: F0F1 ATP synthase subunit α (SAS), succinyl-diaminopimelate (SDD), and cysteinyl-tRNA synthetase (CTS) recombinant proteins; and G4: SAS+SDD+CTS plus GM-CSF DNA vaccine. The lymphocyte subpopulations, and the intracellular interleukin-17A (IL-17A) and interferon-γ production in the draining lymph node cells were immunophenotyped by flow cytometry. The immunophenotyping and lymphocyte proliferation was determined in spleen cells cultured with and without S. aureus stimulus. Immunization with S. aureus recombinant proteins generated memory cells in draining lymph nodes. Immunization with the three recombinant proteins plus GM-CSF DNA led to an increase in the percentage of IL-17A+ cells among overall CD44+ (memory), T CD4+, CD4+ T CD44+ CD27−, γδ TCR, γδ TCR+ CD44+ CD27+, and TCRVγ4+ cells. Vaccination with S. aureus recombinant proteins associated with GM-CSF DNA vaccine downregulated TH2 immunity. Immunization with the three recombinant proteins plus the GM-CSF DNA led to a proliferation of overall memory T, CD4+, and CD4+ TEM cells upon S. aureus stimulus. This approach fostered type 3 immunity, suggesting the development of a protective immune response against S. aureus.

Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal.

Malarial pigment hemozoin (HZ) generates the lipoperoxidation product 4-hydroxynonenal (4-HNE), which is known to cause dysregulation of the immune response in malaria. The inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent differentiation of dendritic cells (DC) by HZ and 4-HNE was previously described in vitro, and the GM-CSF receptor (GM-CSF R) was hypothesised to be a primary target of 4-HNE in monocytes. In this study, we show the functional impact of HZ on GM-CSF R in monocytes and monocyte-derived DC by (i) impairing GM-CSF binding by 50 ± 9% and 65 ± 14%, respectively (n = 3 for both cell types); (ii) decreasing the expression of GM-CSF R functional subunit (CD116) on monocyte’s surface by 36 ± 11% (n = 6) and in cell lysate by 58 ± 16% (n = 3); and (iii) binding of 4-HNE to distinct amino acid residues on CD116. The data suggest that defective DC differentiation in malaria is caused by GM-CSF R dysregulation and GM-CSF R modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit.

A Functional GM-CSF Receptor on Dendritic Cells Is Required for Efficient Protective Anti-Tumor Immunity

Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.

NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence

During skin injury, immune response and repair mechanisms have to be coordinated for rapid skin regeneration and the prevention of microbial infections. Natural Killer (NK) cells infiltrate hypoxic skin lesions and Hypoxia-inducible transcription factors (HIFs) mediate adaptation to low oxygen. We demonstrate that mice lacking the Hypoxia-inducible factor (HIF)-1α isoform in NK cells show impaired release of the cytokines Interferon (IFN)-γ and Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) as part of a blunted immune response. This accelerates skin angiogenesis and wound healing. Despite rapid wound closure, bactericidal activity and the ability to restrict systemic bacterial infection are impaired. Conversely, forced activation of the HIF pathway supports cytokine release and NK cell-mediated antibacterial defence including direct killing of bacteria by NK cells despite delayed wound closure. Our results identify, HIF-1α in NK cells as a nexus that balances antimicrobial defence versus global repair in the skin.

Dinutuximab (Unituxin)

&#x0D; CADTH recommends that Unituxin (in combination with irinotecan, temozolomide, and granulocyte macrophage colony-stimulating factor [GM-CSF]) should be reimbursed by public drug plans for the treatment of patients with relapsed or refractory high-risk neuroblastoma if certain conditions are met.&#x0D; Unituxin should only be reimbursed if delivered in a specialized pediatric cancer centre by health care professionals with experience and knowledge of managing neuroblastoma and the toxicities of anti-GD2 therapy and if the cost of Unituxin is reduced.&#x0D; Unituxin should only be covered for patients who have not had previous treatment for relapsed or refractory high-risk neuroblastoma or have not had a severe reaction or progressive disease with upfront anti-GD2 immunotherapy.&#x0D;

Inflammatory factors are crucial for the pathogenesis of post-traumatic osteoarthritis confirmed by a novel porcine model: “Idealized” anterior cruciate ligament reconstruction” and gait analysis

ObjectiveTo determine whether idealized anterior cruciate ligament reconstruction (IACL-R) restores normal gait features, and whether inflammatory factors are involved in the pathogenesisof post-traumatic osteoarthritis (PTOA). MethodsFourteen mature female minipigs were allocated to a sham group (n = 7) or an IACL-R group (n = 7). Load asymmetry during gait was recorded using a pressure-sensing walkway measurement system to evaluate the gait features of the right knee joint before and after surgery. Inflammatory factors (including interleukin [IL]-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, tumor necrosis factor-α, and granulocyte–macrophage colony-stimulating factor) in synovial fluid were measured using Luminex assays before and after surgery. Cartilage integrity and the subchondral bone plate of the right knee were evaluated using histology and imaging at 3 months postoperatively. ResultsSwing time and stance time returned to their preoperative values on day 31, while maximum force, contact area, peak force ,and impulse returned to their preoperative values on day 45 after the surgery in the IACL-R group (P = 0.073, 0.053, 0.107, 0.052, 0.152, and 0.059, respectively).Thus, IACL-R restored normal gait. Compared with their preoperative concentrations, all tested inflammatory factors showed significantly increased concentrations in the synovial fluid in the IACL-R group, especially at 3, 7, and 15 days postoperatively. X-ray, computed tomography, magnetic resonance imaging, and histological data showed severe cartilage damage in the IACL-R model. ConclusionIACL-R restored normal gait features but caused significant cartilage damage, indicating that significantly elevated inflammatory factors maybe crucial for the pathogenesis of PTOA.

Emerging Evidence for Pleiotropism of Eosinophils.

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.