MIP-3β/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs
TL;DR: CCL19 CSF concentrations were markedly elevated in patients affected with the neuroinflammatory diseasesSRMA and MUO and showed a strong correlation with the CSF cell count, suggesting this chemokine may play an important role in the pathogenesis of SRMA andMUO.
Abstract: Background
Chemokines such as MIP-3β/CCL19 are important factors in the mechanism of cell migration and pathogenesis of central nervous system (CNS) inflammatory reactions. The hypothesis of this study is that CCL19, also known as MIP-3β, is involved in the pathogenesis of inflammatory and non-inflammatory CNS diseases of dogs. Experiments were performed on cerebrospinal fluid (CSF) and serum samples of dogs affected with steroid responsive meningitis-arteritis (SRMA) during the acute phase as well as during treatment. Dogs with SRMA were compared to dogs with presumed meningoencephalomyelitis of unknown origin (MUO), and both groups sub-categorized into dogs receiving no therapy and with patients receiving prednisolone therapy. Idiopathic epilepsy (IE), a group with normal CSF cell count, was used as a control. Additionally, dogs with intervertebral disc disease (IVDD) of varying severity were analyzed. Chemokine concentrations were determined by enzyme linked immunosorbent assay. Migration assays were performed on seven selected CSF samples using a disposable 96-well chemotaxis chamber.
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TL;DR: Companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies, however, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models.
Abstract: Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729.
128 citations
TL;DR: A review of immunosuppressive and immunomodulatory therapies for spinal cord injury can be found in this article, where the positive and negative attributes of the innate and adaptive immune systems in neuroinflammation after SCI are discussed.
35 citations
TL;DR: 10 blood-based biomarkers were selected as most promising biomarkers for HGG: α2-Heremans-Schmid glycoprotein (AHSG, AHSG), albumin, glucose, insulin-like growth factor- binding protein 2 (IGFBP-2), macrophage inflammatory protein 1δ (MIP-1 δ, macrophages inflammatory protein 3ß, neutrophil-lymphocyte ratio (NLR), red blood cell distribution width
Abstract: High-grade gliomas (HGG) are the most common malignant primary brain tumor in adults. During the course of disease, several challenges occur, like measuring tumor burden, monitoring of treatment response, estimating the patient's prognosis, and distinguishing between true progression and pseudo-progression. So far, no blood-based biomarker has been established in the clinical routine to address these challenges. The aim of this systematic review was to analyze the present evidence on blood-based biomarkers for HGG. We systematically searched in PubMed, Web of Sciences, Scopus, and Cochrane Library databases for publications before 30th of March 2018 reporting on associations of blood-based biomarkers in HGG patients with different endpoints as overall survival, progression-free survival, and postoperative monitoring. Quality assessment of the studies according to QUIPS and STARD guidelines was performed. In accordance with the GRADE guidelines, level of evidence (I-IV) for each of the tested biomarkers was assessed. One thousand six hundred eighty unique records were identified. Of these, 170 original articles were included to this review. Four hundred fifteen different blood-based biomarkers analyzed in 15.041 patients with HGG as also their corresponding recurrent tumors. Ten predictive biomarkers reached level II of evidence. No biomarker achieved level I of evidence. In this review, 10 blood-based biomarkers were selected as most promising biomarkers for HGG: α2-Heremans-Schmid glycoprotein (AHSG), albumin, glucose, insulin-like growth factor- binding protein 2 (IGFBP-2), macrophage inflammatory protein 1δ (MIP-1 δ), macrophage inflammatory protein 3s (MIP-3s), neutrophil-lymphocyte ratio (NLR), red blood cell distribution width (RDW), soluble glycoprotein 130 (Sgp130), and chitinase-3-like protein 1 (YKL-40). To further assess the clinical significance of these biomarkers, the evaluation in a larger cohort of HGG and their corresponding subgroups would be necessary.
15 citations
TL;DR: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.
Abstract: Objective: To screen cytokines and chemokines and determine their dynamic changes in the serum and cerebrospinal fluid (CSF) of patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Eight NMOSD with seropositive aquaporin-4 antibody (AQP4-IgG) were enrolled, as well as 8 matched patients with multiple sclerosis (MS) and 8 with noninflammatory neurological diseases, who were included as controls. In total, 102 cytokines and 34 chemokines were detected in the CSF and serum of NMOSD patients and controls. Results: CSF interleukin (IL)-17A levels were significantly higher in NMOSD patients in the relapsing phase (27.15 ± 11.33) than in those in the remitting phase (10.04 ± 3.11, p = 0.0017), and patients with MS (14.72 ± 3.20, p = 0.0283) and other controls (10.39 ± 11.38, p = 0.0021). CSF IL-6 levels were higher in the NMOSD patients in the relapsing phase (12.23 ± 3.47) than in those in the remitting phase (5.87 ± 2.78, p = 0.0001), and MS patients (7.38 ± 2.35, p = 0.0033) and other controls (7.50 ± 0.37, p = 0.0043). CSF CCL19 levels were also significantly higher in NMOSD patients in the relapsing phase (35.87 ± 27.07) than in those in the remitting phase (10.71 ± 3.62, p = 0.0215). Serum IL-19 levels were lower in NMOSD patients in the relapsing phase (6.23 ± 1.95) than in those in the remitting phase (10.72 ± 4.46, p = 0.0092). Further, there was a positive, significant correlation between serum IL-9 concentration and the Expanded Disability Status Scale score in the NMOSD patients in the relapsing phase ( p = 0.04). Conclusion: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis.
14 citations
TL;DR: It is demonstrated that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PM SCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes.
Abstract: Canine inflammatory brain disease (IBD) is a severe inflammatory disorder characterized by infiltration of activated immune cell subsets into the brain and spinal cord. Multipotent mesenchymal stromal cells (MSCs) are a promising therapy for IBD, based on their potent pro-angiogenic, neuroprotective, and immunomodulatory properties. The aims of this study were to compare the immunomodulatory attributes of canine adipose-derived MSCs (ASCs) and placenta-derived MSCs (PMSCs) in vitro. These data will serve as potency information to help inform the optimal MSC cell source to treat naturally occurring canine IBD. Indoleamine 2,3 dioxygenase (IDO) activity and prostaglandin E2 (PGE2) concentration at baseline and after stimulation with interferon gamma (IFNγ) and/or tumor necrosis factor alpha (TNFα) were measured from canine ASC and PMSC cultures. Leukocyte suppression assays (LSAs) were performed to compare the ability of ASCs and PMSCs to inhibit activated peripheral blood mononuclear cell (PBMC) proliferation. IDO activity and PGE2; interleukin (IL)-2, IL-6, and IL-8; TNFα; and vascular endothelial growth factor (VEGF) concentrations were also measured from co-culture supernatants. Cell cycle analysis was performed to determine how ASCs and PMSCs altered lymphocyte proliferation. Activated canine MSCs from both tissue sources secreted high concentrations of IDO and PGE2, after direct stimulation with IFNγ and TNFα, or indirect stimulation by activated PBMCs. Both ASCs and PMSCs inhibited activated PBMC proliferation in LSA assays; however, PMSCs inhibited PBMC proliferation significantly more than ASCs. Blocking PGE2 and IDO in LSA assays determined that PGE2 is important only for ASC inhibition of PBMC proliferation. Activated ASCs increased IL-6 and VEGF secretion and decreased TNFα secretion, while activated PMSCs increased IL-6, IL-8, and VEGF secretion. ASCs inhibited lymphocyte proliferation via cell cycle arrest in the G0/G1 and PMSCs inhibited lymphocyte proliferation via induction of lymphocyte apoptosis. Our results demonstrate that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PMSCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes. These data suggest that the mechanism by which ASCs and PMSCs downregulate PBMC proliferation differs. Additional studies may elucidate additional mechanisms by which canine MSCs modulate neuroinflammatory responses.
10 citations
References
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TL;DR: Methods that are developed to accurately measure function after spinal cord injury in dogs and may have parallels in the development of veterinary models to test putative therapies for other diseases of humans and animals are described.
Abstract: Many interventions have been shown to improve outcome after experimental spinal cord injury in laboratory animals. The challenge now is to determine whether any of these can be translated to become an efficacious therapy for clinical lesions – a process that is often difficult and frequently fails. Here, we discuss the steps that are required to make this transition and the need for rigorous clinical trials. A key component is an outcome measure that is amenable to statistical analysis; we describe methods that we have developed to accurately measure function after spinal cord injury in dogs. The general methodology may have parallels in the development of veterinary models to test putative therapies for other diseases of humans and animals.
43 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...One aim of therapeutic research is to develop specific treatments to modulate the inflammatory response within the CNS [7] in diseases such as SRMA and meningoencephalitides of unknown origin (MUO), and also modulate inflammation in intervertebral disc diseases which may be responsible for secondary wave injury [8-10]....
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TL;DR: The results support the utility of this high-density canine whole-genome array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.
Abstract: Due to their unique population structure, purebred dogs have emerged as a key model for the study of complex genetic disorders. To evaluate the utility of a newly available high-density canine whole-genome array with >170,000 single nucleotide polymorphisms (SNPs), genome-wide association was performed on a small number of case and control dogs to determine disease susceptibility loci in canine necrotizing meningoencephalitis (NME), a disorder with known non-Mendelian inheritance that shares clinical similarities with atypical variants of multiple sclerosis in humans. Genotyping of 30 NME-affected Pug dogs and 68 healthy control Pugs identified 2 loci associated with NME, including a region within dog leukocyte antigen class II on chromosome 12 that remained significant after Bonferroni correction. Our results support the utility of this high-density SNP array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.
40 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...Examples of idiopathic inflammatory disorders of the CNS are NE and GME, in which a strong genetic component [27], occurrence of autoantibodies [28], and the distribution of lymphocytes and macrophages [29], suggest a strong involvement of mononuclear cells in the pathogenesis....
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TL;DR: The complexity emerged from the signaling networks controlling integrin activation and the differences observed in the adhesion mechanisms between leukocyte subtypes and between vascular districts, suggest that future therapies designed to interfere with signal transduction pathways involved in integrin-dependent adhesion may be useful in treating inflammatory diseases of the central nervous system (CNS).
39 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...They up-regulate surface molecules on circulating inflammatory cells in the periphery which enable them to more efficiently adhere to the endothelial cells of the blood– brain barrier (BBB) and react to the CNS chemokine gradients [6]....
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TL;DR: The histopathology of the lesions caused by these conditions and the inflammatory cell populations produced in response to them were examined among dogs affected with GME, NME, or NLE to understand their pathogeneses.
Abstract: In dogs, there are several idiopathic meningoencephalitides, such as necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME). Al...
39 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...Examples of idiopathic inflammatory disorders of the CNS are NE and GME, in which a strong genetic component [27], occurrence of autoantibodies [28], and the distribution of lymphocytes and macrophages [29], suggest a strong involvement of mononuclear cells in the pathogenesis....
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TL;DR: Chemokine and chemokine receptor expression is tightly interrelated to composition of inflammatory cells in CNS lesions and the onset of clinical diseases and provide viable targets for therapeutic intervention.
Abstract: This article focuses on the distinct role of chemokines and chemokine receptors during CNS inflammation in experimental autoimmune encephalomyelitis (EAE) as an animal model for multiple sclerosis (MS). We review the evidence that chemokines and chemokine receptors have an intrinsic role in regulating and amplifying the inflammatory reactions in EAE or MS leading to disease outcome. A variety of studies examining temporal chemokine expression patterns, using chemokine and chemokine receptor knockout mice as well as administering passive anti-chemokine antibodies indicates that these molecules are critical regulatory components for leukocyte recruitment and/or leukocyte retention in the CNS. Therefore, chemokine and chemokine receptor expression is tightly interrelated to composition of inflammatory cells in CNS lesions and the onset of clinical diseases and provide viable targets for therapeutic intervention.
35 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...Chemokines are important factors in the mechanism of cell migration and thus play a relevant role in the pathogenesis of inflammation within the CNS [5]....
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