Chemokine expression in murine experimental allergic encephalomyelitis

Godiska, Ronald; Chantry, David; Dietsch, Gregory N.; Gray, Patrick W.

doi:10.1016/0165-5728(95)00008-p

Cited by 338 publications

(240 citation statements)

References 44 publications

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“…The C-C chemokine RANTES (CCL5) attracts monocytes, activated T-cells and immature dendritic cells during inflammation and immune responses, suggesting a role for RANTES in virus-related diseases [86]. Of special interest, RANTES expression in microglia correlates with the initial symptoms of experimental autoimmune encephalomyelitis [87,88] and the chemokine, together with IP-10, MCP-3 and MCP-5, contributes to the distinct Th1 islet inflammatory infiltrate leading to beta-cell destruction in NOD.scid mice infused with islet-specific TCR transgenic CD4 cells [89].…”

Section: Discussionmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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Section: Discussionmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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“…Tumor necrosis factor-α increased the motility of neural precursors in vitro [99]. Several chemokines were shown to be expressed in the inflamed brain [272]. Among these, stromal derived factor 1 was shown to induce neural stem/ precursor cells migration in stroke [100,101], viralinduced demyelination [102], and trauma [103].…”

Section: Route Of Cell Deliverymentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…The T cell and monocyte/macrophage-attracting chemokines CXCL10 (IFN/IP-10) and CCL5 (regulated upon activation T cell expressed and secreted, RANTES) are increased in WT EAE, but are not prominent in GKO EAE. Conversely, expression of the neutrophil-attracting CXCL2 (MIP-2) is elevated in GKO but not WT EAE (23)(24)(25). We have proposed that IFN-␥ influences chemokine profiles in the CNS, although direct cause and effect have not been established.…”

Section: Ifn-␥-induced Chemokines Synergize With Pertussis Toxin To Pmentioning

confidence: 99%

“…However, AdIFN␥ did not induce expression beyond baseline levels of other chemokines, including CXCL2, CCL2/ MCP-1, or CCL3/MIP-1␣ (data not shown). These chemokines have been implicated in CNS inflammatory responses (25,30,39,40), and their absence in this system suggests that other signals in addition to IFN-␥ are required for immune pathology.…”

Section: Intrathecal Ifn-␥ Induces Selective Chemokine Expression In Cnsmentioning

confidence: 99%

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Millward

Caruso

Campbell

et al. 2007

The Journal of Immunology

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Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-γ, a cytokine not normally expressed in the CNS. To investigate the role of IFN-γ in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-γ (AdIFNγ) to IFN-γ-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-γ that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-γ induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-γR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-γ-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-γ vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-γ induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-γ-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.

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Chemokine expression in murine experimental allergic encephalomyelitis

Cited by 338 publications

References 44 publications

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Cell Therapy for Multiple Sclerosis

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

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