CNS dendritic cells: Critical participants in CNS inflammation?

McMahon, Eileen; Bailey, Samantha; Miller, Stephen D.

doi:10.1016/j.neuint.2006.04.004

Cited by 89 publications

(61 citation statements)

References 87 publications

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“…CCR7 expressed by naïve T cells and DCs is necessary for these cells to enter lymph nodes (Pahuja et al, 2006). Challenge with innate antigen and protein antigens induces CCR7 expression by microglia in vitro and in vivo suggesting that microglia develops into a DC like antigen-presenting cell with migratory potential (Dijkstra et al, 2006;McMahon et al, 2006). Together these data suggest that DCs may arise from both circulating precursors and glial cells.…”

Section: Discussionmentioning

confidence: 91%

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

Cudrici

Ito

Zafranskaia

et al. 2007

Experimental and Molecular Pathology

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We have analyzed the localization of dendritic cells (DCs) in non-lesional gray matter (NLGM) in comparison to non-lesional white matter (NLWM) and acute or chronic active multiple sclerosis (MS) lesions. Immunohistochemistry was performed on cryostat sections for DCs markers (CD209, CD205, CD83) and other markers for inflammatory cells (CD68, CD8, CD4, CD3, CCR7, CCR5). We found cells expressing CD209 and containing myelin basic protein in both perivascular and parenchymal areas of NLGM. Our findings showing the expression of CD209 + cells in NLGM parenchymal areas are surprising relative to the previous literature which reported the presence of CD209 + DCs only in MS plaque perivascular areas. Although less numerous than CD209 + cells, NLGM cells expressing mature DCs marker CD205 were consistently detected in perivascular cuffs of most lesions. In double labeling experiments, some but not all of the CD209 + cells also expressed CD68 and CCR5. We also found CD209 + cells in close contact with CD3 + lymphocytes suggesting that DCs might contribute to the local activation of pathogenic T cells in the NLGM. Since injury to the NLGM is one of the key factors associated with disability accumulation, targeting DCs may represent a possible new therapeutic approach in MS to prevent disease progression.

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Section: Discussionmentioning

confidence: 91%

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

Cudrici

Ito

Zafranskaia

et al. 2007

Experimental and Molecular Pathology

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“…These professional APCs have been suggested to participate in restimulation of myelin-specific CD4 + T cells in the CNS (5,7,39,40). The identification of equal numbers of DCs in the CCR4 −/− and WT CNS at the onset of disease suggested no major differences in CNS migration, but cannot fully exclude that migratory deficits of CCR4 −/− DCs occur at a later time point during disease development.…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4)(5)(6)(7)(8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.…”

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confidence: 99%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

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“…This is particularly significant as although antigen-presenting dendritic cells are not present in the uninflammed brain, dendritic cells are present in the perivascular space and cerebrospinal fluid, into which the perivascular space drains. 52 The potential risks of viral vector leakage into the cerebrospinal fluid and the development of an immune response emphasize the importance of visualizing vector distribution clinically. As such, a number of T1 and T2 contrast agents have been developed to act as surrogate markers of vector distribution.…”

Section: Discussionmentioning

confidence: 99%

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 ml min À1 ) and high infusion rates (2.5 ml min À1 ) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.

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CNS dendritic cells: Critical participants in CNS inflammation?

Cited by 89 publications

References 87 publications

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

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