1,370 research outputs found
Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases
No full textWe have studied the effect of an inhibitor of matrix metalloproteinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guerin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCC (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-α release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animaIs. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but o a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-α production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.</p
Ultrastructural studies of an immune-mediated inflammatory response in the CNS parenchyma directed against a non-CNS antigen
No full textWe have shown previously that heat-killed bacillus Calmette-Guerin injected into the brain parenchyma becomes sequestered behind the blood-brain barrier for months undetected by the immune system. However, independent peripheral sensitization of the immune system to bacillus Calmette-Guerin results in recognition of bacillus Calmette-Guerin in the brain and the induction of focal chronic lesions [Matyszak M.K. and Perry V.H. (1995) Neuroscience 64, 967-977]. We carried out ultrastructural studies of these lesions. Prior to subcutaneous challenge we used immunohistochemistry to detect bacillus Calmette-Guerin which was found in cells with the morphology of macrophages/microglia and in perivascular macrophages. Eight to 14 days after subcutaneous challenge there was a conspicuous leucocyte infiltration at the site of bacillus Calmette-Guerin deposits within the brain parenchyma. The majority of these cells were macrophages and lymphocytes, with some lymphocytes showing characteristic blast morphology. Dendritic cells in close contact with lymphocytes were prominent. Inflammatory cells were found in perivascular cuffs and within the brain parenchyma. The tissue was oedematous and some axons were undergoing Wallerian degeneration with associated myelin degeneration. Throughout the lesions, but more commonly at the edges, we detected macrophages containing myelin in their cytoplasm close to intact axons and axons with evidence of remyelinating sheaths, suggestive of primary demyelination. In older lesions, two to three months after the peripheral challenge, the oedema was less pronounced and there was little evidence of Wallerian degeneration. There were still many macrophages, lymphocytes and dendritic cells, although the number of these cells was lower than in earlier lesions. Late lesions also contained many plasma cells which were not present in early lesions. In these late lesions there were bundles of axons with no myelin or a few axons with thin myelin sheaths, suggestive of persistent or ongoing demyelination or remyelination. These observations show that, during a delayed-type hypersensitivity lesion in the CNS, the leucocyte populations change with time, and suggest that the mechanisms and type of tissue damage are different in the early and late stages of the lesion.</p
The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system
No full textDendritic cells of the rat were studied immunohistochemically with MRC OX62 monoclonal antibody and using electron microscopy. In normal CNS, a small number of OX62+ cells was detected in the choroid plexus and meninges. These cells were absent from other CNS and peripheral nervous system sites studied. Dendritic cells were also studied in two models of immune-mediated inflammatory conditions in the CNS. These were: acute experimental allergic encephalomyelitis and aberrant delayed-type hypersensitivity lesions induced as a response to heat-killed bacillus Calmette-Guerin sequestrated behind the blood-brain barrier. In addition, a group of animals with a delayed- type hypersensitivity response was treated with dexamethasone to assess the effect of steroid treatment on T-cells and OX62+ cells in CNS lesions. Dendritic cells were present in many but not all lesions in acute experimental allergic encephalomyelitis and their numbers were small. In experimental allergic encephalomyelitis lesions, dendritic cells were found predominantly in perivascular cuffs, where they constituted approximately 2% of the total number of major histocompatibility complex class II+ cells. Some of these cells were also detected in the CNS parenchyma, close to the perivascular cuff. In contrast, dendritic cells were present in all delayed- type hypersensitivity lesions studied. Their number in delayed-type hypersensitivity lesions was significantly higher than in experimental allergic encephalomyelitis lesions. Numerous OX62+ cells were found, even in three-month-old lesions. Electron microscopy studies revealed that these cells were often in close contact with lymphocytes. There was no significant change in the density of OX62+ cells, IL2R+ cells and OX19+ T-cells in delayed-type hypersensitivity lesions after seven-day treatment with dexamethasone, although there was a considerable reduction in the number of CD45RA+ T-cells. The high numbers of dendritic cells found in the delayed- type hypersensitivity lesions may be important in contributing to the chronicity of the response. They may also initiate autoimmune responses to CNS antigens uncovered during bystander tissue damage which occurs as a consequence of aberrant delayed-type hypersensitivity responses.</p
Dendritic Cells in Inflammatory Responses in the CNS
No full textThere are a number of bone marrow derived mononuclear phagocytes associated with the central nervous system. These include: microglia in the brain parenchyma, perivascular macrophages and macrophages in the meninges and in the choroid plexus1. MHC class Il is not expressed on microglia in the normal rodent brain, but it can be rapidly upregulated during an inflammatory response. Other macrophages associated with the CNS express MHC class II constitutively. Although the expression of MHC antigens is a prerequisite for antigen presentation, it is not by itself sufficient to stimulate T cell responses. In vitro studies by Fontana and his colleagues showed that both astrocytes and microglia purified from the brains of new born animals, cultured and stimulated with INF-γ can present an antigen to already primed T cells2. In contrast, recent in vitro studies have shown that MHC class II+ microglia rapidly isolated from the adult rat brain are poor accessory cells, even when presenting an antigen to primed T cells, but other macrophages associated with the CNS can efficiently stimulate already primed T cells3. Using bone marrow chimeras Hickey and Kimura showed that perivascular macrophages are important accessory cells for the induction of immune responses in the CNS following peripheral activation of T cells4. However, it is still debatable whether any of the MHC class II+ cells in the CNS can induce a primary immune response
Altered antigen expression of microglia in the aged rodent CNS
No full textMicroglia, the resident macrophages of the central nervous system, are characterised by a highly specialized morphology and unusual antigenic phenotype. Microglia appear to be downregulated by their microenvironment when compared to other tissue macrophages. We have studied the microglia in brains of healthy, aged rats with a panel of monoclonal antibodies. We have found that microglia in the brains of these aged rats express antigens that are downregulated or absent from microglia of juvenile rats. The stimuli which give rise to this upregulated phenotype are not known. Age related changes in the phenotype of microglia should be taken into account when considering the possible role of microglia in neuropathological conditions.</p
Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens
No full textUsing immunocytochemistry we have shown that there is a population of macrophages within the stroma of the choroid plexus of rats and mice which expresses high levels of major histocompatibility complex Class II antigens. In whole mount preparations of the choroid plexus, the morphology and regular distribution of these cells is similar to the Langerhans cells of the skin. These cells reside at an important interface between the central nervous system and the peripheral immune system and their possible role in immune-mediated diseases of the central nervous system is discussed.</p
Axonal damage in acute multiple sclerosis lesions
No full textOne of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.</p
Obituary: Dr M.K. Bhan – A True Leader & Visionary
No full text12The author remembers Dr M.K. Bhan as a true leader, visionary, a passionate scientist, doctor and a wonderful human being, who has given love and affection to everyone around him
M.K. Asante: “It’s Bigger than Hip Hop: Art, Race and Politics”
No full textIncludes descriptive metadata provided by producer in MPEG-4 video file: "Arts and Culture - Video - M.K. Asante: 'It’s Bigger than Hip Hop: Art, Race and Politics.'" By M.K. Asante. Author and filmmaker Asante delivers the annual Walter R. Murray, Jr., Lecture on Oct. 20, 2010 at the Commons Center. He takes questions after his lecture
- …
