Macrophage Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis

Nguyen, Kim B.; McCombe, Pamela A.; Pender, Michael P.

doi:10.1006/jaut.1994.1011

Cited by 73 publications

(33 citation statements)

References 21 publications

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“…There is selective apoptosis of V 8.2 + MBP-reactive T cells (Tabi et al, 1994 andTabi et al, 1995;McCombe et al, 1996a), which may be due to CD95-mediated antigen-specific activation-induced apoptosis (White et al, 1998b). Apoptosis of other cells in the CNS in EAE may be due to non-antigen-specific processes such as withdrawal of growth factors or the effects of endogenous corticosteroids (Pender et al, 1992;Nguyen et al, 1994). We now show that apoptosis of inflammatory cells in the spinal cord in MBP-EAE is increased 16 h after treatment with CsA.…”

Section: Discussionmentioning

confidence: 63%

“…During spontaneous recovery from MBP-EAE, there is apoptosis of T cells (Pender et al, 1991 andPender et al, 1992;Schmied et al, 1993) and macrophages/microglia in the CNS (Nguyen et al, 1994;White et al, 1998a). There is selective apoptosis of V 8.2 + MBP-reactive T cells (Tabi et al, 1994 andTabi et al, 1995;McCombe et al, 1996a), which may be due to CD95-mediated antigen-specific activation-induced apoptosis (White et al, 1998b).…”

Section: Discussionmentioning

confidence: 99%

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Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

McCombe

Harness

Pender

1999

Journal of Neuroimmunology

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Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by inoculation with myelin basic protein (MBP) and adjuvants. Rats were treated with second daily injections of saline or cyclosporin A (CsA) from the day of inoculation. Saline-treated rats had an acute episode of disease followed by clinical recovery. Rats treated with CsA 16 or 32 mg/kg had minimal signs of EAE at the usual time after inoculation, but developed signs of disease after treatment was ceased. Rats treated with CsA 8 mg/kg had a delayed first episode of disease and then developed a relapsing or a chronic persistent course of disease. CsA 4 mg/kg delayed the onset of disease. To study the effects of CsA on the inflammatory infiltrate, cells were extracted from the spinal cords of rats with EAE, 16 h after a single injection of CsA or saline. Extracted cells were labelled with antibodies to T cells, CD11b/c (macrophages/microglia), CD95 (Fas) and Fas ligand. CsA 4 mg/kg did not alter the composition of the inflammatory infiltrate. Treatment with higher single doses of CsA caused a dose-dependent decline in the percentage of T cell receptor (TCR) + cells in the inflammatory infiltrate. All doses of CsA caused a significant increase in the number and percentage of cells that were apoptotic. CsA treatment caused an increase in the percentages of CD5 + and TCR + cells that were apoptotic. There was a decline in the percentage of apoptotic T cells that were V 8.2 + , compared to the percentage of nonapoptotic T cells that were V 8.2 + , in CsA treated rats compared to saline-treated controls. This suggests that, while CsA treatment caused a non-specific increase in the overall level of T cell apoptosis in the spinal cord, it abrogated the selective apoptosis of V 8.2 + encephalitogenic T cells that normally occurs during spontaneous recovery from acute EAE.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

McCombe

Harness

Pender

1999

Journal of Neuroimmunology

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“…Apoptosis of macrophages and T lymphocytes plays a role in the resolution of inflammation in rodents. 51,52 In HIV and SIV infection, the picture is less clear. While viral infection can result in lymphocyte and macrophage death, it can also result in the prolonged life of infected cells as has been observed for HIV-infected macrophages in vitro.…”

Section: Discussionmentioning

confidence: 99%

Proliferating Cellular Nuclear Antigen Expression as a Marker of Perivascular Macrophages in Simian Immunodeficiency Virus Encephalitis

Williams

Schwartz

Corey

et al. 2002

The American Journal of Pathology

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Brain perivascular macrophages are a major target of simian immunodeficiency virus (SIV) infection in rhesus macaques and HIV infection in humans.Perivascular macrophages are distinct from parenchymal microglia in their location, morphology, expression of myeloid markers, and turnover in the CNS. In contrast to parenchymal microglia, perivascular macrophages are continuously repopulated by blood monocytes, which undergo maturation to macrophages on entering the central nervous system (CNS). We studied differences in monocyte/macrophages in vivo that might account for preferential infection of perivascular macrophages by SIV. In situ hybridization for SIV and proliferating cellular nuclear antigen (PCNA) immunohistochemistry demonstrated that SIV-infected and PCNA-positive cells were predominantly found in perivascular cuffs of viremic animals and in histopathological lesions that characterize SIV encephalitis (SIVE) in animals with AIDS. Multilabel techniques including double-label immunohistochemistry and combined in situ hybridization and immunofluorescence confocal microscopy revealed numerous infected perivascular macrophages that were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing macrophage subpopulations were found in the small intestine and lung of animals with AIDS. While PCNA is used as a marker of cell proliferation it is also strongly expressed in nondividing cells undergoing DNA synthesis and repair. Therefore, more specific markers for cell proliferation including Ki-67, topoisomerase II␣, and bromodeoxyuridine (BrdU) incorporation were used which indicated that PCNA-positive cells within SIVE lesions were not proliferating. These observations are consistent with perivascular macrophages as terminally differentiated, non-dividing cells and underscores biological differences that could potentially define mechanisms of preferential, productive infection of perivascular macrophages in the rhesus macaque model of neuroAIDS. These studies suggest that within CNS and non-CNS tissues there exist subpopulations of macrophages that are SIV-infected and express PCNA.

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“…The process of spontaneous recovery is not yet fully understood and many factors have been postulated to play a role, including endogenous corticosteroids MacPhee et al, 1989), suppressor cells (Swierkosz and Swanborg, 1975;Welch et al, 1980) and nitric oxide (O'Brien et al, 1999). Furthermore, during clinical recovery there is apoptosis of inflammatory cells in the CNS (Pender et al, 1991), which involves T cells (Pender et al, 1992;Schmied et al, 1993), B cells (White et al, 2000), macrophages (Nguyen et al, 1994;White et al, 1998a) and microglia (White et al, 1998a) and After recovery from an episode of actively induced EAE, Lewis rats have generally been found to be resistant to the active reinduction of disease (Willenborg, 1979;Hinrichs et al, 1981) and either resistant or susceptible (Willenborg, 1979;Hinrichs et al, 1981) to passively induced EAE. Rats that have recovered from passively induced EAE have been found by some authors to be fully susceptible to the active or passive reinduction of disease (Hinrichs et al, 1981) and by others to be resistant to reinduction by active (Welch et al, 1980;Namikawa et al, 1986) or passive means (Levine et al, 1967).…”

Section: Introductionmentioning

confidence: 99%

Rapid entry and downregulation of T cells in the central nervous system during the reinduction of experimental autoimmune encephalomyelitis

Gordon

Nguyen

White

et al. 2001

Journal of Neuroimmunology

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We investigated the mechanisms whereby a previous attack of experimental autoimmune encephalomyelitis (EAE) modifies a subsequent attack in the Lewis rat. Active immunization with myelin basic protein (MBP) and complete Freund's adjuvant 28 days after the passive transfer of MBP-sensitized spleen cells induced a second episode of EAE, which occurred earlier than in naive control animals, but was less severe overall. The pattern of neurological signs was also different in rechallenged rats, which had less severe tail and hindlimb weakness but more severe forelimb weakness. In rechallenged rats, inflammation was more severe in the cervical spinal cord, cerebellum, brainstem and cerebrum, but less severe in the lumbar spinal cord, than in controls. The early onset of EAE in rechallenged rats was explained by a memory T cell response to MBP [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89] in the draining lymph node and spleen, and by the enhanced entry of T cells into the central nervous system (CNS). However, the number of αβ T cells in the spinal cord of rechallenged rats declined faster than in controls, especially in the lumbosacral cord, where the number of Vβ8.2 + T cells and the frequency of T cells reactive to MBP 72-89 rapidly decreased, indicating rapid downregulation of the immune response in the previously inflamed spinal cord. Apoptosis of inflammatory cells in the CNS was increased in the rechallenged rats and is likely to contribute to this downregulation. Furthermore, during the disease course the generation of encephalitogenic T cells in the peripheral lymphoid organs was limited compared with controls. Thus, a previous attack of EAE modifies a subsequent attack through the interaction of the following processes: a memory T cell response to MBP; facilitated T cell entry into the CNS; downregulation of the immune response in the CNS, including increased apoptosis of inflammatory cells; and a limited generation of encephalitogenic T cells in the peripheral lymphoid organs.

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Macrophage Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis

Cited by 73 publications

References 21 publications

Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

Proliferating Cellular Nuclear Antigen Expression as a Marker of Perivascular Macrophages in Simian Immunodeficiency Virus Encephalitis

Rapid entry and downregulation of T cells in the central nervous system during the reinduction of experimental autoimmune encephalomyelitis

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