High-Dose Methylprednisolone Therapy in Multiple Sclerosis Induces Apoptosis in Peripheral Blood Leukocytes

Leussink, Verena I.; Jung, Stefan; Merschdorf, Ursula; Toyka, Klaus V.; Gold, Ralf

doi:10.1001/archneur.58.1.91

Cited by 119 publications

(84 citation statements)

References 40 publications

(48 reference statements)

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“…In the human MNCs, the CD3-positive T-cells also preferentially underwent mafosfamide-induced apoptosis. The higher variability of early apoptotic and late apoptotic/necrotic cellular changes in the human MNCs was to be expected and can at least partly be explained by the glucocorticosteroid treatment that each patient had received perioperatively before blood donation (Leussink et al, 2001). Additional attempts to yield more stable proportions of viable and dying MNCs, e.g., by addition of IL-2 or stimulation of the T-cell receptor, did not result in significant changes.…”

Section: Discussionmentioning

confidence: 90%

“…Also, the phagocytic capacity of the individual microglial cells as reflected by the phagocytic index in the nonmafosfamide-exposed MNC amounted to only 64.5% in comparison with the apoptotic target cell population. Baseline microglial phagocytosis of nonmafosfamide-treated MNC can at least partly be explained by the varying proportions of apoptotic cells inevitably present in the MNC of the corticosteroid-treated patients, which were prone to undergo apoptosis spontaneously (Leussink et al, 2001).…”

Section: Human Adult Microglia Phagocytoses Autologous Apoptotic Perimentioning

confidence: 99%

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Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

Chan

Séguin

Magnus

et al. 2003

Glia

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Apoptosis of autoaggressive T‐cells in the CNS is an effective, noninflammatory mechanism for the resolution of T‐cell infiltrates, contributing to clinical recovery in T‐cell‐mediated neuroinflammatory diseases. The clearance of apoptotic leukocytes by tissue‐specific phagocytes is critical in the resolution of the inflammatory infiltrate and leads to a profound downregulation of phagocyte immune functions. Adult human microglia from surgically removed normal brain tissue was used in a standardized, light‐microscopic in vitro phagocytosis assay of apoptotic autologous peripheral blood‐derived mononuclear cells (MNCs). Microglia from five different patients had a high capacity for the uptake of apoptotic MNCs in contrast to nonapoptotic target cells with the phagocytosis rate for nonapoptotic MNCs amounting to only 61.6% of the apoptotic MNCs. A newly described phosphatidylserine receptor, critical in the phagocytosis of apoptotic cells by macrophages, is also expressed at similar levels on human microglia. The effects of the therapeutically used immunomodulatory agent interferon‐beta (IFNβ) were investigated using Lewis rat microglia and apoptotic, encephalitogenic, myelin basic protein‐specific autologous T‐cells. Also, rat microglia had a high capacity to phagocytose apoptotic T‐cells specifically. IFNβ increased the phagocytosis of apoptotic T‐cells to 36.8% above the untreated controls. The enhanced phagocytic activity was selective for apoptotic T‐cells and was not mediated by increased IL‐10 secretion. Apoptotic inflammatory cells may be efficiently and rapidly removed by microglial cells in the autoimmune‐inflamed human CNS. The in vitro increase of phagocytosis by IFNβ merits further investigations whether this mechanism could also be therapeutically exploited. © 2003 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 90%

Section: Human Adult Microglia Phagocytoses Autologous Apoptotic Perimentioning

confidence: 99%

Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

Chan

Séguin

Magnus

et al. 2003

Glia

Self Cite

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“…There are numerous in vivo and in vitro reports on corticosteroids and their analogues which effect thymocyte apoptotsis and which also have adverse effects on peripheral T cell activation events. [76][77][78][79][80][81][82] However, a previous study by Wienberg et al 34 demonstrated that TREC levels increased in cord blood transplant recipients even while receiving low-dose steroids as GVHD prophylaxis. However, this data does not exclude the possibility that high dose corticosteroids used in GVHD treatment would have an adverse effect on thymic output.…”

Section: Discussionmentioning

confidence: 97%

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Fallen

McGreavey

Madrigal

et al. 2003

Bone Marrow Transplant

105

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Summary:The factors affecting T cell reconstitution post haematopoietic cell transplantation (HCT) are not well characterised. We carried out a longitudinal analysis of T cell reconstitution in 32 HCT recipients during the first 12 months post transplant. We analysed reconstitution of naı¨ve, memory and effector T cells, their diversity and monitored thymic output using TCR rearrangement excision circles (TRECs). Thymic-independent pathways were responsible for the rapid reconstitution of memory and effector T cells less than 6 months post HCT. Thymic-dependent pathways were activated between 6 and 12 months in the majority of patients with naı¨ve T cell numbers increasing in parallel with TREC levels. Increasing patient age, chronic GVHD and T cell depletion (with or without pretransplant Campath-1H) predicted low TREC levels and slow naı¨ve T cell recovery. Furthermore, increasing patient age also predicted high memory and effector T cell numbers. The effects of post HCT immunosuppression, total body irradiation, donor leucocyte infusions, T cell dose and post HCT infections on T cell recovery were also analysed. However, no effects of these single variables across a variety of different age, GVHD and T cell depletion groups were apparent. This study suggests that future analysis of the factors affecting T cell reconstitution and studies aimed at reactivating the thymus through therapeutic intervention should be analysed in age-, GVHD-and TCD-matched patient groups. While each of these parameters may have mutually exclusive effects on the outcome of the transplant, it is the combination of all of these parameters that will determine the ultimate success of the transplant. Furthermore, the effects of each of these parameters on immune reconstitution post HCT are unclear.The immediate post transplant period is followed by a severe and often prolonged immune deficiency that results in prolonged susceptibility to infection. 8,17,[19][20][21][22] Although infections that occur in the first month after engraftment probably result from deficiencies in both granulocytes and other mononuclear cell subsets, the more prolonged immune deficiency arises from deficiencies in effective CD4 þ T cell and B cell reconstitution and immunosuppressive therapy. 23,[27][28][29] It was then suggested that the reconstitution and maintenance of effective T cell immunity after HCT was dependent on education of T cell precursors in the thymus. [30][31][32] Furthermore, these observations generated considerable interest in the factors affecting the reconstitution of T cell immunity through thymic-dependent pathways. 33,34 Using phenotypic markers of T cell naivety (primarily the CD45RA antigen), initial studies demonstrated that increasing patient age had an adverse effect on the regeneration of naı¨ve CD4 þ T cells, presumably due to age-related thymic involution, 31 observations that were confirmed using the TCR rearrangement excision circle (TREC) assay to measure thymic output. 35,36 In addition, the thymus has been demonstrated to be...

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“…GC are widely used to treat acute relapses in MS patients by exploiting their potent pro-apoptotic and anti-inflammatory activity [38,39]. Previously we had identified peripheral T lymphocytes as essential targets but the specific role of GC actions on T effector cells remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Stable silencing of the glucocorticoid receptor in myelin‐specific T effector cells by retroviral delivery of shRNA: Insight into neuroinflammatory disease

et al. 2009

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Autoimmune responses in the CNS can be induced by adoptive transfer of CD41 T effector cells after antigen-restimulation and expansion of clonal cell lines in vitro. However, pathogenic factors remain partially elusive due to the lack of appropriate methods to achieve gene inactivation. Here we describe a protocol for stable gene silencing in differentiated rat T cells by retroviral transfer of small hairpin RNAs. Through the combination of an expression cassette containing the green fluorescent protein with a puromycin selection cassette this allows for the generation of pure knockdown cell lines suitable for tracking in animals. Exemplified for the glucocorticoid receptor, we demonstrate that gene silencing renders T effector cells unresponsive to ligand-induced apoptosis and gene regulation without affecting their ability to induce EAE in rats. Interestingly, glucocorticoid administration remains effective in the treatment of EAE despite strongly diminished glucocorticoid receptor expression in antigen-specific T cells. This highlights an important role of other cell types and bystander T cells as targets of glucocorticoid therapy. Collectively, our approach provides a simple tool for stable and efficient gene silencing in T effector cells, which should help to better understand brain autoimmune pathophysiology.

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High-Dose Methylprednisolone Therapy in Multiple Sclerosis Induces Apoptosis in Peripheral Blood Leukocytes

Abstract: Corticosteroid pulse therapy is a strong inducer of leukocyte apoptosis. Induction of apoptosis might contribute to the down-regulation of T-cell activity and thereby terminate inflammation in the central nervous system.

Cited by 119 publications

References 40 publications

Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Stable silencing of the glucocorticoid receptor in myelin‐specific T effector cells by retroviral delivery of shRNA: Insight into neuroinflammatory disease

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