Apoptosis Induction in Human Peripheral Blood T Lymphocytes by High-Dose Steroid Therapy

Migita, Kiyoshi; Eguchi, Katsumi; Kawabe, Yojiro; Nakamura, Tatsufumi; Shirabe, Susumu; Tsukada, Toshiaki; Ichinose, Yasufumi; Nakamura, Hideki; Nagataki, Shigenobu

doi:10.1097/00007890-199702270-00017

Cited by 57 publications

(32 citation statements)

References 15 publications

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“…23–25 These potential dexamethasone-induced effects were investigated within the MC38 flank tumor model by measuring absolute cell counts of various T cell subsets in peripheral blood. To accomplish this, peripheral blood from the mice (N = 64) of the previously discussed tumor growth experiment were analyzed at multiple time points including days 8 (pre-treatment), 15 (shortly after anti-PD-1 therapy completion), and 27 (long time after anti-PD-1 therapy) (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…27 Supra-physiologic doses of corticosteroids can induce T cell apoptosis, preferentially in CD4+ compared to CD8+ T cells due to differential Bcl-2 expression profiles. 23–25 Additionally, corticosteroids enhance humoral T helper (T H ) 2 immune responses over cellular responses (T H 1), which are mainly thought to promote antitumor immunity. 12,28 For these reasons, corticosteroids are considered antithetical to the immune-stimulatory effects of cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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“…Acute relapses and optic neuritis in MS patients, for example, are treated by intravenous administration of high GC doses [12], which leads to lymphocyte apoptosis [13,14], suppression of pro-inflammatory cytokines [15,16] and an expansion of regulatory T cells [17]. Furthermore, GC interfere with leukocyte migration through downregulating adhesion molecules [18,19] and restoring the integrity of the BBB [20,21].…”

Section: Introductionmentioning

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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“…17 This regimen also induces apoptosis in the lymphocytes. 18 These facts explain the success of high-dose corticosteroid regimens in immune-mediated diseases. However, the underlying mechanisms for the activity of corticosteroids in aGVHD remain debatable and the question of whether giving corticosteroids in high doses will lead to improved outcomes remains unanswered though it remains a common practice.…”

Section: Discussionmentioning

confidence: 99%

Dismal response to high-dose methylprednisolone after failure to respond to standard dose in patients with acute GVHD

Schechter

Macartney²,

Finkelstein

et al. 2010

Bone Marrow Transplant

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Corticosteroids such as methylprednisolone (MP) remain the primary therapy for acute GVHD (aGVHD). Patients who are refractory to standard treatment (MP 2 mg/kg/day) may be treated with high-dose MP. This study evaluated the response to high-dose MP in children with aGVHD refractory to standard dose MP. Children who underwent hematopoietic SCT (HSCT) at our hospital between 1 June 2002 and 31 July 2006 and were treated with high-dose MP upon developing steroid-refractory aGVHD were included. Response to aGVHD therapy, adverse effects attributed to MP and overall outcomes were documented. Ten children received high-dose MP (X20 mg/kg/day) on 3-5 consecutive days followed by a tapering dose for steroid-refractory aGVHD, at a median of 12 days after starting standard treatment. Nine patients had Xgrade III aGVHD. Only one patient with grade III aGVHD had a complete response. Two patients had a partial response but flared when MP was tapered. Complications included hypertension (100%), hyperglycemia requiring insulin therapy (33%) and four documented severe infections. Five children (50%) died (median follow-up: 5.9 years). Salvage therapy other than high-dose MP should be considered in children who fail to respond to MP 2 mg/kg/day.

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Apoptosis Induction in Human Peripheral Blood T Lymphocytes by High-Dose Steroid Therapy

Cited by 57 publications

References 15 publications

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

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

Dismal response to high-dose methylprednisolone after failure to respond to standard dose in patients with acute GVHD

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