Role of Thalidomide on the Expression of OX40, 4-1BB, and GITR in T Cell Subsets

Kim, B.S.; Kim, J.Y.; Kim, E.J.; Lee, Jae Geun; Joo, Dong Jin; Huh, Kyu Ha; Kim, M.S.; Kim, Y.S.

doi:10.1016/j.transproceed.2015.12.088

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…TM possesses an immunosuppressive function, which may be useful following transplantation, and not only suppresses, but modulates the immune response by regulating key immune‐modulatory molecules, including nuclear factor‐ κ B and pro‐inflammatory cytokines such as tumour necrosis factor‐ α (TNF‐ α ), interferon‐ γ (IFN‐ γ ), interleukin (IL)‐6, IL‐10, IL‐12, and cyclooxygenase 2 . Our previous study further substantiated the immunomodulatory effects of TM, demonstrating that TM selectively suppresses effector T (Teff) cells among total CD4 + T cells . We also found that the immunomodulatory effect of TM was potentiated with glucocorticoid (GC)‐combined treatment .…”

Section: Introductionsupporting

confidence: 56%

“…The TNF receptors are primarily involved in apoptosis and inflammation, and interactions of TNFRSF and TNFSF deliver co‐stimulatory signals to regulate the function of many immune cells . In our previous study, we suggest that the selected co‐stimulatory molecules, OX40, 4‐1BB, and GITR, may be involved in the TM‐induced regulation of proliferation and conversion of Treg cells from Tnaive cells . It has already been proposed by several studies that TM increases the therapeutic efficacy for treatment of multiple myeloma and lupus nephritis when combined with GCs; so, we hypothesized that DX may enhance the action of TM toward the co‐stimulatory molecules.…”

Section: Discussionmentioning

confidence: 94%

“…19,20 In our previous study, we suggest that the selected co-stimulatory molecules, OX40, 4-1BB, and GITR, may be involved in the TM-induced regulation of proliferation and conversion of Treg cells from Tnaive cells. 12 It has already been proposed by several studies that TM increases the therapeutic efficacy for treatment of multiple myeloma and lupus nephritis when combined with GCs; [16][17][18]27 so, we hypothesized that DX may enhance the action of TM toward the co-stimulatory molecules. Indeed, in this study, we demonstrated that co-stimulatory molecule expression changed upon treatment with TM and/or DX.…”

Section: Discussionmentioning

confidence: 96%

“…2,[7][8][9][10][11] Our previous study further substantiated the immunomodulatory effects of TM, demonstrating that TM selectively suppresses effector T (Teff) cells among total CD4 + T cells. 2,12 We also found that the immunomodulatory effect of TM was potentiated with glucocorticoid (GC)-combined treatment. 9 Therefore, this study introduced GC as a complementary agent, as it may play an important role in extending the function of TM.…”

Section: Introductionmentioning

confidence: 88%

“…TM and DX were administered at 10 or 1·5 mg/kg body weight per day, respectively, in all three groups. Doses were determined based on the results of our previous study …”

Section: Methodsmentioning

confidence: 99%

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Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

et al. 2017

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Thalidomide (TM) has been reported to have anti-cancer and anti-inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co-treatment had an enhanced immune-modulatory effect on T cells through regulating the expression of co-stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort-purified and cultured for CD4 T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4-1BB, and glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 μm) decreased CD4 T cell proliferation in a dose-dependent manner, whereas TM/DX (0·1 or 1 nm) co-treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co-stimulatory molecules decreased upon TM/DX co-treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4 T cells isolated from TM- and DX-treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4-1BB expression in CD4 T cells.

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Section: Introductionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 88%

“…TM and DX were administered at 10 or 1·5 mg/kg body weight per day, respectively, in all three groups. Doses were determined based on the results of our previous study …”

Section: Methodsmentioning

confidence: 99%

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Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

et al. 2017

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Immune Regulation in Human Health and Disease

Bartolucci

Piccirillo

2017

Encyclopedia of Life Sciences

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The immune system requires a homeostatic equilibrium among the mechanisms that assure self‐tolerance, those that control the capacity to mount life‐long immunity to pathogenic microbes and those that attenuate effector mechanisms from inducing immune pathology. There are multiple processes in place to ensure that healthy immune regulation and FOXP3 + T regulatory (Treg) cells are thought to be the major players. Treg cells exercise their regulatory role through various contact‐dependent and ‐independent mechanisms, and FOXP3 is the master regulator of their various functions such as inhibiting T effector (Teff) cell proliferation and inflammatory cytokine production. Various autoimmune diseases such as IPEX occur when Treg‐cell function or numbers are abrogated. Although there is evidence that supports the involvement of Treg cells in the development of autoimmune disease, there are inconsistencies in the literature owing to the lack of Treg‐cell‐specific markers. Key Concepts The immune system employs multiple tolerance mechanisms to maintain immune homeostasis. Multiple specialised regulatory cells exist, FOXP3+ T regulatory (Treg) cells being one of the major players in the maintenance of immune tolerance. FOXP3 is the master transcription factor of Treg cells, controlling Treg‐cell phenotype and suppressive functions. Autoimmune diseases such as IPEX arise when Treg cells are defective or lacking, which can be due to mutations at the Foxp3 gene locus. Multiple markers are currently being used to study the Treg‐cell population; however, these markers are not specific to Treg cells and therefore are the cause of inconsistencies in the literature on the topic of Treg‐cell function in health and disease. Disturbances in FOXP3+ Treg‐cell development, homeostasis and/or function are thought to occur in many autoimmune and chronic inflammatory diseases in humans.

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The apoptotic effects of NK-92 cells stimulated with an anti-CD226 antibody on MDA-MB-231 triple-negative breast cancer cells

2023

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Research on immunotherapy in breast cancer treatment has recently gained importance. In this context, natural killer (NK) cells have been shown to kill cancer cells without affecting normal cells. Our study used the NK-92 cells that were stimulated with anti-CD226 antibodies (sNK-92) to increase their activity to target MDA-MB-231 triple-negative breast cancer cells. MCF-12A normal breast cells were used as the control in all experiments. The cytotoxic effects of NK-92 and sNK-92 cells on MDA-MB-231 cells were investigated using lactate dehydrogenase tests. The sNK-92 cells were more cytotoxic than NK-92 cells on MDA-MB-231 cells. In contrast, a signi cant cytotoxic change was not observed in MCF-12A cells cocultured with NK-92 and sNK-92 cells. An increase in granzyme B levels after coculturing with sNK-92 cells was investigated using the granzyme B enzyme-linked immunosorbent assay. The sNK-92 cells secreted more granzyme B than NK-92 cells against MDA-MB-231 cells. This increase was not observed in MCF-12A, indicating that sNK-92 cells speci cally target cancer cells. In addition, immunostaining was used to investigate the synthesis level of BAX, CASP3, and CASP9 proteins to determine whether the observed cytotoxic effect was due to apoptosis. These proteins were synthesized more in MDA-MB-231 cells cocultured with sNK-92 than with NK-92 cells. However, no increase in their synthesis was observed in normal breast cells cocultured with NK-92 and sNK-92 cells. In conclusion, NK-92 cells stimulated with anti-CD226 antibodies secrete more granzyme B, resulting in a greater cytotoxic effect by inducing programmed cell death (apoptosis). The fact that the observed effects on breast cancer cells were not observed in normal breast cells indicates that sNK-92 cells speci cally target breast cancer cells. These results indicate the potential use of CD226-stimulated NK-92 cells in immunotherapy.

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Role of Thalidomide on the Expression of OX40, 4-1BB, and GITR in T Cell Subsets

Cited by 13 publications

References 27 publications

Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

Immune Regulation in Human Health and Disease

The apoptotic effects of NK-92 cells stimulated with an anti-CD226 antibody on MDA-MB-231 triple-negative breast cancer cells

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