The Influence of Thalidomide on the Clinical and Immunologic Manifestation of Erythema Nodosum Leprosum

Sampaio, Elizabeth P.; Kaplan, Gilla; Miranda, Alice; Nery, José A. C.; Miguel, Consuelo P.; Viana, Sergio M.; Sarno, Euzenir Nunes

doi:10.1093/infdis/168.2.408

Cited by 347 publications

(196 citation statements)

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“…The results are consistent with other studies which showed that thalidomide inhibits TNF-α (15)(16)(17)(18)(19). Thalidomide inhibits the synthesis of TNF-α in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 92%

Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line

Girgis¹,

Mahoney²,

Khalil³

et al. 2010

Oncology Letters

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Abstract. Studies conducted in our lab have indicated that thalidomide cytotoxicity in the KG-1a human acute myelogenous leukemia (AML) cell line was enhanced by combining it with arsenic trioxide. The current investigation was conducted in order to evaluate the effect of thalidomide either alone or in combination with arsenic trioxide on the release of tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) from this cell line in an attempt to clarify its possible cytotoxic mechanism(s). Human AML cell line KG-1a was used in this study. The cells were cultured for 48 h in the presence or absence of thalidomide (5 mg/l), and or arsenic trioxide (4 µΜ). The levels of TNF-α and VEGF in the supernatant were determined by ELISA. Results obtained indicate that the levels of TNF-α in the supernatant of KG-1a cell cultures incubated with thalidomide, arsenic trioxide, or combination were statistically lower than those observed in the supernatant of control cells (2.89, 5.07, 4.15 and 16.88 pg/ml, respectively). However, the levels of VEGF in the supernatant of thalidomide-treated cells were statistically higher than those in the supernatant of control cells (69.61 vs. 11.48 pg/l). Arsenic trioxide, whether alone or in combination with thalidomide, did not produce any statistically significant difference in the levels of VEGF as compared to the control or thalidomide-treated cell supernatant. These findings indicate that thalidomide and the arsenic trioxide inhibition of TNF-α production by KG-1a cells may play an important role in their cytotoxic effect.

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“…The results are consistent with other studies which showed that thalidomide inhibits TNF-α (15)(16)(17)(18)(19). Thalidomide inhibits the synthesis of TNF-α in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 92%

Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line

Girgis¹,

Mahoney²,

Khalil³

et al. 2010

Oncology Letters

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“…To overcome these limitations we have analysed paired samples in a cohort of ENL patients during and after remission of reaction. Tumour necrosis factor-alpha (TNF-) levels which have been shown to be raised during ENL reactions [16][17][18] were also increased in our A.ENL group and decreased in P.ENL to the levels observed in L patients, indicating that in the P.ENL group the reaction had indeed subsided ( [19].…”

Section: Discussionmentioning

confidence: 78%

Erythema nodosum leprosum is associated with up-regulation of polyclonal IgG1 antibody synthesis

Kifayet

Shahid

Lucas

et al. 1996

Clinical and Experimental Immunology

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SUMMARYErythema nodosum leprosum (ENL) is a serious complication of lepromatous (L) disease in leprosy. We have previously shown that of the four IgG subclasses, IgG1 and IgG3 Mycobacterium leprae-specific antibodies are significantly lower in leprosy patients during ENL reaction compared with untreated L patients. To see if this decrease results from a down-regulation of antibody synthesis during ENL, the frequency of antibody-secreting B cells (ABSC) in the blood compartment was determined by ELISPOT and related to serum immunoglobulin concentrations (¹g/ABSC). Control groups consisted of 16 patients with stable L disease and 32 healthy endemic controls (EC). Paired samples were analysed during acute ENLS (n 13) and after the reaction had subsided to identify changes associated with ENL. Polyclonal (PC) IgG1 was elevated in L patients compared with EC (325Interestingly, patients during acute ENL showed concentrations higher than L patients (419 ¹ g), which decreased after the reaction had subsided (260 ¹ g), indicating the transient nature of the antibody response. IgG2 antibodies showed the reverse trend and were lower during ENL and increased after the reaction had subsided. The mean concentrations for PC IgG3 and IgG4 antibodies were similar during ENL and after the reaction had subsided. Thus, decrease in M. leprae-specific IgG1 and IgG3 antibodies is not related to down-regulation of B cell responses. Identification of factors which regulate PC IgG1 antibody synthesis may provide additional insights into determinants of ENL reactions.

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“…Moreover, thalidomide stimulates natural killer cell cytotoxicity and inhibits the production of IL-6, TNF␣, and vascular endothelial growth factor. In fact, thalidomide has been found to be a successful treatment in multiple myeloma (53) and in various immune and inflammatory diseases such as RA, chronic cutaneous lupus erythematosus, erythema nodosum leprosum, Crohn's disease, and BD (25)(26)(27)(28)54,55). The effects of thalidomide on the immune response are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, thalidomide selectively (but not completely) inhibits production of the inflammatory cytokine TNF␣ in human monocytes (23), thereby reducing the half-life of its messenger RNA (mRNA) (24). Given the key function of TNF␣ in immune and inflammatory responses, the ability of thalidomide to accelerate TNF␣ degradation may explain its clinical success in a variety of clinical conditions caused by high serum levels of TNF␣, such as erythema nodosum leprosum, chronic cutaneous lupus erythematosus, prurigo nodularis, Crohn's disease (25)(26)(27)(28), and BD (29,30). Thalidomide has been used with clinical success in some autoimmune diseases such as multiple myeloma and RA, in which it was found to have proapoptotic properties, down-regulating NF-B and consequently cFLIP (31).…”

mentioning

confidence: 99%

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

Todaro¹,

Zerilli²,

Triolo³

et al. 2005

Arthritis & Rheumatism

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Objective. To determine whether prolongation of the inflammatory reaction in patients with Behçet's disease (BD) is related to apoptosis resistance and is associated with the up-regulation of antiapoptotic factors.Methods. The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF-B regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down-regulate NF-B nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF-B small interfering RNA.Results. Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95-induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable upregulation of the short form of cellular FLIP ( Conclusion. Taken together, these results indicate that NF-B contributes to the regulation of the apoptosis-related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF-B plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immunemediated disease.

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The Influence of Thalidomide on the Clinical and Immunologic Manifestation of Erythema Nodosum Leprosum

Cited by 347 publications

References 10 publications

Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line

Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line

Erythema nodosum leprosum is associated with up-regulation of polyclonal IgG1 antibody synthesis

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

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