Dysfunction of monocytes in Hodgkin's disease by excessive production of PGE-2 in long-term remission patients

Estévez, María; Ballart, I. J.; Macedo, Marcia Patrao de; Magnasco, H; Nicastro, Mario A.; Sen, Luisa

doi:10.1002/1097-0142(19881115)62:10<2128::aid-cncr2820621011>3.0.co;2-q

Cited by 9 publications

(2 citation statements)

References 36 publications

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“…Furthermore, it is known that monocytes produce increased amounts of PGE 2 in these patients (53,54). We show that the transcriptional profile of CD4 + T cells in patients with Hodgkin's lymphoma has significant similarities to CD4 + T cells of healthy donors treated with PGE 2 .…”

Section: Pge 2 Leads To Inhibition Of Cd4mentioning

confidence: 69%

Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

et al. 2006

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Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E 2 (PGE 2 ), a known inhibitor of CD4 + T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE 2 might have on primary human CD4 + T cells, we used a whole genome-based transcriptional approach and show that PGE 2 severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE 2 at an early step of T cell receptor signaling: indeed, PGE 2 stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE 2 -induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE 2 -treated CD4 + T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27 kip1 . Most importantly, CD4 + T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE 2 in T cells from healthy individuals. These data strongly suggest that PGE 2 is an important factor leading to CD4 + T cell impairment observed in Hodgkin's lymphoma. (Cancer Res 2006; 66(2): 1114-22)

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Section: Pge 2 Leads To Inhibition Of Cd4mentioning

confidence: 69%

Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

et al. 2006

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“…2,10 However, in about 35% of Hodgkin patients, we failed to reactivate LMP2-specific T cells. 10 We hypothesized that this might result from suboptimal DC maturation owing to known defects in monocytes of Hodgkin patients 11 and these defects might be overcome by identifying a more potent cytokine combination to induce DC maturation.…”

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confidence: 99%

Using Dendritic Cell Maturation and IL-12 Producing Capacity as Markers of Function: A Cautionary Tale

Kaka

Foster

Weiss

et al. 2008

Journal of Immunotherapy

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SummaryEffective dendritic cell (DC) function depends on sufficient expression of antigen and costimulatory molecules, and secretion of interleukin (IL)-12. We sought to augment DC stimulatory capacity by optimizing DC phenotype and IL-12 production. DCs, obtained by CD14-selection, were matured using 8 different cytokine cocktails, and expression of costimulatory/major histocompatibility complex molecules and IL-12 production at the end of maturation was assessed. DC stimulatory capacity was determined after pulsing with immunogenic adenoviral CD8 + peptide epitopes or after transduction with an Ad5f35-null vector. Resultant T-cell cultures were analyzed using pentamer and interferon-γ enzyme-linked immunosorbent spot assays. On the basis of DC expression of maturation markers and IL-12 production, we defined prototype "minimal" [tumor necrosis factor-α (TNF-α), prostaglandin E2], "standard" (IL-1, IL-6, TNF-α, prostaglandin E2), and "optimal" (IL-1, IL-6, TNF-α, interferon-α, CD40 ligand) DC cocktails. Optimal DCs were functionally superior when pulsed with CD8 + peptides, but when transduced with Ad5f35, functioned poorly as antigen-presenting cells. We investigated the mechanisms underlying this discrepancy and suggest that prolonged stimulation with potent cytokines (optimal cocktail) in combination with adenoviral transduction alters the kinetics of DC maturation such that the DCs are functionally exhausted by the traditional 48-hour maturation time point. Shortening the DC maturation period posttransduction restored optimal DC stimulatory capacity. Thus, maturation stimuli and viral transduction affects DC phenotype, IL-12 producing capacity, and kinetics of maturation, and all must be considered before designing protocols to generate the optimal DC for cytotoxic T lymphocyte generation. Keywords dendritic cell; IL-12; CTL; adenovirus; maturation cocktailThe generation of polyclonal, antigen-specific T H 1-polarized CD4 + and CD8 + cytotoxic T lymphocyte (CTL) lines in vitro is crucial to the success of adoptive immunotherapy protocols and is dependent on multiple factors, most important being the stimulatory capacity of antigenpresenting cells (APCs) and the source of antigen used to activate the T cells. Dendritic cells (DCs) are the most potent APC, 1 and are widely used to activate and expand CTL in vitro. 2, 3 Effective induction of a T H 1/CTL immune response depends on the ability of DC; (i) to express sufficient antigen-derived peptide epitopes in the context of major histocompatibility complex molecules, (ii) to provide costimulation via B-7 family molecules, and (iii) to secrete interleukin (IL)-12 that polarizes the responding T cells to a T H 1 phenotype. 1,4,5 To achieve Reprints: Ann M. Leen, Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030 (amleen@txccc.org Our group has used monocyte-derived DCs transduced with a chimeric adenoviral vector (Ad5f35) encoding the Epstein-Barr virus (EBV) latent membrane protein (LMP)2 antigen to reactivate ...

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EBV Immunotherapy

Huye¹,

Rooney

2008

DNA Tumor Viruses

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Dysfunction of monocytes in Hodgkin's disease by excessive production of PGE-2 in long-term remission patients

Cited by 9 publications

References 36 publications

Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

Using Dendritic Cell Maturation and IL-12 Producing Capacity as Markers of Function: A Cautionary Tale

EBV Immunotherapy

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