References of "Tasken, Kjetil"
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See detailThe RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice
Singh, Maneesh; Singh, Pratibha; Vaira, Dolores et al

in European Journal of Clinical Investigation (2014), 44(2), 146-152

Background Increased intracellular concentration of cyclic AMP (cAMP) in T cells is associated with various immunodeficiency conditions including human immunodeficiency virus (HIV) infection. Several ... [more ▼]

Background Increased intracellular concentration of cyclic AMP (cAMP) in T cells is associated with various immunodeficiency conditions including human immunodeficiency virus (HIV) infection. Several reports indicate a critical role of activated protein kinase A (PKA) in the susceptibility of cells to HIV infection. We have used a cell permeable, stable peptidomimetic version (P3) of the RI-anchoring disruptor (RIAD), which prevents PKA interaction with A-kinase-anchoring proteins (AKAPs). It is known that RIAD peptide abrogates effects of localized cAMP signalling through anchored type I PKA in lymphocytes and prevents murine AIDS (MAIDS) infection when expressed as a transgene in mice. Methods and Results In vitro HIV-infected human peripheral blood mononuclear cells (PBMCs) show reduced levels of p24 and intracellular cAMP in T cells when treated with RIAD peptidomimetic (RIAD-P3). Humanized NOD/SCID/IL2cnull (NSG) mice infected with HIV-1 JRCSF and treated with RIAD-P3 (3􏰀5 mg) once every 2 weeks showed significantly reduced levels of viral load at +28, +42 and +56 days and increased CD4 numbers at +56 days after the start of treatment. RIAD-P3-treated humanized mice had lower levels of intracellular cAMP in T cells sorted from splenocytes. Conclusions Treatment with RIAD-P3 limits HIV-1 viral replication and stabilizes CD4 levels by mechanisms involving cAMP/PKA-I pathway in human PBMCs and humanized NSG mice. [less ▲]

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See detailMice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency
Mosenden, Randi; Singh, Pratibha; Cornez, Isabelle et al

in Journal of Immunology (2011), 186(9), 5119-30

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C ... [more ▼]

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIADtransgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases. [less ▲]

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See detailProstaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway.
Zeddou, Mustapha ULg; Greimers, Roland ULg; de Valensart, Nicolas et al

in Biochemical Pharmacology (2005), 70(5), 714-24

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small ... [more ▼]

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated T cells, predominantly of CD8+ phenotype. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In an attempt to identify the mechanisms leading to inhibitory NKR upregulation on T cells, we analyzed the expression of the CD94/NKG2A heterodimer on human CTLs activated with anti-CD3 mAb in the presence of PGE2 or with 8-CPT-cAMP, an analogue of cyclic AMP. As previously described, anti-CD3 mAb-mediated activation induced the expression of CD94/NKG2A on a small fraction of CD8+ T cells. Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher. This upregulation was partially prevented by PKA inhibitors, such as KT5720 and Rp-8-Br-cAMP (type I selective). We also report that cAMP induces upregulation of NKG2A at the mRNA level. We further demonstrated that cross-linking of CD94 on CD8+ T cells expressing the CD94/NKG2A heterodimer inhibits their cytotoxic activity in a bispecific antibody redirected lysis assay. Our findings clearly demonstrate that the PGE2/cAMP/PKA type I axis is involved in the expression of CD94/NKG2A receptor on human CD8+ T lymphocytes. [less ▲]

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See detailCyclo-oxygenase type 2-dependent prostaglandin E-2 secretion is involved in retrovirus-induced T-cell dysfunction in mice
Rahmouni, Souad ULg; Aandahl, Einar Martin; Nayjib, Btissam ULg et al

in Biochemical Journal (2004), 384(Pt 3), 469-476

MAIDS (murine AIDS) is caused by infection with the murine leukaemia retrovirus RadLV-Rs and is characterized by a severe immunodeficiency and T-cell anergy combined with a lymphoproliferative disease ... [more ▼]

MAIDS (murine AIDS) is caused by infection with the murine leukaemia retrovirus RadLV-Rs and is characterized by a severe immunodeficiency and T-cell anergy combined with a lymphoproliferative disease affecting both B- and T-cells. Hyperactivation of the cAMP-protein kinase A pathway is involved in the T-cell dysfunction of MAIDS and HIV by inhibiting T-cell activation through the T-cell receptor. In the present study, we show that MAIDS involves a strong and selective up-regulation of cyclo-oxygenase type 2 in the CD11b+ subpopulation of T- and B-cells of the lymph nodes, leading to increased levels of PGE2 (prostaglandin E2). PGE2 activates the cAMP pathway through G-protein-coupled receptors. Treatment with cyclo-oxygenase type 2 inhibitors reduces the level of PGE2 and thereby reverses the T-cell anergy, restores the T-cell immune function and ameliorates the lymphoproliferative disease. [less ▲]

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See detailUSE OF COX-2 INHIBITORS FOR PREVENTING IMMUNODEFICIENCY
TASKÉN, Kjetil; Moutschen, Michel ULg; Rahmouni, Souad ULg et al

Patent (2002)

The present invention provides a method for treating or preventing a disorder typified by an immunodificiency (e.g. HIV), wherein the patient is administered a COX-2 inhibitor or derivative or ... [more ▼]

The present invention provides a method for treating or preventing a disorder typified by an immunodificiency (e.g. HIV), wherein the patient is administered a COX-2 inhibitor or derivative or pharmaceutically acceptable salt thereof, preferably diisopropylfluorophasphaate, L-745337, rofecoxi, NS 398, SC 58125, etodolac, meloxicam, celecoxib flusolide or nimesulide, and compositions and products containing the same or use of the same in preparing medicaments and for treatment. [less ▲]

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See detailIncreased Camp Levels and Protein Kinase (Pka) Type I Activation in Cd4+ T Cells and B Cells Contribute to Retrovirus-Induced Immunodeficiency of Mice (Maids): A Useful in Vivo Model for Drug Testing
Rahmouni, Souad ULg; Aandahl, Einar Martin; Trebak, Mohamed et al

in FASEB Journal (2001), 15(8), 1466-1468

Murine AIDS (MAIDS) is characterized by a lymphoproliferative disease and a profound anergy, which involves mostly CD4(+) T cells. To better define the mechanisms responsible for anergy, we measured cAMP ... [more ▼]

Murine AIDS (MAIDS) is characterized by a lymphoproliferative disease and a profound anergy, which involves mostly CD4(+) T cells. To better define the mechanisms responsible for anergy, we measured cAMP concentrations in the different lymphocyte subsets of the infected mice. CD4(+) T cells and B cells displayed a dramatic 10- to 30-fold increase of cAMP. cAMP was also significantly increased in CD8(+) T cells, although to a far lesser extent. The unusual CD4(+) CD90(-) T cells, typical of MAIDS, were characterized by a much higher cAMP level than their CD90(+) counterparts. T cells of the infected mice were much more sensitive to inhibition by the cAMP analogue 8-CPT-cAMP, which confirmed increased in vivo exposure to cAMP. In accordance with the increased cAMP levels, PKA type I was constitutively activated and its C subunit was translocated to the nucleus. Finally, the profound T-cell anergy associated with MAIDS could be reversed by treating T cells with a PKA type I-selective antagonist ex vivo. MAIDS could constitute a suitable model for the study of new pharmacological agents aimed at reversing the immunosuppressive effects of cAMP previously shown to be involved in several pathological states, including HIV infection and common variable immunodeficiency. [less ▲]

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