Effect of erythropoietin on primed leucocyte expression profile

Resistance to erythropoietin (EPO) affects a significant number of anaemic patients with end-stage renal disease. Previous reports suggest that inflammation is one of the major independent predictors of EPO resistance, and the effects of EPO treatment on inflammatory mediators are not well established. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leucocytes. Microarray experiments were performed on primed ex vivo peripheral blood mononuclear cells (PBMCs) and treated with human EPO-α. Data suggested that EPO-α modulated genes involved in cell movement and interaction in primed PBMCs. Of note, EPO-α exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-α increases expression of genes relating to promotion of inflammation encoding for IL-1β and CCL8, and induces de novo synthesis of IL-1α, CXCL1 and CXCL5 in primed cells. The reduction in MAPK p38-α activity is involved in modulating both IL-1β and IL-8 expression. Unlike the induction of MAPK, Erk1/2 activity leads to upregulation of IL-1β, but does not affect IL-8 expression and release. Furthermore, EPO-α treatment of primed cells induces the activation of caspase-1 upstream higher secretion of IL-1β, and this process is not dependent on caspase-8 activation. In conclusion, our findings highlight new potential molecules involved in EPO resistance and confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario in which the positive correlation found between EPO resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself.

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The Influence of Methylsulfonylmethane on Inflammation-Associated Cytokine Release before and following Strenuous Exercise

Journal of Sports Medicine ◽

10.1155/2016/7498359 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Mariè van der Merwe ◽

Richard J. Bloomer

Keyword(s):

Whole Blood ◽

Mononuclear Cells ◽

Ex Vivo ◽

Knee Extension ◽

Strenuous Exercise ◽

Peripheral Blood Mononuclear ◽

Physically Active ◽

Inflammatory Molecules

Background. Inflammation is associated with strenuous exercise and methylsulfonylmethane (MSM) has been shown to have anti-inflammatory properties.Methods. Physically active men were supplemented with either placebo or MSM (3 grams per day) for 28 days before performing 100 repetitions of eccentric knee extension exercise.Ex vivoandin vitrotesting consisted of evaluating cytokine production in blood (whole blood and isolated peripheral blood mononuclear cells (PBMCs)) exposed to lipopolysaccharide (LPS), before and through 72 hours after exercise, whilein vivotesting included the evaluation of cytokines before and through 72 hours after exercise.Results. LPS stimulation of whole blood after MSM supplementation resulted in decreased induction of IL-1β, with no effect on IL-6, TNF-α, or IL-8. After exercise, there was a reduced response to LPS in the placebo, but MSM resulted in robust release of IL-6 and TNF-α. A small decrease in resting levels of proinflammatory cytokines was noted with MSM, while an acute postexercise increase in IL-10 was observed with MSM.Conclusion. Strenuous exercise causes a robust inflammatory reaction that precludes the cells from efficiently responding to additional stimuli. MSM appears to dampen the release of inflammatory molecules in response to exercise, resulting in a less incendiary environment, allowing cells to still have the capacity to mount an appropriate response to an additional stimulus after exercise.

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Potential TH9402-Based ECP Treatment for cGvHD Patients.

Blood ◽

10.1182/blood.v104.11.5119.5119 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5119-5119

Author(s):

Annie Levesque ◽

Ann-Louise Savard ◽

Denis-Claude Roy ◽

Francine Foss ◽

Christian Scotto

Keyword(s):

T Cells ◽

Cell Death ◽

Mononuclear Cells ◽

Ex Vivo ◽

Chronic Phase ◽

Dose Effect ◽

Peripheral Blood Mononuclear ◽

Hematopoietic Stem

Abstract Although the risk of graft versus host disease (GvHD) can be reduced by improved donor-recipient matching and by the depletion of T cells before transplantation, GvHD still develops in 30–70% of allogeneic hematopoietic stem cell transplantation (HSCT) patients. The chronic phase of the disease (cGvHD), for which the pathogenesis is similar to autoimmune diseases, involves profound immune dysregulation leading to both immunodeficiency and autoimmunity. Standard therapies for cGvHD such as corticosteroids and immunosuppressants are associated with high toxicity and have demonstrated limited efficacy in patients with extensive disease. Extracorporeal photopheresis (ECP) has been shown by others in the clinic as a non-aggressive and beneficial alternative treatment for cGvHD, inducing Th1/Th2 immunomodulation that restores immunological tolerance. Celmed has developed an alternative approach to eliminate immunoreactive T cells using the Theralux™ photodynamic cell therapy (PDT) system based on the use of the rhodamine-123 derivative TH9402 illuminated ex vivo with a visible light source (λ =514nm). It has been suggested that the apoptotic cells, when returned to the patient, may be able to modulate the immune system as seen with other ECP methods. We aimed to evaluate in vivo and in vitro the possibility of also using the Theralux™ system in the ECP setting. A preliminary mouse model suggested that splenic T cells pre-treated with the Theralux™ system were able to induce an improvement of overall survival (p<0.05) in mice with acute GvHD. Additionally, we developed a simplified PDT process and conducted a series of experiments with peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers. These studies have shown that the intra- and inter-donor variability in TH9402 incorporation are very low (~5% and 10%, respectively). A dose-effect study has shown a relationship of the PDT conditions with the levels of cell death, allowing significant control of the level of apoptosis induced. Phenotypic analyses have shown that this process results in an increase of AnnexinV positive cells as well as a decrease in the absolute number of CD3+ cells, CD19+/CD20+ cells and CD14+ cells and an increase in CD11c+ cells. This would suggest that apoptosis could be induced in both autoreactive T and B cells which could potentially stimulate an immune response against them. Moreover, the increase in CD11c+ cells combined with the decrease in CD14+ cells could reflect the maturation of macrophages into dendritic cells that are very potent antigen presenting cells. The mechanism by which these specific PDT conditions induce cell death is still under investigation but preliminary studies have shown that the cell death in unselected resting PBMCs may be caspase-independent. Finally, the evaluation of the effect of PDT on samples from cGvHD patients also demonstrated the capacity of this treatment strategy to induce apoptosis in these cells. Based on these data, we intend to begin a pilot clinical study evaluating two controlled PDT conditions inducing different levels of apoptosis in order to assess the safety and biological effect of the Theralux™ ECP system to treat patients with cGvHD.

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Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo

Journal of Virology ◽

10.1128/jvi.74.3.1094-1100.2000 ◽

2000 ◽

Vol 74 (3) ◽

pp. 1094-1100 ◽

Cited By ~ 78

Author(s):

Joshua T. Bartoe ◽

Björn Albrecht ◽

Nathaniel D. Collins ◽

Michael D. Robek ◽

Lee Ratner ◽

...

Keyword(s):

Virus Type ◽

Mononuclear Cells ◽

Ex Vivo ◽

Peripheral Blood Mononuclear ◽

T Lymphotropic Virus ◽

Viral Loads

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is associated with a variety of immune-mediated disorders. The role of four open reading frames (ORFs), located between env and the 3′ long terminal repeat of HTLV-1, in mediating disease is not entirely clear. By differential splicing, ORF II encodes two proteins, p13II and p30II, both of which have not been functionally defined. p13II localizes to mitochondria and may alter the configuration of the tubular network of this cellular organelle. p30II localizes to the nucleolus and shares homology with the transcription factors Oct-1 and -2, Pit-1, and POU-M1. Both p13II and p30II are dispensable for infection and immortalization of primary human and rabbit lymphocytes in vitro. To test the role of ORF II gene products in vivo, we inoculated rabbits with lethally irradiated cell lines expressing the wild-type molecular clone of HTLV-1 (ACH.1) or a clone containing selected mutations in ORF II (ACH.30/13.1). ACH.1-inoculated animals maintained higher HTLV-1-specific antibody titers than animals inoculated with ACH.30/13.1. Viral p19 antigen was transiently detected in ex vivo cultures of peripheral blood mononuclear cells (PBMC) from only two ACH.30/13.1-inoculated rabbits, while PBMC cultures from all ACH.1-inoculated rabbits routinely produced p19 antigen. In only three of six animals exposed to the ACH.p30II/p13IIclone could provirus be consistently PCR amplified from extracted PBMC DNA and quantitative competitive PCR showed the proviral loads in PBMC from ACH.p30II/p13II-infected rabbits to be dramatically lower than the proviral loads in rabbits exposed to ACH. Our data indicate selected mutations in pX ORF II diminish the ability of HTLV-1 to maintain high viral loads in vivo and suggest an important function for p13II and p30II in viral pathogenesis.

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Leukocyte Production of Inflammatory Mediators Is Inhibited by the Antioxidants Phloretin, Silymarin, Hesperetin, and Resveratrol

Mediators of Inflammation ◽

10.1155/2014/938712 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 30

Author(s):

Jezrom B. Fordham ◽

Afsar Raza Naqvi ◽

Salvador Nares

Keyword(s):

Inflammatory Mediators ◽

Mononuclear Cells ◽

Therapeutic Potential ◽

Aggregatibacter Actinomycetemcomitans ◽

Significant Inhibition ◽

Periodontal Pathogen ◽

Enzyme Linked Immunosorbent Assay ◽

Peripheral Blood Mononuclear ◽

Differentiation Factors

Antioxidants possess significant therapeutic potential for the treatment of inflammatory disorders. One such disorder is periodontitis characterised by an antimicrobial immune response, inflammation, and irreversible changes to the supporting structures of the teeth. Recognition of conserved pathogen-associated molecular patterns is a crucial component of innate immunity to Gram-negative bacteria such asEscherichia coli, as well as the periodontal pathogenAggregatibacter actinomycetemcomitans. In this study, we investigated the antioxidants Phloretin, Silymarin, Hesperetin, and Resveratrol to ascertain whether they altered the production of inflammatory mediators by innately-activated leukocytes. Peripheral blood mononuclear cells were stimulated with lipopolysaccharide purified fromAggregatibacter actinomycetemcomitans, and the production of cytokines, chemokines, and differentiation factors was assayed by enzyme-linked immunosorbent assay, cytometric bead array, and RT-PCR. Significant inhibition of these factors was achieved upon treatment with Phloretin, Silymarin, Hesperetin, and Resveratrol. These data further characterise the potent anti-inflammatory properties of antioxidants. Their ability to inhibit the production of inflammatory cytokines, chemokines, and differentiation factors by a heterogeneous population of leukocytes has clear implications for their therapeutic potentialin vivo.

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Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417320112 ◽

2015 ◽

Vol 112 (19) ◽

pp. 6140-6145 ◽

Cited By ~ 301

Author(s):

Emanuela Romano ◽

Monika Kusio-Kobialka ◽

Periklis G. Foukas ◽

Petra Baumgaertner ◽

Christiane Meyer ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Clinical Efficacy ◽

Mechanism Of Action ◽

Mononuclear Cells ◽

Ex Vivo ◽

Immune Checkpoints ◽

Peripheral Blood Mononuclear ◽

Dependent Cell

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4–specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14++CD16− monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68+/CD163+ macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti–CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

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Anti-Inflammatory Activity of Fucoidan Extracts In Vitro

Marine Drugs ◽

10.3390/md19120702 ◽

2021 ◽

Vol 19 (12) ◽

pp. 702

Author(s):

Tauseef Ahmad ◽

Mathew Suji Eapen ◽

Muhammad Ishaq ◽

Ah Young Park ◽

Samuel S. Karpiniec ◽

...

Keyword(s):

Mononuclear Cells ◽

Cytokine Production ◽

Human Peripheral Blood ◽

Laminaria Japonica ◽

Macrocystis Pyrifera ◽

Human Macrophage ◽

Peripheral Blood Mononuclear ◽

Anti Inflammatory

Fucoidans are sulfated, complex, fucose-rich polymers found in brown seaweeds. Fucoidans have been shown to have multiple bioactivities, including anti-inflammatory effects, and are known to inhibit inflammatory processes via a number of pathways such as selectin blockade and enzyme inhibition, and have demonstrated inhibition of inflammatory pathologies in vivo. In this current investigation, fucoidan extracts from Undaria pinnatifida, Fucus vesiculosus, Macrocystis pyrifera, Ascophyllum nodosum, and Laminaria japonica were assessed for modulation of pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-6) by human peripheral blood mononuclear cells (PBMCs) and in a human macrophage line (THP-1). Fucoidan extracts exhibited no signs of cytotoxicity in THP-1 cells after incubation of 48 h. Additionally, all fucoidan extracts reduced cytokine production in LPS stimulated PBMCs and human THP-1 cells in a dose-dependent fashion. Notably, the 5–30 kDa subfraction from Macrocystis pyrifera was a highly effective inhibitor at lower concentrations. Fucoidan extracts from all species had significant anti-inflammatory effects, but the lowest molecular weight subfractions had maximal effects at low concentrations. These observations on various fucoidan extracts offer insight into strategies that improve their efficacy against inflammation-related pathology. Further studies should be conducted to elucidate the mechanism of action of these extracts.

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Ex vivo peripheral blood mononuclear cell response to R848 in children after supplementation with the probiotic Lactobacillus acidophilus NCFM/Bifidobacterium lactis Bi-07

Beneficial Microbes ◽

10.3920/bm2020.0068 ◽

2021 ◽

Vol 12 (1) ◽

pp. 85-93

Author(s):

G.P. DeMuri ◽

L.M. Lehtoranta ◽

J.C. Eickhoff ◽

M.J. Lehtinen ◽

E.R. Wald

Keyword(s):

Lactobacillus Acidophilus ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Ex Vivo ◽

Open Label ◽

Peripheral Blood Mononuclear ◽

Upper Respiratory Infection ◽

Beneficial Effects ◽

Inflammatory Protein ◽

Anti Inflammatory

Several studies have demonstrated a decrease in upper respiratory infection (URI) frequency and severity in subjects taking probiotic supplements. We hypothesised beneficial effects of probiotics on viral URI in children are due to modulation of inflammatory innate immune responses. We tested this hypothesis, providing children with a probiotic combination of Lactobacillus acidophilus/Bidfidobacterium animalis ssp. lactis Bi-07 (NCFM/Bi-07) and measuring levels of cytokines in response to stimulation of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 7/8 agonist resiquimod (R848). In this open label study, 21 (2 dropouts) children received probiotic containing 5×109 cfu each of NCFM/(Bi-07) daily for 30 days. Whole blood was taken from each subject at study entry and 30 days for culture of PBMCs. PBMCs stimulated with resiquimod (R848) or unstimulated were incubated and a panel of immune markers was measured. There was a significant decrease in the net (stimulated-null) level of myeloid progenitor inhibitory factor 1 (MPIF-1) (mean decrease 0.1 ng/ml, 95% confidence interval 0.01-0.24, P=0.032) following probiotic supplementation. The change in immune marker levels after supplementation, when analysed together with respect to expected inflammatory/anti-inflammatory effects, was increased for interleukin (IL)-10 and decreased for MPIF-1, IL-8, interferon gamma induced protein 10, macrophage inflammatory protein 3 alpha (MIP-3α) and E-selectin (P=0.01). Adverse events were mild. In conclusion, supplementation with this probiotic combination was safe and resulted in significant modulation of PBMC limited immune response to TLR7/8 agonist R848 and in levels of MPIF-1 and MIP-3α. The anti-inflammatory effect may be one mechanism by which probiotics modulate the immune system however further study is needed.

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Influence of Prior Exposure to Zidovudine on Stavudine Phosphorylation In Vivo and Ex Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.577-582.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 577-582 ◽

Cited By ~ 10

Author(s):

P. G. Hoggard ◽

S. D. Sales ◽

D. Phiboonbanakit ◽

J. Lloyd ◽

B. A. Maher ◽

...

Keyword(s):

High Performance ◽

Mononuclear Cells ◽

Ex Vivo ◽

Hiv Positive ◽

Peripheral Blood Mononuclear ◽

Significant Difference ◽

Immunodeficiency Virus ◽

Ex Vivo Study ◽

Level 2

ABSTRACT Intracellular phosphorylation of stavudine (d4T) and zidovudine (ZDV) was investigated in peripheral blood mononuclear cells (PBMCs) isolated from ZDV-naive and ZDV-experienced human immunodeficiency virus (HIV)-positive patients. An in vivo study measured the amount of d4T triphosphate (d4TTP), while an ex vivo study assessed the capacity of cells to phosphorylate added d4T. Endogenous dTTP was also measured. d4TTP and dTTP were determined in vivo using a reverse transcriptase chain termination assay. In ex vivo studies, d4T (1 μM) was incubated in resting and phytohemagglutinin-stimulated (10 μg ml−1; 72 h) PBMCs for 24 h. After washing and methanol extraction, radiolabeled anabolites were detected by high-performance liquid chromatography. d4TTP reached its highest level 2 to 4 h after dosing (0.21 ± 0.14 pmol/106cells; n = 27 [mean ± standard deviation]). Comparison of ZDV-naive and ZDV-experienced individuals showed no significant difference in levels of d4TTP (ZDV naive, 0.23 ± 0.17 pmol/106 cells [n = 7] versus ZDV experienced, 0.20 ± 0.14 pmol/106 cells [n = 20]; P = 0.473) or the d4TTP/dTTP ratio (0.14 ± 0.12 [n = 7] and 0.10 ± 0.08 [n = 20], respectively;p = 0.391). Ex vivo data demonstrated no significant difference in the formation of d4TTP or total d4T phosphates in naive and experienced patients (0.086 ± 0.055 pmol/106cells in ZDV-naive patients [n = 17] versus 0.081 ± 0.038 pmol/106 cells in ZDV-experienced patients [n = 22]; P = 0.767). The ability of HIV-infected patients to phosphorylate d4T in vivo and ex vivo was unchanged with increasing exposure to ZDV.

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Combinatorial Action of Triterpenoid, Flavonoid, and Alkaloid on Inflammation

Natural Product Communications ◽

10.1177/1934578x19868877 ◽

2019 ◽

Vol 14 (8) ◽

pp. 1934578X1986887

Author(s):

Vidya Sabu ◽

Jasmine Peter ◽

Aswathy Indira Bai Sasidharan Nair ◽

Santhi Krishnan ◽

Lal Preethi Sathyaseelan Suja ◽

...

Keyword(s):

Inflammatory Mediators ◽

Mononuclear Cells ◽

Nuclear Translocation ◽

Inflammatory Diseases ◽

Human Peripheral Blood ◽

Synergistic Effects ◽

Signaling Cascade ◽

Peripheral Blood Mononuclear ◽

Cox 2 ◽

Anti Inflammatory

In the present study, the synergistic effects of BASk, a combination of betulinic acid (B), apigenin (A), and skimmianine (Sk) in the ratio of 1:1:1, were studied to construct a novel drug mixture against inflammation via the TLR4-nuclear factor Kappa light chain enhancer of activated B cells (NFκB) signaling pathway. In silico drug likeness and docking studies recommended 3 bioactive compounds as suitable ligands for drug development. BASk inhibited TLR4 from its dimerization with MD2 and blocked the TLR4 signaling cascade. Reduced nuclear translocation of NFκB inhibited the release of pro-inflammatory mediators (IL-1β and TNF-α), COX-2 expression, and PGE2. Similarly, BASk exerted its protective role by reducing pro-inflammatory mediators and elevating anti-inflammatory cytokine, IL-10. This confirms the inhibiting potential of BASk in the activation of the TLR4-NFκB signaling cascade. Thus, BASk was superior in its anti-inflammatory effect on oxidized low density lipoprotein (ox-LDL) induced human peripheral blood mononuclear cells than its individual components synergistically. Since BASk inhibited COX-2 expression and further release of PGE2, it is a potent therapeutic agent with better efficacy against inflammation because COX-2 is the target site for treating inflammatory diseases. Thus, it can be clearly stated that this innovation will be a breakthrough in the treatment of inflammatory diseases.

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Bovine Leukemia Virus-Induced Persistent Lymphocytosis in Cattle Does Not Correlate with Increased Ex Vivo Survival of B Lymphocytes

Journal of Virology ◽

10.1128/jvi.73.2.1127-1137.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 1127-1137 ◽

Cited By ~ 18

Author(s):

Franck Dequiedt ◽

Glenn H. Cantor ◽

Valerie T. Hamilton ◽

Suzanne M. Pritchard ◽

William C. Davis ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Bovine Leukemia Virus ◽

Mononuclear Cells ◽

Ex Vivo ◽

Leukemia Virus ◽

Spontaneous Apoptosis ◽

Persistent Lymphocytosis ◽

Peripheral Blood Mononuclear

ABSTRACT Bovine leukemia virus (BLV) is an oncogenic retrovirus associated with B-cell lymphocytosis, leukemia, and lymphosarcoma in the ovine and bovine species. We have recently reported that in sheep, BLV protects the total population of peripheral blood mononuclear cells (PBMCs) from ex vivo spontaneous apoptosis. This global decrease in the apoptosis rates resulted from both direct and indirect mechanisms which allow extension of cell survival. Although sheep are not natural hosts for BLV, these animals are prone to develop virus-induced leukemia at very high frequencies. Most infected cattle, however, remain clinically healthy. This difference in the susceptibilities to development of leukemia in these two species might be related to alterations of the apoptotic processes. Therefore, we designed this study to unravel the mechanisms of programmed cell death in cattle. We have observed that PBMCs from persistently lymphocytotic BLV-infected cows were more susceptible to spontaneous ex vivo apoptosis than cells from uninfected or aleukemic animals. These higher apoptosis rates were the consequence of an increased proportion of B cells exhibiting lower survival abilities. About one-third of the BLV-expressing cells did not survive the ex vivo culture conditions, demonstrating that viral expression is not strictly associated with cell survival in cattle. Surprisingly, culture supernatants from persistently lymphocytotic cows exhibited efficient antiapoptotic properties on both uninfected bovine and uninfected ovine cells. It thus appears that indirect inhibition of cell death can occur even in the presence of high apoptosis rates. Together, these results demonstrate that the protection against spontaneous apoptosis associated with BLV is different in cattle and in sheep. The higher levels of ex vivo apoptosis occurring in cattle might indicate a decreased susceptibility to development of leukemia in vivo.

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