Self-organisation in LTE networks : an investigation

Mobile telecommunications networks based on Long Term Evolution (LTE) technology promise faster throughput to their users. LTE networks are however susceptible to a phenomenon known as inter-cell interference which can greatly reduce the throughput of the network causing unacceptable degradation of performance for cell edge users. A number of approaches to mitigating or minimising inter-cell interference have been presented in the literature such as randomisation, cancellation and coordination. The possibility of coordination between network nodes in an LTE network is made possible through the introduction of the X2 network link. This thesis explores approaches to reducing the effect of inter-cell interference on the throughput of LTE networks by using the X2 link to coordinate the scheduling of radio resources. Three approaches to the reduction of inter-cell interference were developed. Localised organisation is a centralised scheme in which a scheduler is optimised by a Genetic Algorithm (GA) to reduce interference. Networked organisation makes use of the X2 communications link to enable the network nodes to exchange scheduling information in a way that lowers the level of interference across the whole network. Finally a more distributed and de-centralised approach is taken in which each of the network nodes optimises its own scheduling in coordination with its neighbours. An LTE network simulator was built to allow for experimental comparison between these techniques and a number of existing approaches and to serve as a test bed for future algorithm development. These approaches were found to significantly improve the throughput of the cell edge users who were most affected by intereference. In particular the networked aspect of these approaches yielded the best initial results showing clear improvement over the existing state of the art. The distributed approach shows significant promise given further development.EPSR

Measurement of cytokines (pg/ml) one day after triggering TLR7 and/or 8 in unfractionated PBMC and PBMC without DC (n = 2).

<p>All data presented in this table were measured by bead assay as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001999#s4" target="_blank">Material and Method</a> section.</p

Triggering TLR8 and/or 7/8 blocks HIV replication after HIV entry but before integration.

<p>(A) Unspecific inhibitory effects of the compounds triggering TLR7 and/or 8 on HIV entry was examined with a cell-cell-based fusion assay, in which one cell line expresses the HIV-gp120 and an LTR-driven <i>lacZ</i> gene (HeLa SX CCR5) and the other cell line expresses the HIV receptor complex (CD4 and CCR5) and Tat (HeLa 243). Fusion of these cell lines will result in Tat driven LTR <i>lacZ</i> gene expression which we quantified histochemically by staining for β-galactosidase activity (n = 2). (B and C) Percentage of C4+ T-cells expressing CCR5 and CXCR4 was quantified by flow-cytometry two days after triggering TLR7 and/or 8 of PBMC Dashed lines indicate the matched samples. (D) Replication incompetent lentiviral viruses pseudotyped with VSV envelope which encodes a luciferase reporter gene were used to assess whether TLR7 and/or 8 triggering affects the early step in the replication cycle of HIV. Notably VSV uses a totally different entry mechanism than HIV which is highly unlikely to be affected by the TLR7 and/or 8 agonists. (E) Assessment whether TLR agonists have any effects on HIV replication at the transcriptional level or later in the HIV replication cycle. For this purpose, CD4+ T-cells were infected with HIV and spreading infection was blocked by adding the fusion inhibitor enfurvitide. These CD4+ T-cells with integrated HIV were co-cultured with either autologous PBMC devoid of CD4+ T-cells previously stimulated by TLR7 and/or 8 agonists vs unstimulated autologous PBMC devoid of CD4+ T-cells. Thus, any change in HIV output would be due to the effects on either transcription or later events in the HIV replication cycle due to TLR7 and/or 8 triggering (analysis of variance: n.s.; n = 6).</p

Soluble factors are critical to the anti-HIV effects after triggering TLR8 and 7/8.

<p>(A) Isolated CD4+ T-cells of PBMC were infected with HIV overnight. Transwells were added with the purpose to separate the HIV infected CD4+ T-cells by a semi-permeable membrane (indicated by the dashed line) from autologous uninfected PBMC devoid of CD4+ T-cells. TLR agonists were added to the culture medium as indicated in the figure. Infected PBMC where the TLR agonists were added to the insert served as positive control for the TLRs' efficient antiviral activity. Notably, CD4+ T-cells do not express TLR7 and 8 and thus do not react to the TLR agonists added. In this setup any inhibitory HIV activity observed when HIV infected CD4+ T-cells were separated by a semi-permeable membrane from the PBMC (devoid of CD4+ T-cells) must be due to factors secreted by the PBMC into the medium, which then diffuse through the semi-permeable membrane (n = 3). This setup with separated cells was compared to PBMC which have been treated identically. Control indicates PBMC infected with HIV. B) Blocking the IFN-α/β receptor (IFN-α/β R) does not reverse the TLR7/8 triggering mediated inhibition of HIV. Neutralizing antibodies to IFN-α/β R was added at 10 µg/ml 30 minutes prior to R-848 to PBMC which was infected two days later with HIV. All values were indicated as relative to the matched control which was arbitrarily set to 1.</p

Triggering TLR8 or 7/8 results in strong activation of NK and CD8+ T-cells.

<p>PBMC were treated with the TLR agonists and 24 h later analyzed for intracellular IFN-γ, TNF-α and CD107a expression for CD8+ T-cells (A) and NK (B), for the expression of CD69 on NK cells (n = 3) (C) and for the NKs' cytolytic activity against K562 cells (n = 3) (D). Data were first analyzed by one-way analysis of variance and if tested significantly different, by Bonferroni's multiple comparison test.</p

Neutralization of cytokines had no impact on anti-HIV activity subsequent to triggering TLR8 and/or 7/8; indicated are the percent inhibition of anti-HIV activity (median (25 to 75% percentile).

#<p>P = 0.012 (paired T-test)</p

Triggering TLR7 and/or 8 results in strong anti-HIV activity that varied with the origin of human lymphatic tissue.

<p>Dose-dependent blocking of HIV by the compounds tested (▪ = 3M-001, ▴ = 3M-002, ♦ = R-848) when exposing tonsillar lymphoid suspension cells to (A) the R5-tropic strain 49.5 (n = 2) or (B) the X4-tropic strain NL4-3 (n = 6 for 3M-001 and 3M-002 and for data points 3, 10, 30 µm, otherwise n = 2). (C) No toxic effects were noted in lymphoid tissue at 3 µm of any of the TLR agonists, as measured by the WST-1 assay (n = 6). Anti-HIV activities (D) in tonsillar lymphoid suspension cells and (E) in PBMC. Data obtained with R-848 were partially published before <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001999#pone.0001999-Schlaepfer1" target="_blank">[12]</a>. Data were first analyzed by one-way analysis of variance and if tested significantly different, by Bonferroni's multiple comparison test.</p

NK cells and CD8+ T-cells are the effector cells responsible for the anti-HIV effects in PBMC after triggering TLR8 or TLR7/8.

<p>PBMC from different donors were either depleted of CD8+ T-cells or NK or both, treated with the various TLR7 and/or 8 agonists and infected with the X4-tropic strain NL4-3 two days later. HIV infection was monitored by measuring p24 antigen in the supernatant over time. Statistical analysis was done by paired t-test.</p

Differential cell count in PBMC and tonsillar lymphoid suspension cells in % (avg±std; n = 4).

<p>Differential cell count in PBMC and tonsillar lymphoid suspension cells in % (avg±std; n = 4).</p

Induction of cytokines one day after triggering TLR7 and/or 8 in PBMC; indicated in each box upper line are the average±std fold induction# and lower line the corresponding absolute concentrations of cytokines measured in the supernatant [pg/ml] (n = 3) ¶.

<p>* ¥ IFN-α, IFN-γ, IL-6, IL-8, MIP-1α, MIP-1β, RANTES were measured by enzyme immunoassays, IL-12(p40) and TNF-α were measured with a bead assay (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001999#s4" target="_blank">material and method</a> section).</p