Targeted delivery of anti-inflammatory therapy to rheumatoid tissue by fusion proteins containing an IL-4-linked synovial targeting peptide

We provide first-time evidence that the synovial endothelium-targeting peptide (SyETP) CKSTHDRLC successfully delivers conjugated IL-4 to human rheumatoid synovium transplanted into SCID mice. SyETP, previously isolated by in vivo phage display and shown to preferentially localize to synovial xenografts, was linked by recombinant technology to hIL-4 via an MMP-cleavable sequence. Both IL-4 and the MMP-cleavable sequence were shown to be functional. IL-4-SyETP augmented production of IL-1ra by synoviocytes stimulated with IL-1[beta] in a dose-dependent manner. In vivo imaging confirmed increased retention of SyETP-linked-IL-4 in synovial grafts which was enhanced by increasing number of copies (one to three) in the constructs. Strikingly, SyETP delivered bioactive IL-4 in vivo as demonstrated by increased pSTAT6 in synovial grafts. Thus, this study provides proof of concept for peptide-tissue-specific targeted immunotherapy in rheumatoid arthritis. This technology is potentially applicable to other biological therapies providing enhanced potency to inflammatory sites and reducing systemic toxicity

OX40 Ligand and Programmed Cell Death 1 Ligand 2 Expression on Inflammatory Dendritic Cells Regulates CD4 T Cell Cytokine Production in the Lung during Viral Disease

CD4-T-helper-cell (Th) differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on ‘inflammatory’ (CD11b+) DCs in the lung during recall responses is not fully understood, but important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1- or type 2-biased cytokine responses respectively upon RSV-challenge, we found expression of CD40 and OX40L on lung inflammatory DCs was higher in rVVF- than in rVVG-primed mice early after RSV-challenge, while the reverse was observed later in the response. Conversely, PD-L2 was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed OX40L on type 1-biased DCs promoted IL-5, while on type 2-biased DCs enhanced IFNγ production by antigen-reactive Th cells. In contrast, PD-L2 promoted IFNγ production irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses

Can primary care data be used to monitor regional smoking prevalence? An analysis of The Health Improvement Network primary care data

<p>Abstract</p> <p>Background</p> <p>Accurate and timely regional data on smoking trends allow tobacco control interventions to be targeted at the areas most in need and facilitate the evaluation of such interventions. Electronic primary care databases have the potential to provide a valuable source of such data due to their size, continuity and the availability of socio-demographic data. UK electronic primary care data on smoking prevalence from The Health Improvement Network (THIN) have previously been validated at the national level, but may be less representative at the regional level due to reduced sample sizes. We investigated whether this database provides valid regional data and whether it can be used to compare smoking prevalence in different UK regions.</p> <p>Methods</p> <p>Annual estimates of smoking prevalence by government office region (GOR) from THIN were compared with estimates of smoking prevalence from the General Lifestyle Survey (GLF) from 2000 to 2008.</p> <p>Results</p> <p>For all regions, THIN prevalence data were generally found to be highly comparable with GLF data from 2006 onwards.</p> <p>Conclusions</p> <p>THIN primary care data could be used to monitor regional smoking prevalence and highlight regional differences in smoking in the UK.</p