Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Consortium biology in immunology: the perspective from the Immunological Genome Project.

    3 September 2018

    Although the field has a long collaborative tradition, immunology has made less use than genetics of 'consortium biology', wherein groups of investigators together tackle large integrated questions or problems. However, immunology is naturally suited to large-scale integrative and systems-level approaches, owing to the multicellular and adaptive nature of the cells it encompasses. Here, we discuss the value and drawbacks of this organization of research, in the context of the long-running 'big science' debate, and consider the opportunities that may exist for the immunology community. We position this analysis in light of our own experience, both positive and negative, as participants of the Immunological Genome Project.

  • Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3.

    3 July 2018

    Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.

  • Application of autofluorescence robotic histology for quantitative evaluation of the 3-dimensional morphology of murine articular cartilage.

    28 June 2018

    Murine models of osteoarthritis (OA) are increasingly important for understating pathogenesis and for testing new therapeutic approaches. Their translational potential is, however, limited by the reduced size of mouse limbs which requires a much higher resolution to evaluate their articular cartilage compared to clinical imaging tools. In experimental models, this tissue has been predominantly assessed by time-consuming histopathology using standardized semi-quantitative scoring systems. This study aimed to develop a novel imaging method for 3-dimensional (3D) histology of mouse articular cartilage, using a robotic system-termed here "3D histocutter"-which automatically sections tissue samples and serially acquires fluorescence microscopy images of each section. Tibiae dissected from C57Bl/6 mice, either naïve or OA-induced by surgical destabilization of the medial meniscus (DMM), were imaged using the 3D histocutter by exploiting tissue autofluorescence. Accuracy of 3D imaging was validated by ex vivo contrast-enhanced micro-CT and sensitivity to lesion detection compared with conventional histology. Reconstructions of tibiae obtained from 3D histocutter serial sections showed an excellent agreement with contrast-enhanced micro-CT reconstructions. Furthermore, osteoarthritic features, including articular cartilage loss and osteophytes, were also visualized. An in-house developed software allowed to automatically evaluate articular cartilage morphology, eliminating the subjectivity associated to semi-quantitative scoring and considerably increasing analysis throughput. The novelty of this methodology is, not only the increased throughput in imaging and evaluating mouse articular cartilage morphology starting from conventionally embedded samples, but also the ability to add the third dimension to conventional histomorphometry which might be useful to improve disease assessment in the model.

  • Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis.

    1 October 2018

    Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1-/- macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.

  • Understanding of regional variation in the use of surgery.

    3 July 2018

    The use of common surgical procedures varies widely across regions. Differences in illness burden, diagnostic practices, and patient attitudes about medical intervention explain only a small degree of regional variation in surgery rates. Evidence suggests that surgical variation results mainly from differences in physician beliefs about the indications for surgery, and the extent to which patient preferences are incorporated into treatment decisions. These two components of clinical decision making help to explain the so-called surgical signatures of specific procedures, and why some consistently vary more than others. Variation in clinical decision making is, in turn, affected by broad environmental factors, including technology diffusion, supply of specialists, local training frameworks, financial incentives, and regulatory factors, which vary across countries. Better scientific evidence about the comparative effectiveness of surgical and non-surgical interventions could help to mitigate regional variation, but broader dissemination of shared decision aids will be essential to reduce variation in preference-sensitive disorders.

  • Changing the mindset in life sciences toward translation: a consensus.

    3 July 2018

    Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.

  • Inflammatory Arthritis Microbiome Consortium

    15 May 2017

    Bacteria and other microorganisms of the intestinal tract (collectively known as the gut microbiota) have fundamental roles in maintaining a healthy immune system. The ultimate goal of the Inflammatory Arthritis Microbiome Consortium (IAMC) is to manipulate the human microbiota for the treatment of inflammatory arthritis.

  • Inflammatory Arthritis Microbiome Consortium

    11 November 2015

    Kennedy Institute leads international consortium to investigate the link between gut bacteria and arthritis.

  • Homepage

    2 July 2015

  • A New Location

    15 May 2017

    As part of its relocation to Oxford the Kennedy Institute moved to a new £34 million purpose-built building located on the University Old Road Campus in 2013.

  • Events

    14 December 2015

  • Contact Us

    11 October 2015

  • About the Kennedy Institute

    1 January 2012

    The Kennedy Institute of Rheumatology is a world-leading medical research centre where discovery research drives development of transformative therapies for chronic inflammatory and degenerative disease.

  • External DPhil programmes

    15 October 2015

  • The technology

    8 October 2015