Inflammation

We have a robust and growing portfolio in the area of Inflammation. For example, we have a strong knowledge of classic rheumatoid arthritis (RA) models and proficiency in imaging of RA, as well as acute inflammation disease. We work with our clients to develop multi-faceted studies that involve biomarker testing and validation to expedite both short-term and long-term decision making for lead molecule development.

We have validated numerous In vivo imaging-based protocols for RA, including Collagen Antibody-Induced Arthritis (CAIA), Collagen-Induced Arthritis (CIA) and LPS-Synchronized Collagen-Induced Arthritis (CIA) to quantify both the acute and chronic aspects of the disease. We also have documented proficiency in several classic, convenient models of acute inflammation. As a company, we continually leverage our experience in imaging technology to expand the boundaries of our inflammation-disease knowledge to benefit our clients.

  • Rheumatoid Arthritis (RA)

    RA is traditionally considered a chronic, inflammatory, autoimmune disorder that causes the immune system to attack joint tissues. Once triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells. There is no known cure. Current treatments focus on alleviating symptoms. One potential reason for the lack of treatments is the limitations of available preclinical animal models. Each model has strengths and weaknesses when compared with the human disease aspects. In vivo imaging-based protocols provide an opportunity to quantify both the acute and chronic aspects of RA. Imaging readouts provide more accurate, and more rapid, disease and response assessment. Our validated imaging methods in RA models include:

     

  • Collagen Antibody-Induced Arthritis (CAIA)

    This model has the advantage of inducing disease in many strains of mice that are resistant to the traditional collagen-induced form of arthritis (CIA). CAIA relies on the injection of a cocktail of monoclonal antibodies directed against type II collagen (C-II), followed by a single injection of lipopolysaccharide (LPS). In animals, a significant part of the inflammatory attack on the joints is mediated by pathogenic antibodies directed against C-II.

    In CAIA, symptoms appear within 7-8 days and studies can be completed within 18 days, allowing completion of compound assessment in a relatively, short time period. We can also assess the effects of agents on the resolution phase of the disease. CAIA is dependent on interleukin-1b (IL-1β), and tumor necrosis factor alpha (TNF-α), but is independent of the effects of interleukin-6 (IL-6). Our robust, rat and mouse, CAIA models produce disease in virtually 100% of the induced animals.

  • Collagen-Induced Arthritis (CIA)

    This inflammation model of rheumatoid arthritis (RA) is widely used to address questions of disease pathogenesis and to validate therapeutic targets. CIA models, in mice or rats, are performed by immunization with heterologous type II collagen (C-II) in adjuvant. Susceptibility to CIA is strongly associated with major histocompatibility complex class II genes, and the development of RA is accompanied by a robust T-cell and B-cell inflammatory response to C-II.

    The chief pathological features of CIA include a proliferative synovitis with infiltration of polymorphonuclear and mononuclear cells, pannus formation, cartilage degradation, erosion of bone, and fibrosis. Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1b (IL-1β) and interleukin-6 (IL-6) are increased in CIA similar to RA. Biological therapies designed to interfere with these mediators are active in our CIA models.

  • LPS-Synchronized Collagen-Induced Arthritis (CIA)

    Lipopolysaccharide (LPS) is an endotoxin that binds the CD14/TLR4/MD2 receptor complex and induces a strong response from the immune system. LPS dramatically increases the secretion of pro-inflammatory cytokines in many cell types, but especially in macrophages. This model enhances CIA and produces a 100% incidence of arthritic symptoms in mice within 24 to 48 hours after LPS injection. Unlike the CIA model, in the LPS-synchronized CIA model, arthritis progresses rapidly, within a few hours compared to weeks. The pathological features of this model are similar to the CIA pathological features.

  • Sponge (Air Pouch) Granuloma

    The sponge (air pouch) granuloma model is a convenient, flexible model of acute inflammation. The model can be used for a functional assessment of the ability of a compound to inhibit cellular recruitment and the release of inflammatory mediators in response to an agonist. It can employ various inflammatory insults and be left in place for as little as a few hours, or as long as several days. Combining traditional in vitro measures in this model with in vivo imaging biomarkers allows the assessment of cathepsin, MMP and macrophage activity.

  • Carrageenan-Induced Footpad Edema (CFE)

    CFE is a classic model of acute inflammation. It can be used for the assessment of the overall inflammatory process and as a method to assess acute inflammatory pain. The readout of footpad swelling is an indirect measure of inflammation and the inflammatory exudate in the paw can be collected and examined. The pathological features of this model include acute swelling and hyperalgesia. Imaging may be used to compliment traditional readouts in this model, for example by non-invasive assessment of cathepsin, MPP and macrophage activity.