What is inflammation?
Inflammation in biology is the response of the innate immune system to injury of the tissue. This aims to remove harmful factors, minimize further injury and initiate healing of the tissue. Consequently, a multitude of cell types become activated. Further a complex interplay between cells, e.g. macrophages, is initiated by exposure to factors like cytokines. In an activated state, these cells produce reactive oxygen metabolites, kill tumor cells, eliminate intracellular microorganisms and secrete proinflammatory cytokines including TNFα.
Absence of inhibitory factors or an overshoot of the innate immune system regarding the inflammation response may cause a chronic inflammation inducing additional tissue damage by the increased inflammation reaction, leading to a self-sustaining loop of inflammation with a lack of inhibition. An ongoing chronic inflammation is the underlying cause of inflammatory diseases. For example, Rheumatoid Arthritis (RA) and inflammatory bowel disease (IBD). In the former, the innate immune response activates first the adaptive immune system, which then activates the inflammatory response. In the latter, the innate immune response directly causes the inflammatory response.
Drug development for inflammatory bowel disease (IBD).
IBD is a chronic, inflammatory disease of the gastrointestinal tract. Crohn’s disease (CD) and ulcerative colitis (UC) are the main types of IBD. The increasing incidence of IBD worldwide causes an economic burden. The direct annual healthcare costs in Europe alone are estimated to be €4.6 – 5.6 billion. Medical treatment of IBD is complex and despite the therapeutic advances, still approximately 20% of patients with IBD requires intestinal resection surgery, whereas the development of novel immunotherapeutics requires years of clinical study often accompanied with late stage go/no-go decision-making. TRACER, together with its strategic partners and world-wide renowned gastroenterologists at the UMCG, are on the quest of serving the patient population with inflammatory diseases at the fastest pace and most reliable molecular imaging data possible.
The ultimate goal of medicinal treatment of inflammatory diseases like IBD and RA is induction of remission of the disease and consequently reduce symptoms and improve quality of life. Molecular optical and nuclear imaging provide the opportunity to image molecular events and therefore, could identify early changes in inflammation and moreover on- and off-target effects of fluorescent or nuclear labelled therapeutic compounds in microdosing studies. Moreover, it could be implemented in already available methods like fluorescence guided endoscopy and thus providing targeted fluorescence molecular imaging.
Molecular imaging and Inflammatory Disease.
Near-infrared fluorescence imaging combines optical imaging with a NIR (wavelength: 650–900 nm) targeted fluorescence tracer binding to a specific molecule. By choosing a fluorescence tracer binding to a specific anti-inflammation therapeutic compound, the presence and possible extent of the inflammation can be real-time visualized. Optical imaging has several advantages over current methods for visualizing tumor and inflammation characteristics: it does not use ionizing radiation, it provides real-time molecular information, it is cheap and it can be used as part of current endoscopic procedures. Improved tissue penetration is achieved by less absorption of hemoglobin in the NIR region. At the same time, less autofluorescence results in less background signal and higher signal-to-background ratio. These advantages make NIR fluorescence imaging appropriate for both in vivo molecular imaging and additionally ex vivo histopathological cross-correlation of the biodistribution of a fluorescent tagged therapeutic compound, as described by Koller et al (Nature Communications 2018).
TRACER has access to state-of-the-art fluorescence quantification techniques such as multi-diameter single fiber reflectance (MDSFR) and single-fiber fluorescence (SFF) spectroscopy.
This technique makes use of one fiber that can pass through the working channel of an endoscope and can then be placed on the surface of the tissue of interest. Subsequently, MDSFR spectroscopy determines the tissue absorption and scattering properties, while SFF spectroscopy corrects the tissue fluorescence for tissue optical properties, resulting in intrinsic tissue fluorescence, allowing a quantitative measure of the fluorescence emitted by the fluorescent tracer in a predetermined volume of tissue. In various studies carried out by our strategic partners at the UMCG and our own TRACER team has shown that MDSFR-SFF spectroscopy can be successfully applied in vivo and ex vivo in clinical studies related to fluorescent molecular imaging.