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Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune‐mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100‐fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ signaling in human basophils (IC50: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K δ/γ‐mediated immune signaling in the rat in a dose‐related manner. In addition, HM5023507 inhibited semiestablished collagen‐induced arthritic inflammation in the rats (ED50 of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology‐ and micro‐computed tomography (µCT)‐based indices of joint damage, bone destruction, and attenuated the levels of anti‐collagen antibody, with an overall anti‐inflammatory profile matching that of a TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting.

Inflammation is a complex biological reaction to invasion of the host by a pathogen or harmful stimulus and is a normal response to maintain homeostasis after injury. However, unregulated or aberrant inflammatory responses are believed to be involved in the pathogenesis of a wide range of diseases, including Alzheimer’s disease, chronic depression, and autoimmune disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Imaging the immune response and inflammation in preclinical models is important in the understanding of these disorders and for the development of novel therapeutics. Many processes associated with inflammation are amenable to imaging, including changes in local blood flow and cellular metabolism, presence of phagocytic cells, increased enzymatic activity, and the overexpression of certain cell surface markers that are characteristic of the immune response. Techniques such as optical fluorescence and bioluminescence imaging, magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), endoscopic imaging, and ultrasound play an important role in imaging inflammation. Visualization of drug delivery with imaging would be vital to ensure adequate exposure at the site of inflammation, particularly for targeted therapies that have been developed to reduce or eliminate toxicities from systemic exposure. Indeed, imaging plays a vital role in initial diagnosis and patient selection and for monitoring response to treatment over time. This chapter introduces inflammation and the immune system and describes numerous methods for imaging the inflammatory response, with specific applications in neuroinflammation, RA, and IBD.

Protection against leakage is one of the key consumer needs for tampon products. The absorbency of tampons depends on both the density of material inside the device, and the density gradient which pulls fluid into the core. Measuring tampon densities in a non-destructive manner was achieved using high-resolution three-dimensional computed tomography (CT) imaging. X-ray density was converted to mass density, using imaging of fiber pellets of known density. Two tampon types were scanned, and density and density gradients were calculated in both regions of interest and voxel-by-voxel. The CT scan density data were used to explain the results from a consumer use study that indicated a higher density prototype resulted in higher leakage versus a commercially available product that had a lower density profile at the periphery of the tampon and a higher density at its core.

Neuroinflammation and the accompanying activation of glial cells is an important feature of many neurodegenerative conditions. It is known that factors such as peripheral infections and stress can influence immune processes in the brain. However, the effect of these stressors on astrocyte activation in vivo remains elusive. In this study, transgenic Gfap-luc mice expressing the luciferase gene under the transcriptional control of the glial fibrillary acidic protein promoter were used to quantify the kinetics of in vivo astrocyte activation following immune challenges relevant to clinical inflammation. It was found that astrocytes respond rapidly to peripheral immune activation elicited by either bacterial lipopolysaccharide (LPS) or the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)). By measuring bioluminescence and 18-kDa translocator protein radioligand binding in the same animal it was observed that LPS induces both astrocyte as well as microglial activation at 6 h post-administration. Furthermore, the astrocyte response decreased upon repeated systemic LPS injections, indicating development of tolerance to the LPS challenge. Finally, restraining Gfap-luc mice for 1 h daily on 5 consecutive days did not affect brain bioluminescence, thereby indicating that sub-chronic stress does not influence astrocyte activation under unchallenged conditions. However, stressed animals showed a reduced response to a subsequent systemic LPS injection, suggesting that the immune system is compromised in these animals. Here, we demonstrate that Gfap-luc mice can be used to study astrocyte activation in response to stimuli relevant for clinical inflammation and that this approach may provide a more complete characterization of existing and novel models of neuroinflammation