Translational studies humanized animal disease models

The above observations clearly indicate that IL-4 is an important neutrophil activator in vitro. Recently, one study was conducted in order to assess the capacity of IL-4 and IL-IO to block neutrophil activation in an ex vivo human model system, and to confirm their effect on neutrophil function in an animal model of arthritis [75]. In the rat adjuvant arthritis model, treatment with systemic murine IL-4 (mIL-4 and mIL-10) was found to be effective against even the most severely diseased [75]. IL-4 (and IL-10) was effective in lowering the absolute neutrophil cell number recovered and the neutrophil activation state in the joint synovia. Both cytokines reduced the phagocytic activation of human neutrophils in response to proinflammatory cytokines. Collectively, the results demonstrate that IL-4 (and IL-10) can exert powerful regulatory effects on neutrophil function that translate into a therapeutic response in a disease model of arthritis. The authors concluded that treatment with IL-4 (or IL-10) alone or in combination might therefore be very usefiil in the management of patients with rheumatoid arthritis [75]. 

As will be discussed in the following sections, there are various diseased animal models, including spontaneous, chemically/surgically induced, or genetically engineered models for academic and pharmaceutical research applications. However, details of each existing or newer models are outside the scope of this chapter. Key perspectives discussed include strengths and weaknesses of commonly used animal models, potential causes/factors for poor translation of safety liabilities from animals to humans, and their application in the nonclinical mechanistic and safety studies. 

Further studies are required to determine whether these new findings can be translated to the diseased vessels of other animal models, or in humans where the dimensions of atherosclerotic plaques and their position beneath the endothelial cell layer are much larger than that seen in the diseased aortas of ApoE (— / —) mice. This question has recently been partially answered by the application of a mid-IR laser to image a patterned reflective surface through 150 mm thick films of blood. Our results show that one can detect the presence of atherosclerotic risk factors beneath a layer of endothelial cells, at least in the mouse model system. If this can be applied to humans in vim, and with continuing physics and engineering innovations, there will be an opportunity for the development of a new intravascular diagnostic modality which can... 

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