Animal models cell-based therapies

Stem cell-based therapy for cerebral ischemia will be more complicated, because the extensive cell death and massive inflammatory response make these brains a more hostile environment for cell grafts. Various sources of cells have been tested for their ability to reconstruct the forebrain and improve function after transplantation in animal models of stroke (Lindvall and Kokaia, 2004). In most cases, only a few grafted cells could survive. Some recent exciting findings in rodents suggest that stroke can induce an increase in neurogenesis thus, a new therapeutic approach based on self-repair has been brought forth, as discussed in Sect. 13.11.1. 

Cell-based products present similarities as well as complex issues not encountered with traditional biologicals. Innovative uses of animal models have contributed to advances toward clinically applicable treatment options based on studies designed to answer specific questions. Novel models and experimental paradigms are best considered as a case-by-case approach applied to each specific product. Noninvasive imaging methods play a critical role in cell therapy by identifying how many cells reach the desired target and, if they survive, divide and differentiate to fulfill their intended function. 

Further evidence for the importance of imine formation for T cell function was derived from the discovery that tucaresol and other small molecules with an aromatic aldehyde moiety capable of forming Schiff bases, produces a signal to CD4+ T helper (Th) cells [62]. Tucaresol reacts in vitro with free CD4+ T cell surface amines from receptors like CD2 within seconds to cause a co-stimulatory signal to produce a Thl response with the release of interferon y (IFN-y) and a 5- to 10-fold increase of interleukin 2 (IL-2). Such a Thl response is believed to be important for intracellular pathogens such as viruses, mycobacteria, protozoa and tumors. Studies in vivo show that low concentrations of tucaresol enhance not only CD4+ Th cells in response to antigens but also CD 8+ CTL and that this response has a beneficial effect in antiviral and antitumor therapy in animal models. Mechanistically, formation of Schiff bases with tucaresol has been shown to greatly affect intracellular potassium and sodium ion concentrations by the co-stimulation of mitogen-activated protein kinase (MAP kinase) and thus activation of ion channels in T cells [62,102]. Some of these mechanistic features are depicted in Fig. 19. 

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