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    • Afterward Fluc hNIS mMABs were

    2018-11-09

    Afterward, Fluc-hNIS+ mMABs were bilaterally injected into the femoral polo like kinase and successfully monitored via both BLI and small-animal PET. After systemic administration, we were clearly able to monitor mMABs for several days via small-animal PET. Long-term cell monitoring was not feasible because of cell loss over time and the lower sensitivity of PET compared to BLI (Massoud and Gambhir, 2003). To overcome this limitation, more potent promoters combined with enhancers need to be used to increase the expression levels of the reporter gene (Minn et al., 2014). One other imaging study has been performed for MAB therapy of MDs. In this study, a direct cell labeling approach via iron nanoparticles was performed to monitor the cells via MRI (Odintsov et al., 2011). This cell labeling approach is limited by contrast agent dilution, no discrimination between viable and nonviable cells, and nonspecific uptake by macrophages (Li et al., 2008). In the study of Odintsov et al. (2011) iron oxide labeled MABs were injected in mdx mice and nonspecific uptake of nanoparticles by the macrophages was observed. Furthermore, they were not able to visualize mMABs after systemic delivery. At present, a major limitation for cell transplantation is cell rejection by the host (Alpdogan, 2013). Contrasting results have been found for MABs and their reaction with the immune system. English et al. (2013) demonstrated that human MABs are capable of suppressing T cell proliferation. Guttinger et al. (2006) also observed no activation of T cells after stimulation with mMABs. However, isolated T cells from mMAB-injected muscles were clearly reactive against re-exposure to mMABs. Noviello et al. (2014) also indicated that human MABs exposed to inflammatory conditions or during differentiation are capable of inducing T cell expansion and are becoming sensitive to T cell mediated killing. In this study, we were able to noninvasively monitor non-H2 matched mMAB survival and to evaluate both the reaction of mMABs with the immune system and the efficacy of different immune suppressants. This imaging-based assessment has already been demonstrated to be successful by several other groups (Everaert et al., 2012; Gheysens et al., 2006; Huber et al., 2013). Currently, chronic immunosuppressive therapy is the gold standard, but has modest and variable results in patients and lifelong immunosuppression makes them prone for secondary malignancies and opportunistic infections (Fischer et al., 2011). CsA is a widely used clinical immune suppressant that blocks T cell activation via blocking of cytokine gene expression, including interleukin (IL)-2 and IL-4 (Krönke et al., 1984). However, it is associated with numerous side effects and variable results in suppressing graft rejection have been observed (Fischer et al., 2011; Gheysens et al., 2006; Huber et al., 2013; Patel and Kobashigawa, 2004). Therefore, novel methods with only short-term suppression of the immune system are currently under investigation (Alpdogan, 2013). Huber et al. (2013) demonstrated that a short regimen of co-stim (consisting of CTLA4-Ig and anti-LFA-1) outcompetes CsA in maintaining cell survival after intramuscular and intracardiac injection of human embryonic stem cell (hESC)-derived endothelial cells or hESC-derived cardiomyocytes, respectively. Co-stim functions via the inhibition of the co-stimulatory signals that are required for proper T cell activation. CTLA4-Ig has a higher affinity for CD80 and CD86, which are present on antigen presenting cells (APCs), and therefore blocks the CD28-CD80 or CD86 pathway, which is important for T cell stimulation (Boise et al., 1995). Anti-LFA-1 is responsible for the blocking of the LFA-1-ICAM-1 pathway and inhibits T cell activation (Nicolls et al., 2000). It has been demonstrated that the ICAM-1 pathway played a major role in the sensitivity of MABs toward T cell mediated rejection (Noviello et al., 2014). Our BLI data demonstrated a slower decrease in cell viability in co-stim treated animals compared to Sgca mice without immune suppression or treated with CsA. This improved cell survival under co-stim, and the inability of CsA to improve cell survival has also been demonstrated by others (Everaert et al., 2012; Gheysens et al., 2006; Huber et al., 2013). The relative stable cell survival the first days after injection followed by a drastic reduction is indicative of the role of the adaptive immune system. This is in line with previous publications indicating the importance of T cells in graft rejection (Rosenberg et al., 1987; Strom et al., 1975). Despite the beneficial effects of co-stim, stable cell survival could not be achieved for more than 21 days post-injection, which is 15 days after stopping co-stim immune suppression.