The immunosuppressive activity of mesenchymal stromal cells (MSC) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSC are undetectable following administration. Therefore, understanding the fate of infused MSC could help to predict clinical responses. Using a murine model of graft-versus-host disease (GvHD) we demonstrate that MSC are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSC we found a striking parallel, whereby only those with high cytotoxic activity against MSC responded to MSC infusion whereas those with low activity did not. Importantly, the need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSC generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSC and produce indoleamine 2,3-dioxygenase (IDO) that is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSC or that all patients could be treated with ex vivo apoptotic MSC.
Blood lead levels have been decreasing in the US population. The reference level also should decrease. It is still important to monitor blood lead levels in the population, especially among pregnant women and children aged 1 to 5 years.
Obesity is a major health problem worldwide. Although diet and physical activity are crucial in the management of obesity, the long-term success rate is low. Therefore antiobesity drugs are of great interest, especially when lifestyle modification has failed. As obesity is not an immediate life-threatening disease, these drugs are required to be safe. Antiobesity drugs that have been developed so far have limited efficacies and considerable adverse effects affecting tolerability and safety. Therefore, most antiobesity drugs have been withdrawn. Fenfluramine and dexfenfluramine were withdrawn because of the potential damage to heart valves. Sibutramine was associated with an increase in major adverse cardiovascular events in the Sibutramine Cardiovascular Outcomes (SCOUT) trial and it was withdrawn from the market in 2010. Rimonabant was withdrawn because of significant psychiatric adverse effects. Orlistat was approved in Europe and the United States for long-term treatment of obesity, but many patients cannot tolerate its gastrointestinal side effects. Phentermine and diethylpropion can only be used for less than 12 weeks because the long-term safety of these drugs is unknown. Ephedrine and caffeine are natural substances but the effects on weight reduction are modest. As a result there is a huge unmet need for effective and safe antiobesity drugs. Recently lorcaserin and topiramate plus phentermine have been approved for the treatment of obesity but long-term safety data are lacking.
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