Migration of encephalitogenic CD8 T cells into the central nervous system is dependent on the α4β1-integrin

Although CD8 T cells are key players in neuroinflammation, little is known about their trafficking cues into the central nervous system (CNS). We used a murine model of CNS autoimmunity to define the molecules involved in cytotoxic CD8 T-cell migration into the CNS. Using a panel of mAbs, we here show that the α4β1-integrin is essential for CD8 T-cell interaction with CNS endothelium. We also investigated which α4β1-integrin ligands expressed by endothelial cells are implicated. The blockade of VCAM-1 did not protect against autoimmune encephalomyelitis, and only partly decreased the CD8(+) T-cell infiltration into the CNS. In addition, inhibition of junctional adhesion molecule-B expressed by CNS endothelial cells also decreases CD8 T-cell infiltration. CD8 T cells may use additional and possibly unidentified adhesion molecules to gain access to the CNS.

Graft preservation solutions in cardiovascular surgery.

Vein grafts are still the most commonly used graft material in cardiovascular surgery and much effort has been spent in recent years on investigating the optimal harvesting technique. One other related topic of similar importance remained more or less an incidental one. The storage solutions of vein grafts following procurement and prior to implantation are, despite their assumed impact, a relatively neglected theme. There is no doubt that the endothelium plays a key role in long-term patency of vein grafts, but the effects of the different storage solutions on the endothelium remain unclear : In a review of the literature, we could find 20 specific papers that addressed the question, of which the currently available preservation solutions are superior, harmless, damaging or ineffective. The focus lies on saline and autologous whole blood. Besides these two storage media, novel or alternative solutions have been investigated with surprising findings. In addition, a few words will be spent on potential alternatives and novel solutions on the market. As there is currently no randomized clinical trial regarding saline versus autologous whole blood available, this review compares all previous studies and methods of analysis to provide a certain level of evidence on this topic. In summary, saline has negative effects on the endothelial layers and therefore may compromise graft patency. Related factors, such as distension pressure, may outbalance the initial benefit of autologous whole blood or storage solutions and intensify the harmful effects of warm saline. In addition, there is no uniform consent on the superiority of autologous whole blood for vein graft storage. This may open the door to alternatives such as the University of Wisconsin solution or one of the specific designed storage solutions like TiProtec™ or Somaluthion™. Whether these preservation solutions are superior or advantageous remains the subject of further studies.

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.