Year 2

In this proposal investigations are being performed to develop clinically relevant approaches to reduce the risk of rejection of embryonic stem cells (ESCs) and their derived cell products. We have identified that ESCs are readily rejected in the setting where they are mismatched to the recipient which is the clinical scenario for future intervention. We are exploring the role of naturally occurring immune regulatory cells such as regulatory T (Treg) cells and natural killer T (NK-T) cells in preventing rejection. We have found that these cells alone are not capable of preventing rejection but can be used in addition to total lymphoid irradiation (TLI) for the prevention of ESC rejection. We have observed that the use of TLI plus Treg is an effective and clinically relevant strategy for prevention of ESC rejection.

Additional studies are being performed on the analysis of strategies to prevent rejection of cells that are derived from ESCs. In the eventual clinical application of ESC based therapies it is likely that differentiated progeny will be the most likely cellular product since ESCs alone develop into tumors called teratomas. We are investigating the use of endothelial cells derived from ESCs which could be useful for re-vascularization for example following heart damage. These studies are just being initiated in the third year of this proposal.

In summary, immune regulatory strategies hold promise to overcome the rejection of ESCs and their derived progeny. It is expected that at the completion of this proposal we will have investigated how total lymphoid irradiation in combination with Treg or NK-T cells can be used as a strategy to avoid immune rejection.