Molecular biological modification of the target organ

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The ultimate goal of the clinical organ transplantation is to establish an immunological tolerance of the recipient. Ideally, this is to be achieved not by interfering the recipient's immunological defense mechanism but by altering the immunogeneicity of the donor graft, thus minimizing the risk of immunosuppression of the recipient. This concept is the basis of the present research.The graft is a target organ which is succumbed to immunological attack by the recipient. From the aspect of molecular biology, this type of cytotoxicity of the graft organ results from apoptosis of the cell. We hypothesize that prevention of apoptosis can be achieved by modulating the apoptosis-associated molecules with the use of genetic manipulation. We used hepatocytes and endothelial cells as the target cells. We have found that tacrolimus, commonly used immunoxsuppressant, is capable of reducing Fas antigen expression of the hepatocytes. The endothelial cells are known to be the prime target of both ischemia reperfusion injury and immunological cytotoxicity. This type of cytotoxicity is also noted to be as a result of apoptosis. We were able to transfect human copper, zinc-super oxide dismutase (Cu, Zn-SOD) into the endothelial cells. These cells became resistant to the free radical which is the principal form of cytotoxicity associated with preservation injury of the graft. Simultaneously, we found that cytosolic calcium is increased in association with endothelial cell apoptosis which suggests calcium blocking as a useful means for prevention of apoptosis.We, therefore, believe that biological manipulation of the apoptosis-associated molecules can prevent cytotoxicity in organ transplantation which may ultimately establish immunological tolerance.