Natural Liver Suppressor Factors Induced by Liver Allograft

Early allograft survival has dramatically improved in all organ transplantation as a result of advances over the past decade in the treatment. However, chronic rejection and graft-versus-host disease (GVHD) which are two major unsolved problems in clinical transplantation medicine, have recently shadowed the success of solid organ transplantation except orthotopic liver transplantation (OLT). The unique immunology of liver transplantation appears to provide many hints to solve such confronting problems since the liver is less susceptible to all forms of immunologic injuries including hyperacute, acute, and chronic rejection, and also graft-versus-host reaction. A better understanding of the underlying mechanisms of such immunologic privileges rendered by liver transplantation would potentially yield lessons and strategies that could be used to protect not only liver allograft but other organ and tissue from rejection or GVH reaction. We have identified and characterized a total of 7 immunosuppressive proteins in the serum of tolerogenic orthotopic liver transplantaion (OLT) rats, three of which are novel proteins designated as liver suppressor factors (LSF-1, LSF-2, LSF-3) and the rest are FasL, Apo-E, Clusterin and CTLA4Ig. These proteins are synthesized in the absence of any immunosuppressive drugs, suggesting that the proteins are associated with drug-free tolerance. Our previous studies have demonstrated that LSF-1 as well as the potential human homologue has a strong immunosuppressive activity in vivo transplantation model. In the proposed study, we wish to further characterize and then evaluate the potential of these proteins to develop a novel diagnostic tool for "drug-free" tolerance,and also to establish a novel strategy to combat chronic rejection and GVHD. Our specific aims of this projects are as follows. To complete characterization and cDNA cloning of the immunosuppressive proteins. To identify the cellular targets of the immunosuppressive proteins. To assay the immunosuppressive activity of recombinant proteins in vitro and in vivo. To evaluate diagnostic values of these natural immunosuppressive proteins: We will investigate whether the natural immunosuppressive proteins, development of antibodies against these proteins and identification of their responsible genes, would be likely candidates to establish a "tolerance assay" to determine when immunosuppressive drugs can be stopped for long term surviving post-transplant patients. To distnguish and elucidate the differences between "real" tolerance and graft acceptance without tolerance ("pseudo" tolerance). To develop novel therapeutic strategies to combat acute rejection, chronic rejection or GVHR, which currently remains major problems in clinical transplantation. We believe that our research will have great potential to promote novel scientific advances and improvements of quality of life in patients and patient care, and socioeconomic benefit to the public health.

Project ID:PG9103-0419
External Project ID:NHRI-EX91-8904SL