Jan. 29, 1998 Researchers at the University of Pennsylvania Medical Center, working in a rodent model, have succeeded in transplanting livers without the need for immunosuppressive drugs. In a scientific first, a gene therapy strategy was used to alter the donor liver prior to surgery so that the immune system of the recipient became permanently tolerant of the new organ. The new findings are reported in the February issue of Nature Medicine.
Although additional animal studies will be required before human clinical trials of the approach can be considered, the advantages of such a localized system for countering the immune-system rejection of newly engrafted organs are potentially significant. The powerful immunosuppressive drugs now required to allow a life-saving transplanted organ to survive in a recipient's body without rejection do their work only at a substantial cost to the overall well-being of the recipient.
"Currently, all immunosuppression is systemic and lifelong," says Kim M. Olthoff, MD, an assistant professor of surgery and lead author on the study. "So, to protect the new organ from rejection, long-term drugs that suppress the entire immune system must be given, making the person susceptible to infections, cancers, and a number of other complications, including nerve and kidney damage. In our study, a one-time gene therapy treatment of only the donor liver made the recipient's immune system tolerant of the new organ without the need for any further immunosuppression."
The technique developed by the Penn team makes use of an adenovirus -- a virus usually associated with the common cold -- that has been engineered to incorporate the gene that encodes for a protein called CTLA4Ig. The gene-bearing virus, referred to as a vector, is then introduced into an organ preservation solution used to maintain the liver after harvesting and prior to engraftment, resulting in uptake by the organ. The procedure is performed in low-temperature conditions that further enhance preservation of the organ.
After the transplant surgery, the gene is expressed in the liver in the form of the CTLA4Ig protein. This protein blocks the so-called costimulatory signal required to fully activate T cells, the cells responsible for recognizing and responding to foreign antigens such as those presented by the tissues of a transplanted organ.
The term costimulatory refers to the fact that two chemical signals are required to trigger T cells to attack foreign tissues. A primary signal that alerts the cell to the presence of a foreign antigen occurs at the site of a molecule called the major histocompatibility complex, or MHC. Without a second signal, however -- the costimulatory signal -- the T cell will not develop into a cytotoxic T cell that destroys the invader tissues.
In fact, earlier research has shown that if the pathway for the costimulatory signal is blocked at the time of foreign antigen presentation -- at the time of surgery and in the period immediately thereafter, in this case -- then the T cells become permanently tolerant of the new tissue. It is this learned tolerance that explains why the gene therapy tactic employed by the Penn researchers resulted in successful long-term liver engraftment without the need for continuing immunosuppressive drug therapy.
"What we have developed is a feasible model for a gene therapy approach to local immunosuppression in liver transplantation," says Abraham Shaked, MD, PhD, associate professor of surgery and senior author on the Nature Medicine report. "We were able to deliver the gene for a protein that blocks the immune system from attacking an engrafted organ, and we were able to do so with a single treatment that obviated the need for follow-up drug therapy. Taken together, these are exciting initial results that we're now working to extend."
In addition to Olthoff and Shaked, the remaining Penn-based coauthors are Thomas A. Judge, MD, Andrew E. Gelman, Xiu Da Shen, and Laurence A. Turka, MD. Wayne W. Hancock, MD, at Harvard Medical School is also a coauthor.
Primary grant funding for this work was provided by the National Institutes of Health. Additional support came from the Thomas B. McCabe Fund and the American Heart Association.
The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period.
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