Gene Therapy Enables Transplantation Without Immunosuppres...( . The procedure is performed in low-tem...)

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 work
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Contact: Franklin Hoke
hokef@mail.med.upenn.edu
215-349-5659
University of Pennsylvania School of Medicine
29-Jan-1998