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Gene Therapy Aids Organ Transplant

February 2, 1998 — Gene therapy may someday spare organ transplant patients from having to take immunosupressant drugs, according to a new study.

“What we have developed is a feasible model for a gene therapy approach to local immunosuppression in liver transplantation,” said Dr. Abraham Shaked, associate professor of surgery at the University of Pennsylvania Medical Center, and senior author of a report published in the current issue of Nature Medicine.

Organ transplant always carries the risk that the patient’s own immune system will recognize the new tissue as an invader, and seek to destroy it. Powerful immunosuppression drugs can subdue that response, but the side effects of the drugs can be severe, including increased risk of infections, cancer, and nerve and kidney damage.

Shaked and his colleagues investigated the mechanisms of the immune system response. They knew that two molecular signals are necessary to trigger rejection on the cellular level. The signals originate in a molecule known as major histocompatibility complex (MHC). Responding to what it assumes to be a threat, MHC sends out two separate signals aimed at alerting the immune system’s T cells to attack.

But the Pennsylvania team engineered simple virus cells to carry genes capable of stimulating production of a protein called CTLA41g. This protein has the ability to block that second, crucial signal switching on the T cell response.

The engineered virus was mixed into the solution used to preserve harvested livers during the hours before transplantation. Surrounded by the solution, the liver effectively “soaked up” the virus, and along with it, the CTLA41g-manufacturing gene.

The result? Livers already primed to prevent rejection by the host. “We were able to deliver the gene for a protein that blocks the immune system from attacking an engrafted organ,” Shaked explained, “and we were able to do so with a single treatment that obviated the need for follow-up drug therapy.”

“Although not immediately applicable in the clinical setting, there is definite potential for future clinical intervention,” write the researchers. “…Future studies are needed to determine whether expression and recombinant protein activity can be restricted to the graft, and whether a similar system will be effective in the induction of hyporesponsiveness in a large animal/primate… without the need for additional induction strategies.”