CTLA4Ig gene transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft

Organ transplantation requires lifelong antirejection therapy, which carrie s the risk of infection and cancer. A revolutionary approach is to transduc e the organ graft with immunomodulatory genes to render them tolerated with no need of systemic immunosuppression. Prolonged allograft survival was ac hieved by adenovirus-mediated transduction of the cold-preserved kidney wit h sequences encoding CTLA4Ig, a recombinant fusion protein that blocks T ce ll activation. Organ expression of the transgene was achieved associated wi th mild infiltration of mononuclear cells in the transfected kidney. Mixed lymphocyte reaction as well as the production of both Th1 and Th2 cytokines were reduced. Thus, the gene transfer technique to prolong graft survival is indeed effective and safe and can induce donor-specific unresponsiveness . Pending appropriate large animal testing, ex vivo genetic manipulation of the organ before surgery may hopefully represent a major step forward in h uman transplant medicine.