At present, therapy of organ transplant rejection is dependent on immunosuppressive drugs. These agents, which may need to be taken for the lifetime of the patient, depress the whole immune system, and often result in increased risk of infections, and in some cases, cancer. The host response to organ transplantation is initiated and controlled by a specialized population of white blood cells, termed dendritic cells (DC). We have demonstrated recently that the administration of donor immature DC can be used to regulate recipient immune responses, and to inhibit the specific response against graft antigens without impairing the whole immune system. Although this approach offers several advantages, a drawback is that immature donor DC may become mature at some stage after their injection, and elicit harmful immune responses to the graft. Therefore, arresting of DC maturation is extremely important for the further development of a DC-based antirejection therapy. One of the important molecules that regulates DC maturation and function is nuclear transcription factor kB (NF-kB). Our preliminary studies have shown that blockade of this molecule by NF-kB specific oligodeoxyribonucleotide (ODN) decoys significantly inhibits DC maturation. Administration of DC genetically modified with NF-kB ODN (NF-kB ODN DC) prior to heart transplantation significantly prolongs allograft survival in mice. DC treatment with NF-kB ODN is safe, efficient, and inexpensive.

In this proposal, we will determine the optimal conditions for the generation of NF-kB ODN DC, and ascertain the most appropriate regimen of NF-kB ODN DC-based therapy for prevention of organ allograft rejection in a mouse-vascularized heart transplantation model. Positive results from this proposal will provide a basis for a trial of a genetically modified DC therapy in patients receiving organ transplants.