July 16, 1998 PITTSBURGH, Penn., July 10 -- Genetically altered dendritic cells (DCs) could significantly improve the body's acceptance of a transplanted organ, according to University of Pittsburgh researchers in reports made at the 17th World Congress of the Transplantation Society held July 12-17 in Montreal. Known as the pacemakers of the immune system, DCs are specialized white blood cells that regulate the activity of other immune cells within the body. In the case of organ transplantation, investigators are harnessing DCs to teach T cells to tolerate transplanted organs that would normally be recognized by the body as foreign.
"DCs can be manipulated to disable the host's T cell response to a new organ," noted Angus Thomson, Ph.D., D.Sc., F.R.C.Path., professor of surgery and director of transplant immunology at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute.
One catch, however, is that donor dendritic cells transplanted together with an organ carry the same tissue markers that spur the host's immune system to reject a new graft. In effect, they could suffer rejection similar to a new organ, according to Dr. Thomson. In an animal transplant model, Pitt researchers circumvented this potential snag by genetically modifying donor-derived dendritic cells to churn out their own local supply of immunosuppressants.
"The benefits are two-fold," explained Dr. Thomson. "First, by producing their own localized immunosuppressant, dendritic cells buy enough time to teach host T cells not to attack and 'evict' the new organ, as it were. Second, the immunosuppressants also dampen the attack of T cells on the new organ. And because these dendritic cells produce immunosuppressants at a local, rather than systemic level, this engineered process minimizes side effects such as infection associated with systemic delivery of immunosuppressants."
In one study, Dr. Thomson's team used an adenovirus to shuttle the gene for the immunosuppressant protein transforming growth factor beta (TGF$1) into dendritic cells taken from the bone marrow of one mouse strain. Next, they took these DCs and transplanted them along with a heart to another immunologically distinct strain of mice. These altered DCs prolonged the survival of the new heart grafts in mice compared with mice who received donor hearts and DCs that had not been genetically modified with TGF$1.
"In another tissue culture study, the Pittsburgh investigators found that DCs genetically altered with an adenovirus to carry a gene for CTLA4-Ig were less likely themselves to be rejected by a host's immune system. CTLA4-Ig is an immunosuppressant that has been used in clinical trials to treat psoriasis. "This research gives us yet another indication that donor DCs genetically modified to protect themselves are less likely to disappear quickly within a donor body before they have a chance to teach T cells to tolerate a new organ."
In a related animal study, the researchers found that the CTLA4-Ig protein plus a monoclonal antibody, anti-CD40 ligand, effectively inhibits organ rejection in animal transplant recipients with immune systems that have been pre-sensitized to reject a new organ. This pre-sensitization can occur after a previous transplant or after events unrelated to transplantation such as multiple pregnancies or multiple blood transfusions.
"In essence, the immune systems of these transplant recipients are pre-armed to fight off a transplant." said Dr. Thomson.
The Pittsburgh team is currently planning clinical protocols incorporating the use of genetically altered DCs for delivery to patients as they receive organ transplants. They also expect to develop protocols using CTLA4-Ig and anti-CD40 ligand for pre-sensitized, difficult-to-treat transplant recipients. The CTLA4-Ig used in the research was provided by Immunex Inc. of Seattle.
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