In 1992, biopsies taken
from the long-surviving patients’ transplanted organs, lymph nodes,
skin and other tissues revealed that donor leukocytes, or white blood
cells, had migrated from the transplanted organs to recipient tissues,
where they persisted years after transplantation. Researchers also found
recipient cells continuing to coexist with donor cells within the transplanted
organs. Such an observation provided confirmation that in organ transplantation,
surgeons are not only replacing organ function but they are also exposing
the recipient to the donor’s immune system.
Among the types of donor
cells that most often migrate to other tissues are stem
cells, from which all cells derive, and dendritic cells, which
originate in bone marrow. Dendritic cells capture antigens (foreign
or self particles) and present them to T and B cells, cells important
in modulating immune responses to infections, cancer and transplanted
organs. Researchers hypothesize that in order for chimeric dendritic
cells to induce donor-specific tolerance, they must either present a
foreign antigen in an altered way, thus allowing for its acceptance,
or they must directly inhibit T cells that are reacting against the
foreign antigen. Today, research continues to understand more fully
the role of this cell in transplant acceptance and functional tolerance.
Current understanding
suggests that four closely linked steps are required for completely
successful organ engraftment. The process begins once the donor leukocytes
home to recipient lymphoid tissues. Here, the donor cells induce the
recipient anti-graft T cells in an immunological war game. But both
types of cells—the T cells and the donor leukocytes—are left
exhausted and ineffective in the process and essentially cancel each
other out. These first two steps accomplished—clonal deletion of
the recipient response and clonal deletion of the donor-leukocyte response—the
third step required is to maintain this neutral status, called clonal
exhaustion. Finally, in order to sustain acceptance of the transplanted
organ, the donor organ must remain nearly depleted of its donor immune
system cells and replaced with like-recipient cells. Not only are the
donor cells more useful at other sites within the recipient, but their
presence within the organ might raise a red flag, thus signaling a targeted
host immune response.
Immunosuppressive drugs
are required, at least initially, to allow the donor cells to migrate
and coexist peacefully with recipient cells. Perhaps at first acting
as traffic directors, the drugs permit the immune cells to travel within
the body until arriving at their permanent destinations. Ultimately,
the drugs may work by striking a delicate balance between the two divergent
cell groups. Without the drugs, the patient’s immune system may
tilt in one direction, causing rejection and loss of the transplanted
organ, or the other, causing graft vs. host disease (GVHD), the complication
that involves donor immune cells attacking the recipient’s tissues.
While drugs may be needed
to strike the delicate balance of donor and recipient cells thereby
establishing the stable chimeric environment necessary for acceptance,
new evidence suggests the drugs may not be needed in the long run to
maintain this balance in a significant number of patients, contrary
to traditional belief.
Several long-term liver
transplant patients, who had received their transplants between five
and 21 years ago, have been successfully weaned from immunosuppressive
drugs as part of a controlled protocol. Others, including children,
with severe complications of immunosuppression, have also been successfully
weaned. Customarily, it has been thought that transplant recipients
need to take drugs for the rest of their lives to prevent the natural
defenses of their immune systems from attacking the transplanted organs.
Normally with suppressed immune systems, these patients are constantly
susceptible to infections, some of which can be deadly. However, if
carefully managed by a physician, some transplant recipients can either
completely stop or drastically reduce their doses of drugs without incidence
of rejection, the study has found. For transplant recipients, a life
without immunosuppression means a life free of unpleasant side effects,
associated medical complications as well as the risk for infections.
Chimerism research may ultimately improve the quality of life for all
transplant recipients, especially children, whose outward appearance
and growth can be negatively affected by the drugs they take.
Encouraged by these results,
the researchers are investigating ways to augment chimerism. One method
under clinical study involves providing an added supply of donor immune
system cells at the time of transplantation. Solid organ transplantation
and simultaneous bone marrow infusion from the same donor have been
found to be safe, with little risk of GVHD, and to augment the level
of chimerism. Long-term follow-up of patients will determine if it promotes
the acceptance of the transplanted organs.
Since Dec. 1992, more
than 225 patients have received bone marrow infusions at the time of
their liver, kidney, pancreas, lung or heart transplants. In addition,
some patients have also received pancreatic islet cells with either
kidney or liver transplants.
With some patients beyond
the five-year milestone, researchers will begin to assess whether these
patients can be partially or completely weaned of the need for immunosuppressive
drugs.