Mechanism Found Behind Drug-Free Acceptance Of Transplants
COLUMBUS, Ohio -- Scientists at Ohio State University may have
discovered how a few rare organ transplant recipients manage to prevent their
bodies from rejecting their new organs without the help of drugs.
In this unusual category of patients -- who retain healthy function of their
transplants even when they go off immunosuppressive drugs -- the immune
system still reacts normally. However, the system essentially counteracts its
own normal combative response against the donor organ, researchers found.
"It's like two negatives making a positive," said Anne M. VanBuskirk,
research scientist at Ohio State's department of surgery and lead author of the
study. VanBuskirk and her colleagues reported their findings in a recent issue
of the Journal of Clinical Investigation.
A detailed understanding of the regulatory pattern uncovered by the
researchers would help doctors monitor transplant patients more effectively by
reducing their dependence on immunosuppressants. Eventually, this might
prove to be an important step toward the ultimate goal of transplantation:
getting recipients to accept a transplanted organ without administering drugs.
Left to their own devices, most patients' immune systems would reject organs
transplanted into them. It is only with a daily dose of drugs -- often several
pills taken together -- that transplant recipients keep their immune systems
from reacting violently to the foreign organ.
When patients discontinue their regimen of immunosuppressants, the majority
of them rapidly lose function of their transplants or grafts. In a small number of
such patients, however, the transplants continue to work just fine.
VanBuskirk and her colleagues, including Dr. William J. Burlingham, associate
professor of surgery at the University of Wisconsin, Madison, studied three
patients from this unusual group, hoping to understand the mechanism of graft
acceptance.
Two of the subjects were kidney transplant recipients who had stopped taking
immunosuppressive medication 1.5 and 5 years after their transplants. The
third patient had received a liver graft, and had gone off drugs -- by choice,
like the others -- two years after the surgery. At the time of the study, the
three grafts had been functioning well without drugs for 5, 28 and 4 years
respectively.
The scientists developed a novel technique -- the trans-vivo DTH test -- to
uncover the mechanism behind the transplant acceptance shown by these
patients. They started by focusing attention on "delayed type hypersensitivity"
(DTH) -- a common immune reaction that doctors use in the diagnosis of
many infectious diseases, including tuberculosis.
In the tuberculin test, injecting a person's skin with material from the
TB-causing micro-organism causes inflammation if the person has been
infected by the germ at any time in the past. DTH is thus a memory response,
since the immune system causes the inflammation upon recognizing a foreign
protein that it has encountered earlier.
For each of the donor-recipient pairs in the study, the scientists extracted
antigen from the donor's blood, added it to cells taken from the patient and
injected the combination into the footpad or ear of a SCID mouse -- a mouse
which lacked functional T and B immune cells.
Ordinarily, (and for the vast majority of transplant recipients), the footpad
would have shown swelling -- evidence of a response by the patient's cells
against the donor antigen. But for these three unusual cases, the footpads did
not swell up.
The natural conclusion would be that the patients' cells had not reacted to the
antigen of their respective donors. A non-response, in fact, would be quite
expected, since each of the three patients had accepted their grafts.
However, based on what they had learned from mice studies, the researchers
suspected that this was a simplistic -- and incorrect - explanation. It didn't
explain, for instance, why the presence of the donor antigen prevented the
cells from showing a DTH reaction to tetanus toxoid (TT) - a test antigen that
normally elicits a response. "We figured that the donor antigen was triggering
some sort of a reaction that muffled the normal DTH response," VanBuskirk
said.
To unmask what they believed was an anti-inflammatory response working
against the natural inflammatory reaction, the researchers blocked certain
cytokines -- proteins involved in immune regulation. Sure enough, when one of
two cytokines (TGF-B and IL-10) were inhibited at the DTH site, the
footpads swelled up. "It showed that the DTH response was not absent, but
invisible because of a simultaneous anti-DTH response," explained Charles G.
Orosz, professor of surgery and a co-author of the study. "Also, that this
downregulation of DTH was linked to the donor antigen, and was dependent
on either TGF-B or IL-10."
In addition to the three cases at the heart of the study, the scientists observed
the regulatory mechanism in four other patients still on immunosuppression.
"We need to study this further to see how common the mechanism is, when it
arises, and if patients who have this mechanism while they are taking
immunosuppression would retain their transplant functions if they went off
medication," VanBuskirk said.
Editor's Note: The original news release can be found at
osu.edu |
