Sep. 25, 2000 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.
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