By David Leff

Auto mechanics make it a point to assure their customers that the replacement parts they put into an ailing automobile are guaranteed authentic components, direct from the manufacturer. Organ transplant surgeons can offer no such assurances.

Quite the contrary: A cadaver donor heart, lung, kidney, liver or pancreas would be seen by the recipient's immune-defense T cells as foreign, and destroyed in hours or days, were it not for drugs that suppress the immune system. The only clinical exceptions to this acute rejection process are transplants of donor corneas into damaged eyes, cartilage to failing joints and a donor organ from the beneficiary's identical twin.

What with some 66,000 Americans awaiting a replacement organ, but only 10,000 donors available, and similar shortages elsewhere in the world, surgeons and immunologists are striving to make donor organs as immunologically welcome as that from an identical twin. In other words, fostering immune tolerance in recipients.

Consider corneal transplants: "It's been known for a while," observed nephrologist and molecular geneticist Laurence Turka, "that certain anatomical sites in the body are what people call 'immune privileged,' meaning that immune responses almost don't occur in these sites. The main ones are testis, ovary and the eye's anterior chamber.

"Think of cells as having two different types of suicidal death - "apoptosis, which is non-inflammatory, and necrosis, which is," Turka explained. "Recent research shows that immune cells in the eye undergo non-inflammatory apoptotic cell death. Therefore one of the obvious reasons we think of the eye as an immune privileged site is that the immune T cells that go into the eye die by apoptosis. They can't carry on an immune response.

"We now know," he continued, "that the recipient tends to become tolerant to that donor corneal antigen, not just in the eye but throughout his or her body. We are trying to devise strategies enabling one to create immune tolerance to donor-organ antigens in other sites."

Back-To-Back Papers Outline Tolerance Strategy

Turka is an endowed professor of medicine at the University of Pennsylvania, where he heads the renal division. He is co-senior author of a paper in the current Nature Medicine for November 1999, titled, "Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance." A back-to-back article in the same issue bears the title, "Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance."

In both of these journal articles, Turka's co-senior author is nephrologist Terry Strom, who is co-chief of immunology at Harvard-affiliated Beth Israel Deaconess Medical Center.

Turka observed that "the immune suppressor cyclosporin A has been a great advance in minimizing the incidence of acute graft rejection, and in prolonging transplant survival for virtually all organs. But," he told BioWorld Today," I think that neither cyclosporin A nor any of the more recent such drugs have solved the problems of chronic graft rejection, occurring several months to several years later at a very slow and insidious pace.

"The mechanism by which we've induced tolerance, as we describe in these two papers," Turka continued, "is based on the concept of co-stimulatory blockade. The idea is that T cells are not activated by stimulation with antigens alone. That first signal provides some type of immunological specificity to the response, but is not sufficient to enable T cells to make cytokines. That requires a second signal - and also a third co-stimulatory one.

"These co-stimulatory signals," Turka pointed out, "are mediated through T-cell surface receptors; one is CD28, another CD154. The concept of inducing tolerance by using anti-rejection agents, which are present as biologic molecules, is to block these co-stimulatory receptors, thus preventing these T cells from receiving those co-stimulatory signals, and thereby trying to block that rejection pathway.

"What our papers show is that to induce tolerance in these models means killing or getting rid of activated T cells, that is, T cells activated without receiving co-stimulatory signals, and so undergo apoptosis - programmed cell suicide."

One of the cytokines that T cells mobilize is interleukin-2 (IL-2), which both promotes T cell proliferation and, paradoxically, primes them for suicide.

Mice Clinch Actions Of Two Anti-Rejection Agents

Turka and Strom, between their two laboratories, conducted three mouse experiments confirming their new approach to tolerance induction.

"After we did our initial studies," Turka recalled, "it was discovered that co-stimulaory signals not only induced growth factors but cell survival genes as well, in particular Bcl-x_L. So we asked whether the important effect of co-stimulatory blockade, which we thought was blocking cytokine genes, might actually be blocking cell survival genes.

"To investigate that," he recounted, "we used mice genetically engineered to express Bcl-x_L T cells even without co-stimulation. And we found that cells from those animals survived for very long periods of time, and were able to reject their transplants even when they were treated with co-stimulatory blockade. They resisted tolerance.

"The second paper," Turka narrated, "physically demonstrated that activated proliferating T cells do indeed undergo cell death by apoptosis, which is significantly enhanced by the co-stimulatory blockade, and an experimental immune suppressor drug, rapamycin, synergizes with that to enhance it even further."

Then, in mouse models of heart, skin and islets of Langerhans, the co-authors showed that co-stimulation blockade seemed to work by promoting suicide of transplant-rejecting T cells. Here too, rapamycin amplified the effect in skin cells, the most susceptible to graft rejection.

Ironically, Harvard's Strom observed, "we also found that cyclosporins inhibited tolerance with rapamycin by blocking this apoptosis. This does not mean," he added, "that cyclosporin is detrimental to organ transplant recipients, but we do feel that progress to the next level may require new drug combinations without cyclosporin."