“Survivor”-style sitcoms top the charts of TV shows today. Television producers are feverishly proliferating these psuedo-real programs, which viewers relish just as if the danger and suspense were true. Truly true are the danger and suspense of organ transplantation, despite its growing surgical successes.
Consider the odds of this clinical lottery: Some 12,000 organ replacements a year take place in the U.S. alone. Meanwhile, nearly 6,000 hapless patients annually 16 a day on average die while on standby for a life-saving donor organ. They are among the 79,000 people on organ-transplant waiting lists.
Now look at a lucky survivor who makes it all the way to a solid-organ transplant. However, lying in wait with its own death sentence is acute graft rejection whereby the recipient’s immune-system killer T cells, outraged by an alien, intruder tissue, as marked by its donor antigens destroy the transplant. To remain a survivor, rather than a casualty, the fortunate graft recipient must spend the rest of his or her lifetime on immunosuppressant drugs that frustrate the fatal rejection.
But the recipient is not out of the jungle yet if ever. By definition, a blunted immune system opens wide the entry to infection by marauding viruses, bacteria, fungi and parasites. What immunologists are striving for is a built-in immune system element that would allow the body to tolerate the donor organ’s rejection antigens.
They may have found it in the online version of Nature Immunology’s February 2002 issue. The paper announcing this discovery bears the title: “Tolerization of dendritic cells by Ts cells: the crucial role of inhibitory receptors ILT3 and ILT4.” Its senior author is immunologist Nicole Suciu-Foca, who directs immunogenetics and immunology at Columbia University in New York.
“We found an antigen-specific population of immunosuppressor cells, which act directly via the body’s dendritic cells,” Suciu-Foca told BioWorld Today. “These cells induce the upregulation of two specific receptors, ILT-3 and ILT-4, which are responsible for the inhibition of T-cell activity,” she explained.
Another Prime Target: Autoimmune Diseases
“And this is of capital importance,” Suciu-Foca continued, “because until now it was difficult to generate a model for inducing specific tolerance for example, to an organ transplant. Also,” she added, “to an organ in the body that is being attacked by your own T cells. That’s autoimmunity, as in diabetes, multiple sclerosis, psoriasis, autoimmune hepatitis, lupus, rheumatoid arthritis. For all these autoimmune diseases, we should like to have a specific inhibitory mechanism, instead of nonspecifically suppressing the immune response, and so opening the way to infection and malignancy.
“You’d like to have a tool,” she went on, “that will protect you by directly inhibiting the autoimmune response in this manner. In other words, you want a dendritic cell loaded with graft-rejection antigens and inhibited. Evidently, there are other diseases cancer and AIDS for example where you would not want suppressors around, which can induce ILT-3 and ILT-4 in dendritic cells. We’d like to downregulate these molecules, or prevent them from being upregulated block them.”
She noted, “The ILT genes had been found before, but nobody knew their function until now. It was not known that the dendritic cells in fact can induce tolerance.” In in vitro cell-culture studies, she and her co-authors showed how increasing the activity of ILT3 and ILT4 on dendritic cells could make the immune system tolerate antigens.
“We also analyzed the blood of heart transplant recipients,” Suciu-Foca recounted, “and showed that those patients who did not reject donor hearts had circulating T-suppressor cells that induced the activity of ILT-3 and ILT-4 in donor dendritic cells. These results,” she pointed out, “show that the heart recipients without rejection had T-suppressor cells that had been primed to suppress a response to foreign hearts.”
She added, “The findings of our study also have implications for Type I diabetes and other autoimmune diseases, in which the immune system attacks normal body tissue rather than being tolerant of it. Enhancing the activity of ILT3 and ILT4 in dendritic cells, which present the target antigen, might help affected patients suppress that autoimmune response.
“On the other hand,” Suciu-Foca pointed out, “physicians would like to boost the immune response against malignant and HIV-infected cells to help fight cancer and AIDS.”
She and her team are now writing a follow-up paper for Nature. “In a general way we are looking at a cascade of immunological phenomena treated by this suppressor population. We can use them for inducing tolerance together in transplants, and we’re also looking very intensively at AIDS. We need the help of biotechnology in that aspect,” Suciu-Foca allowed. “The protocols are very straightforward, but it takes more hands that we can put to it.”
“The university has a patent pending,” she pointed out, “of which I am principal inventor. The patent was filed in 1998 when we first discovered this repressor, and ILT3 and ILT4, which cover all its aspects.”
Contrarian Therapies: Cancer, AIDS
“The clinical applications are monumental,” Suciu-Foca stated. “In the first place, pharmaceutical companies have on their shelves thousands of chemicals drugs which they don’t know what to do with. Simply by testing the capacity of a drug to upregulate these small molecules, they would know which one might be of use for induction of specific tolerance. The pharmacological application is going to be dividing drugs for upregulation and downregulation.
“The next application will be to generate tolerogenic vaccines. They would operate by loading the patient’s own dendritic cells with tissue antigens. Apoptotic necrotic cells of pancreatic islets, for example, would be eaten up by the dendritic cells, which would be treated so as to upregulate the ILT-3 and ILT4. Then the cells would be reinjected, and perform cell therapy for induction of specific tolerance. That’s what we want to prove in an experimental model.”
Although she has not yet contacted any biotech companies, Suciu-Foca sums up “what they can do with this invention: for diagnostic kits; for screening immunosuppressive agents; developing tolerogenic vaccines. It’s going to be particularly important for induction of tolerance in bone-marrow and solid-organ transplantation and the pharmacology of AIDS. That,” she concluded, “is going to be very, very important for us.”