o prevent a transplant patients body from attacking a donated heart, liver, or kidney, strong drugs are used to suppress the patients immune system. But the medications also suppress the bodys defenses against everything else, including foreign pathogens and cancer cells.
New research findings by Dr. Nicole Suciu-Foca, professor of pathology, may someday radically change the way the immune system is suppressed in transplant patients. She and colleagues at P&S, Washington University, and the University of Rome have discovered the role a pair of protein receptors play in the immune systems ability to develop tolerance to a specific target or antigen.
Controlling the expression of this duo, ILT3 and ILT4, may allow the immune system to tolerate the donor organ but leave the rest of the immune response alone, avoiding the risk of infections and malignancies observed with non-specific immunosuppression. The research was published online in Nature Immunology on Jan. 28, in advance of the March print version.
Immunologists have been searching for the full explanation of tolerance for 30 years to help improve the acceptance of transplanted organs. Tolerance prevents our immune system from attacking our own tissues and harmless foreign antigens. Self-tolerance can be partly explained by the destruction of self-tissue by T cells that react to self-antigens. But some self-reactive T cells slip through the destruction process, killing tissue in the body. How are these self-reactive T cells prevented from attacking our own bodies under normal conditions? How do our bodies prevent T cell attacks on harmless foreign antigens? And is there a way doctors can manipulate the system to prevent organ rejection?
In the past few years, some immunologists have tried to answer these questions by focusing on a special set of T cells called T suppressors. So far, the set of cells identified do not appear to act in an antigen-specific manner. But Dr. Suciu-Foca says the T suppressors that induce tolerance should be no different from other members of the immune system, which react to and remember specific antigens.
Convinced an antigen-specific mechanism of tolerance exists, Dr. Suciu-Foca several years ago began looking for and then found a different set of T cells. These suppressor T cells induce tolerance after recognizing the antigens on the surface on another type of immune cell, called dendritic cells, which process and present antigens to T cells, including T suppressor, T helper, and T killer cells. Somehow, after this recognition, the T suppressor cell robs the dendritic cells ability to activate T helper and T killer cells to respond to the same antigen. Without active T helper and T killer cells, the immune response to the antigen is put on hold.
The researchers then found that these two proteins are directly responsible for turning off the dendritic cell activity and the immune response. When they added antibodies against ILT3 and ILT4 to a cell culture, the antibodies blocked the ILT3 and ILT4 receptors and restored the ability of the dendritic cells to activate the T helpers and T killers.
The finding has immediate implications for organ transplantation. If we want to induce tolerance in a transplant patient, Dr. Suciu-Foca says, we have to induce ILT3 and ILT4 in the transplanted organs antigen presenting or dendritic cells. Experiments to induce tolerance by pre-treating organs with an agent that increases expression of the pair are in the planning stages. But data from the Nature Immunology paper suggest the approach is promising.
Looking at the outcome of 15 heart transplant patients, Dr. Suciu-Foca found the two proteins play a role in vivo. In organ transplant, the patients immune system initially reacts against dendritic cells that come from the donated organ. If these dendritic cells could be suppressed, the patient may have a lower risk of rejection. In Dr. Suciu-Focas study, five out of six patients who had T suppressor cells capable of suppressing the donors dendritic cells experienced no acute rejection episodes. Nine other patients could not suppress the dendritic cells and all nine experienced two to three rejection episodes.
Dr. Suciu-Foca also says modulation of ILT3 and ILT4 expression may help treat diseases, such as AIDS and cancer, but in these cases by boosting the immune response instead of stopping it. By preventing the upregulation of ILT3 and ILT4 in AIDS patients, doctors might someday be able to bolster the immune response against HIV.
In cancer, increased ILT3 and ILT4 expression also may prevent the immune system from attacking tumor cells. Though the immune system recognizes malignant cells in cancers early stages, it stops attacking the cells as the cancer progresses. Tolerant dendritic cells overexpressing ILT3 and ILT4 inside the tumor may be responsible for stopping the immune systems attack. Dr. Suciu-Foca is studying lymph node tumors to see if ILT3 and ILT4 expression in the tumors dendritic cells affects treatment outcome.
I hope we will be able to translate our results into clinical practice soon, Dr. Suciu-Foca says. But that will take much more research.