Discovery might help organ recipients avoid drugs
By Faith Reidenbach
NEW YORK, Jan 28 (Reuters Health) - In an advance that might have implications for a wide range of diseases, scientists have identified a potential way to "turn off" a person's immune response when they receive a transplanted organ or bone marrow.
Transplant recipients typically have to take strong drugs to suppress the immune system, which otherwise tries to fight off foreign substances in the donated organ. But the drugs can have debilitating side effects, they leave the patient vulnerable to viral illnesses and other infections, and the body sometimes rejects the organ anyway.
A better option, which has been the subject of much research, would be to turn off T cells, which are key players in initiating and conducting immune responses. Scientists led by Dr. Nicole Suciu-Foca of Columbia University in New York have suggested a possible way to do just that.
In previous studies the research team identified a special group of T cells, called suppressor T cells, that can shut down the normal function of other important immune system cells called monocytes and dendritic cells. Normally, monocytes and dendritic cells help trigger immune responses.
In the current study, Suciu-Foca and her colleagues discovered how suppressor T cells work. They observed that when monocytes and dendritic cells were exposed to suppressor T cells in the laboratory, levels of two inhibitory proteins, ILT3 and ILT4, increased on their surfaces.
The increase in the inhibitory proteins makes monocytes and dendritic cells tolerate foreign substances from donor tissue rather than launching an attack against them, Suciu-Foca's group reports.
The researchers looked at blood samples from patients who had received heart transplants without rejecting them. They saw suppressor T cells in these blood samples and high levels of ILT3 and ILT4, which had apparently shut down monocytes from the heart donors and thus prevented organ rejection.
In the January 27th online edition of Nature Immunology, Suciu-Foca's group suggests that it might be possible to make transplant recipients tolerant of donor tissue by treating the tissue with a drug that increases levels of ILT3 and ILT4.
But "the most important, the most exciting finding of all," Suciu-Foca told Reuters Health, is that by determining the role of ILT3 and ILT4, she and her team have identified the body's "central mechanism of tolerance." The study results have implications for "multiple sclerosis, psoriasis, celiac disease, rheumatoid arthritis" and other autoimmune diseases, Suciu-Foca said.
In such diseases, the immune system goes haywire and begins to react against parts of the body, such as the nerve fibers (as in multiple sclerosis) or the joints (as in rheumatoid arthritis). Suciu-Foca explained that someday, these diseases might be treatable with "a dendritic cell manipulated (in the laboratory) so it expresses a high level of ILT3 and ILT4." When injected into a patient, this "vaccine" would presumably shut down the unwanted immune response.
On the other hand, sometimes the immune response is very much needed, as in cancer patients, where the threat is malignant cells, or in AIDS patients, where the threat is HIV-infected cells. "So then the challenge is to inhibit the expression of ILT3 and ILT4," Suciu-Foca said.
The interactions between dendritic cells and T cells are extremely complicated, Dr. Mark B. Feinberg, a professor of medicine and microbiology and immunology at Emory University, Atlanta, Georgia, cautioned in a separate interview with Reuters Health.
Feinberg, who was not involved in the research, said that the study "lays the groundwork for future developmental efforts to try to test, in a rigorous way, whether these inhibitory receptors (ILT3 and ILT4) can be used to modulate immune responses."
However, he added, "it is a preliminary step. For patients who may be recipients of transplants or people suffering from autoimmune diseases, I don't think that they should expect that this work would be readily translatable into something that might help them."
Still, he said, "People working in the field are firm believers that one day we'll be able to modulate immune responses beneficially. I think in the next 5 to 10 years there are going to be substantial advances that really can benefit people. I think it's going to be a very exciting time."
SOURCE: Nature Immunology 2002;10.1038/ni760.
Published online: 28 January 2002, DOI:10.1038/ni760
Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4
C C Chang, R Ciubotariu, J S Manavalan, J Yuan, A I Colovai, F Piazza, S Lederman, M Colonna, R Cortesini, R Dalla-Favera & N Suciu-Foca
1 Department of Pathology, Columbia University, New York, NY 10032, USA.
2 Laboratory of Molecular Immunology, Columbia University, New York, NY 10032, USA.
3 Washington University, School of Medicine, St. Louis, MO 63110, USA.
4 University of Rome "La Sapienza", Rome, Italy.
Immunoglobulin-like transcript 3 (ILT3) and ILT4 belong to a family of inhibitory receptors expressed by human monocytes and dendritic cells. We show here that CD8+CD28- alloantigen-specific T suppressor (TS) cells induce the up-regulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering these antigen-presenting cells (APCs) tolerogenic. Tolerogenic APCs show reduced expression of costimulatory molecules and induce antigen-specific unresponsiveness in CD4+ T helper cells. Studies of human heart transplant recipients showed that rejection-free patients have circulating TS cells, which induce the up-regulation of ILT3 and ILT4 in donor APCs. These findings demonstrate an important mechanism of immune regulation. |
