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Researchers Identify a Key "Brake" of the Immune Response

Finding Could Allow Clinicians Someday To Improve Transplantation Acceptance and Treatment For AIDS and Cancer

NEW YORK (Jan 27, 2002)

When the body is exposed to a foreign substance, such as a virus or bacteria, the immune system responds in an elaborate process by making cells and agents that fight off the invaders.

But sometimes physicians want to be able to turn off the immune response, such as during bone marrow or organ transplants to prevent the host from rejecting the donor tissue. On the other hand, doctors would like to boost the immune response against malignant cells and HIV-infected cells to help fight cancer and AIDS.

Now scientists at Columbia University College of Physicians & Surgeons and elsewhere report they have identified a key pair of molecules, called ILT3 and ILT4, that could help clinicians precisely modulate the immune response to help treat a variety of diseases. The molecules are the first to be characterized on antigen presenting immune cells, called dendritic cells, to function as a brake for the immune response. Antigens are molecules, such as proteins from viruses or even from the body's own tissue, that can elicit an immune response.

The findings are being reported Jan. 27 in the online version of Nature Immunology and in the February issue of the publication.

Led by Dr. Nicole Suciu-Foca, professor of clinical pathology, the researchers provide evidence for how increasing the amount of ILT3 and ILT4 on dendritic cells could create tolerance to foreign tissues, such as donor tissue or bone marrow. Their results also suggest that somehow decreasing the amount of ILT3 and ILT4 on these cells might allow the body to better fight AIDS and cancer cells.

ILT3 and ILT4 on dendritic cells function as a brake for the immune system, shutting off the immune response and then creating a state of tolerance to antigens, which can be foreign or derived from the body itself, explains Dr. Suciu-Foca. To shut down the immune response, the body presses its "foot" harder on the brake pedal to boost ILT3 and ILT4 activity in the dendritic cells. To enhance the immune response, the body lowers the ILT3 and ILT4 activity.

In the study, the investigators showed how other cells of the immune system, the T-suppressor cells, are responsible for slowing down the activity of the dendritic cells. Dendritic cells present to T cells, including T suppressor cells, the specific antigen against which the immune response had been initiated.

In the study, the researchers showed in cell culture how increasing the activity of ILT3 and ILT4 on dendritic cells could make the immune system tolerant to antigens. They also analyzed the blood of heart transplant recipients and showed that those who did not reject donor hearts had T-suppressor cells that induced the activity of ILT3 and ILT4 in donor dendritic cells. The results show that the heart recipients without rejection had T-suppressor cells that had been primed to suppress a response to foreign hearts.

The findings of the study also have implications for type I diabetes and other autoimmune diseases, Dr. Suciu-Foca says. In autoimmune disease, the immune system attacks normal body tissue rather than being tolerant of it. Enhancing activity of ILT3 and ILT4 in dendritic cells, which present the target antigen in such patients, might help affected patients suppress the immune response against their own tissues.

Dr. Suciu-Foca and her colleagues are now investigating the possible use of ILT3 and ILT4 to treat patients with AIDS, cancer, or transplants.

The research was supported by grants from the National Institutes of Health and the Interuniversity Organ Transplantation Consortium in Rome, Italy.

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