Natural mechanism protecting tissue allografts from rejection

A molecule expressed during pregnancy seems to turn down the immune system, making it more tolerant of welcome visitors such as a fetus or maybe a transplanted heart, researchers say.

Human leukocyte antigen G, or HLA-G, is a member of a gene family called major histocompatibility complex that provokes an immune response, says Dr. Anatolij Horuzsko, reproductive immunologist at the Medical College of Georgia.

Like an errant child, HLA-G instead promotes tolerance, and researchers have found it can even make other gene family members more accepting, says Dr. Horuzsko, who is presenting his research during the Fourth International Conference on HLA-G July 10-13 in Paris and chairing a session on structure and receptor interaction. His research also is featured in the August issue of the European Journal of Immunology.

The placenta expresses HLA-G from the earliest stages of embryo implantation and the molecule goes away toward the end of pregnancy. Growth factors and cytokines - signaling compounds involved in the development and function of the immune system - bring to the surface inhibitory receptors previously buried inside immune cells so they can interact with the HLA-G.

Amazingly, scientists have documented this natural immunosuppression, to a lesser extent, in at least one more situation: when an organ is transplanted. Dr. Horuzsko wants to augment this natural process so transplant patients won't require a lifetime of generalized immune suppression that puts them at risk for many other diseases.

He has created animal models in which these inhibitory receptors are expressed on the cell surface. Using the same mixture the body uses - cytokines and growth factors - he also gets the receptors expressed on the surface of human cells in a test tube. He gives HLA-G in both situations and studies the response.

In dendritic cells, major orchestrators of the immune response, he has watched how activated inhibitory receptors down-regulate the function of stimulators of the immune response also present on the cell surface. Interestingly, the targets are members of the major histocompatibility complex family to which HLA-G belongs.

"These dendritic cells are not defective, but they develop tolerogenic properties, which are not normal for them," says Dr. Horuzsko, who equates modifying the immune response to turning down the volume of a television. "We think we can help them into a tolerogenic pathway by giving HLA-G and get them to ignore the antigen coming from transplanted tissue," he says. Unfortunately, he notes, cancer and some viruses seem capable of similar manipulation.

Using this approach, he has been able to prolong acceptance of skin grafts, which are typically rapidly rejected, sometimes indefinitely.

He's also getting T cells, another major player in the immune response, to express inhibitory receptors. Normally dendritic cells show an invader to T cells which produce cytotoxic T cells to destroy it. But when T cells express the inhibitory receptor, they go silent and may even die.

A long list of other cells that provoke an immune response might be "kept under control" by this approach, Dr. Horuzsko says.

He envisions, in the not too distant future, giving cytokines and growth factors to patients so targeted cells will express inhibitory receptors then delivering a sort of HLA-G manufacturing plant, probably blood-derived stem cells modified to produce it. In patients who already express inhibitory receptors, it may be enough to give only HLA-G. Dr. Horuzsko plans to further investigate this expression that occurs soon after an organ transplant in some patients.

These natural approaches would be used to prepare a patient for transplant and activated when problems with rejection emerge.

"I believe this natural mechanism is a very powerful tool for protecting tissue allografts from rejection," says Dr. Horuzsko.