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Pregnancy Molecule May Aid Transplant Recipients

A molecule expressed during pregnancy seems to make the immune system more tolerant of welcome visitors such as a fetus or transplanted organ, researchers say.

Human leukocyte antigen G, or HLAG, is a member of a gene family called major histocompatibility complex that provokes an immune response. But like an errant child, HLAG instead promotes tolerance, and researchers have found it can make other gene family members more accepting, said Dr. Anatolij Horuzsko, MCG reproductive immunologist. He presented his research during the Fourth International Conference on HLAG in July 2006 in Paris. His research also was featured in the August 2006 issue of the European Journal of Immunology.

The placenta expresses HLAG upon conception and the molecule disappears toward the end of pregnancy. Growth factors and cytokines—signaling compounds involved in the immune system—bring to the surface inhibitory receptors previously buried inside immune cells so they can interact with the HLAG.

Amazingly, scientists have documented this natural immunosuppression in organ transplantation. Dr. Horuzsko wants to enhance this process to preclude a lifetime of generalized immune suppression for transplant recipients.

He has created animal models that express these inhibitory receptors 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 HLAG in both situations and studies the response.

In dendritic cells, major orchestrators of the immune response, he has watched how activated inhibitory receptors downregulate 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 HLAG belongs.

“These dendritic cells are not defective, but they develop tolerogenic properties, which are not normal for them,” said Dr. Horuzsko. “We think HLAG will get them to ignore the antigen coming from transplanted tissue.” Unfortunately, he noted, 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. He also is prompting T cells, another major player in the immune response, to express inhibitory receptors.

Normally, dendritic cells prompt T cells to destroy invaders. 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 controlled by this approach, Dr. Horuzsko said.

He envisions giving cytokines and growth factors to patients so targeted cells will express inhibitory receptors, then delivering bloodderived stem cells modified to produce HLAG. HLAG alone might be sufficient for patients who already express inhibitory receptors.

Toni Baker

 

 

The Medical College of Georgia is the state’s health sciences university with a tripartite mission of education, research and patient care.