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08 April 2008
Blood Pressure Enzyme Can Have Tumor-Sensing Role
By increasing production of a blood pressure-regulating enzyme in mice, researchers have found they can enhance the mouse immune system's ability to sense tumor growth.

When scientists at Emory University School of Medicine engineered mice that make more angiotensin-converting enzyme in white blood cells called macrophages, the mice could more effectively limit the growth of injected tumors.

The enzyme works by "trimming" small bits of protein that originate from the tumors, allowing the immune system to identify the tumors and mount a response more efficiently.

The results are published online in the Journal of Biological Chemistry (JBC).

Senior author Kenneth Bernstein, MD, Emory distinguished service professor of pathology and laboratory medicine, says his group's findings suggest a strategy for amplifying immune system function in humans.

"We think we've discovered a means of tweaking the immune response by modifying the process of antigen presentation," Dr. Bernstein says.

In the clinic, doctors might be able to enhance a cancer patient's ability to resist a tumor by removing his or her white blood cells, boosting their production of angiotensin-converting enzyme, and re-infusing them, he says.

Antigen presentation refers to how proteins from within the body are constantly recycled and chewed up into small bits called peptides, which appear on the surfaces of cells. While the immune system generally ignores peptides from proteins in the body, it can respond to the peptides from foreign invaders.

Angiotensin-converting enzyme, or ACE, plays a critical role in controlling blood pressure and is the target of common medications. The hormone angiotensin (a peptide) constricts blood vessels, increases the brain's perception of thirst and indirectly causes the kidneys to retain sodium, thus limiting its production can reduce blood pressure.

ACE acts chemically by removing amino acids, the building blocks of proteins, from one end of a larger protein. In the body, ACE converts an inactive form of angiotensin into an active form by clipping off two amino acids.

But angiotensin is not ACE's only target. In previous studies, Bernstein and his co-workers found that manipulating its activity also affects processes such as fertility and the generation of red blood cells in the bone marrow.

To dissect out ACE's role in the immune system, they created mice with a genetic alteration in the ACE gene, forcing the gene to be turned on only in macrophages.

Macrophages are especially good at displaying peptides on their surfaces to other white blood cells called T cells so that the T cells are stimulated to grow. The T cells in turn kill virally infected cells. Depending on the situation, they can sometimes kill tumor cells as well.

When injected with several types of melanoma or lymphoma, the altered mice developed smaller tumors than normal mice. The tumors they did have contained more white blood cells attacking the cancerous cells.

In the JBC paper, the researchers show that ACE boosts cells' ability to display some foreign peptides, increasing their ability to stimulate T cells by several-fold.

Bernstein cautions that normally, macrophages make little ACE, so its effects must be seen as artificial. He notes that ACE inhibitors such as enalapril and lisinopril are taken by millions of people with high blood pressure and have not been reported to weaken the immune system.

However, cells similar to macrophages have been shown to produce ACE in response to pathogens such as sarcoid or leprosy, he says.

The first author of the paper is postdoctoral fellow Xiao Shen, PhD, with contributions from Aron Lukacher MD, PhD and Ifor Williams MD, PhD, both Emory associate professors of pathology and laboratory medicine.

The research was supported by the National Institutes of Health and the American Heart Association.

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