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New collaborative work by the Queen's Center for Biomedical Research (QCBR) has made a discovery that may one day allow doctors to boost the body's immune system response for the elderly, and to combat diseases like cancer. Conversely, doctors may also be able to suppress the immune response for organ transplantation, or to slow debilitating autoimmune diseases. The research was published in the journal Science (Launay, P., Cheng, H., Srivatsan, S., Penner, R., Fleig, A. & Kinet, J.P. (2004) TRPM4 regulates calcium oscillations after T cell activation. Science 19:1374-1377).

The research involves lymphocytes, which make up a significant part of a body's white blood cells. QCBR focused their research on a type of lymphocyte called a T-cell. When an antigen stimulates a T-cell receptor, the T-cell experiences increases in intracellular calcium levels that mobilize the body's immune response. These increases in calcium concentration, however, occur in multiple waves and oscillate up and down. QCBR knew that the underlying mechanism for these calcium signals were caused by calcium ions flowing from the outside of the cell into the cells through ion channels. The unsolved question was the cause of the oscillations. The researchers discovered that the T-cells open another ion channel, a sodium channel called TRPM4, discovered earlier by QCBR as a channel that opens when calcium increases inside a cell.

Thus, the T-cell opens the calcium channel, which increases the levels of intracellular calcium, and that in turn activates the sodium channel. The flow of sodium into the cell then depolarizes the cell, which reduces the amount of calcium entering into the cell. When the calcium is reduced, there is not enough of it to keep the sodium channel open, which then allows more calcium to come in, hence the oscillations. By "knocking out" the sodium channels from cells, the researchers abolished the oscillations, and cells that lack TRMP4 now responded with a sustained increase in intracellular calcium concentration that no longer oscillated, thus proving their theory of how the mechanism works.

The implication to health care is that if oscillations are minimized by blocking TRMP4, body's immune response can be boosted. Conversely, if the activity of TRPM4 is enhanced, the immune response is suppressed. QCBR is currently working on compounds that influence the ion channels. "A compound may one day lead to a therapeutic drug," said Reinhold Penner, MD, PhD, director of QCBR. "but that's another paper."

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