UH shares immune-
system discovery

The finding holds big implications
for AIDS, allergies, arthritis
and organ transplants

Hawaii researchers and mainland colleagues have discovered a mechanism in the body that can be used to boost the immune system to fight AIDS, cancer and other diseases.

Conversely, it can be used to reduce the immune response for organ transplants and debilitating autoimmune diseases, they report.

Key figures in the discovery were Drs. Reinhold Penner, research director, Andrea Fleig, associate research director, and Henrique Cheng, biomedical researcher, at the Queen's Center for Biomedical Research, operated with the University of Hawaii John A. Burns School of Medicine.

The group is working with a pharmaceutical company in Massachusetts on drugs that will move the immune system up or down as needed, based on their findings, Penner said in a recent interview. "It can be tailored to particular patients."

Penner and Fleig are UH professors of cell and molecular biology and world-renowned cellular researchers. They have made a number of discoveries about the function of ion channels, tiny pores that control flow of substances in and out of the body's cells.

Their latest findings with associates Jean-Pierre Kinet, Subhashini Srivatsan and Pierre Launay at the Beth Israel Deaconess Medical Center and Harvard Medical School were published in the November issue of the journal Science.

Penner said there are two possible issues with the immune system: "It may not work as it should, in which case there is reduced defense mechanism against invading pathogens. Alternatively, it can be a problem when you have an overactive immune system."

The body's immune system attacks its own tissues in autoimmune disorders, he pointed out. They include rheumatoid arthritis.

Minor issues also are involved, such as allergies, causing a person's eyes and nose to run, which is "very disturbing for everyday life," Fleig added. Medications for allergies could be improved with better understanding of the molecular mechanism, she said.

Their research involves lymphocytes, which comprise a major part of a body's white blood cells, and it focuses on a type of lymphocyte called a T-cell.

One of the primary problems with AIDS is that patients do not have enough T-cells because they are destroyed by the virus, Penner said.

When the immune system is weakened, all kinds of problems crop up, including cancers. "One of the important things in cancer is to try and kill cells that are proliferating or dividing in an uncontrolled manner," he said.

A great number of immune cells coordinate their actions to mount a defense against bacteria and other invaders from outside the body, as well as things happening inside, Penner said. "That's what the immune system is there for."

Many cells are activated in a similar way, usually with mechanisms that allow the cells to respond appropriately, he said.

He said the research team analyzed how the T-cell actually works, explaining that it is normally triggered by a T-cell receptor, a protein in the lymphocyte.

A specific antigen stimulates the T-cell receptor, and calcium levels are increased that mobilize the body's immune response, he said.

Cells produced by T-cells called cytokines increase the calcium concentrate when the receptor is stimulated, he said. But the increases oscillate up and down, which was puzzling.

"It's like if you have an on switch," Fleig said. "You also have to have an off switch. We didn't understand what is the off switch."

Looking for the cause of the oscillations, the researchers unraveled complex interactions of ion channels related to positive and negative charges of the ions.

In earlier work, Penner and Fleig characterized what they call "store-operated" ion channels that let calcium in and others that do not let calcium in, but let potassium out.

"We knew these guys were there, but we didn't know what their role and function was in shaping this type of calcium signal," Penner said.

What they found is that the T-cell opens the calcium channel, which increases the levels of intracellular calcium, and that activates an ion sodium channel they discovered earlier called TRPM4 (transient receptor potential).

The flow of sodium into the cell depolarizes the cell, which reduces calcium entering into it, Penner explained. With the calcium reduced, there is not enough to keep the sodium channel open, which allows more calcium to come in.

So the sodium channel, TRPM4, regulates calcium oscillations, he said.

The researchers knocked sodium channels out of cells, which ended the oscillations and allowed a huge increase in calcium. When TRPM4 was activated to let sodium in, the calcium did not like it, which resulted in more oscillations.

Thus, the body's immune response can be boosted by blocking the TRPM4 sodium channel to minimize oscillations, or TRPM4 activity can be increased to suppress the immune system, Penner said.

"We have experimental compounds (tested on animals) that will do both," he said.

"We are further ahead with this channel in regard to drug testing than is usual when you have a finding of this nature," Fleig noted. "Usually, it takes several years."