OREGON STATE UNIVERSITY

Basic studies shed light on immune function

09/21/1998

CORVALLIS - Immunologists at Oregon State University have recently uncovered some important clues to how the immune system works on a fundamental level, with long-term implications for creating new vaccines, improving existing ones or fighting autoimmune diseases.

The key, scientists say, is understanding how some of the "T cells" - which are sort of the quarterbacks of the immune system that direct other cells to go do the dirty work - can get stimulated to do their work even better, or tone it down a bit in the case of an autoimmune problem such as arthritis.

Some intriguing findings about this process have already been made, other professional publications are planned and a major new approach to influencing immune function may be possible, said Anthony Vella, an assistant professor of microbiology at OSU.

"We're learning about the mechanisms that can influence T cell driven immune response," Vella said. "In theory, you could increase the immune response if you wanted to make a vaccine work better, or you could try to limit its action to counteract an inappropriate immune response, which happens in such diseases as arthritis or allergies."

A more thorough basic understanding in this area, Vella said, could even have value for new treatments of cancer.

According to Vella, one of the things that has often intrigued scientists is the apparent correlation between inflammation and a dysfunctional immune response, especially with autoimmune diseases. Steroid treatments, for instance, which have strong anti-inflammatory effects, are often used to treat some of these diseases.

"But using a powerful steroid drug, which can have many side effects, to indirectly affect something as delicate as the immune system is like hitting an ant with a sledgehammer," Vella said. "What we've tried to identify is exactly how the process of inflammation is related to immune function and what cellular processes are involved."

In one recent breakthrough, the OSU research program determined that inflammation in conjunction with the activation of other T cell stimulatory molecules can help T cell growth and increase the number of "fighting" T cells.

In experiments, OSU researchers showed that injecting mice with an antigen caused significant death of the antigen-responsive T cells; however, when inflammation was present it prevented the death of these cells.

"An activation or increase in T cells is often part of a natural immune response, and is usually essential to make a vaccine work," Vella said. "But the body also controls excessive T cell production, which is also essential. Inappropriate levels of certain activated T cells can set the stage for an autoimmune disease, in which the body literally attacks itself."

And now, the scientists believe they are getting closer to understanding the actual processes involved on a basic cellular level.

In cell membranes of certain bacteria, Vella said, there is a natural bacterial lipid called lipopolysaccharide, or LPS. It appears that LPS can play a role in causing inflammation, and keeping activated T cells alive.

One theory under study is that excessive levels of LPS is inducing production of tumor necrosis factor, or TNF, an immunologic hormone that can kill tumors. TNF in turn may induce another hormone called interleukin-6 (IL-6), and-or IL-1, which other research has linked to arthritis and other autoimmune diseases.

OSU researchers have recently shown that the LPS inflammatory signal which prevents T cell death is dependent on IL-1 and TNF stimulation of IL-6. This result is of interest beyond immunology, since IL-6 is a major factor involved in neurological function. Although there is no supporting data, Vella speculates that there may be a potential link between the nervous system and T cell survival.

"There is still a lot of fundamental research to be done before we're ready to devise actual medical therapies or do clinical studies," Vella said. "But there clearly are some important possibilities in this area of study. Some drugs are already under development that tap into this biological process, even though the process itself is still so poorly understood."

An improved understanding of the basic biology in this area could set the stage for a whole new approach to either treating autoimmune disease or improving the efficacy of the immune response in certain situations, such as the performance of vaccines.

"We're going to figure out what it is about inflammation that encourages the survival of certain immune system cells, what kind of survival signal these T cells are getting that can either cause autoimmune problems, or, in different cases, affect the performance of vaccines," Vella said. "And when we do there may be a huge potential here for new disease therapies."