Do We Fight Disease or Dance with It?

In the view of researcher Larry Pease, PhD., chair of the Mayo Clinic Department of Immunology, we do a bit of both to preserve health. Concentrating on the pure biological warfare that the immune system is capable of yields only a partial understanding of this astonishingly complex system—and therefore limits researchers' ability to enlist immune powers to serve health. "There's this dance that goes on," Dr. Pease says, spiraling a hand in the air to convey the many choreographed motions of immune system components. "Understanding this dance is a big part of our research."

Noting that immune function cuts across all disease categories and organ systems Dr. Pease adds: "What we do here has widespread applications and implications far beyond us. It's really an engine that enriches the entire Mayo Clinic research environment"

A federation of 20 Mayo Clinic laboratories with multidisciplinary focus, the Department of Immunology is one of the largest within Mayo Clinic's research domain. It is regarded by peers as one of the top research departments in the country, with a distinguished publishing record. Because its creative collaborations are so numerous and productive, its pathbreaking findings regularly appear in top biomedical journals.

The Dance Defined

The dance of the immune system is a complex, cascading interplay of changing molecular partners, structured movements, swirling turns, precise timing and breathtaking maneuvers. It's an emerging picture on which Mayo Clinic scientists, surgeons and clinicians collaborate.

And it's giving rise to a new vision of the way the immune system works: not with a blunt instrument, but with precise movements and complex patterns. Following the body's lead is a way for researchers to enlist the body's own innate immune properties to develop new treatments in an approach known as immunotherapy. Immunotherapy holds the promise of a new generation of cancer treatments that do not tax the body with the debilitating side effects associated with conventional anti-cancer treatments using radiation and chemotherapy.

The conditions and diseases addressed by immunology and immunotherapy research at Mayo Clinic reflect a commitment to discovery that is both deep and wide. Topics include:

• Organ transplantation
• Childhood leukemias
• Malignant melanoma and other cancers
• HIV infection and AIDs
• Autoimmune diseases and infectious agents
• Development of new vaccines

Among the immune system components researchers investigate are:

• Specialized attack cells
• Co-stimulatory molecules that turn immune cells on or off, depending on their biochemical context
• Pathways for communicating messages of cellular action or inaction
• Regulatory systems
• Various chemical, biological and genetic aspects of the immune system

Molecule School: How Cells Learn to Fight

To harness the body's innate immune properties, researchers need to understand the communication between cells. David McKean, Ph.D., focuses on just that. In particular, his group is interested in the cellular communication that regulates "thymocytes"(THIGH-mo-sites).

Think of thymocytes as future "T" cells, which are attack cells that destroy invaders. Thymocytes are cells that have moved from their point of origin—stem cells in the bone marrow—to the thymus gland that lies near the heart. They are on their way to developing into "T" lymphocytes. When mature, "T" lymphocytes will migrate to the lymph tissue where they will be fully able to attack foreign invaders.

But first, they must go to school in the thymus, as "T" cells in training. It is in the thymus gland that they learn what is "self," and what is "non-self," or invader. This is a key distinction to protecting the body from disease. If the immune system makes a mistake about what is friend and what is foe, it attacks its own body causing auto-immune disease. The instruction that cells receive during their "education"in the thymus is vital.

Thymocytes are educated in the thymus through stimulation by different molecules on their cell. Depending on the signals the cell receives, the developing "T" cell either is killed, or it matures into a functional "T" lymphocyte. As a result: the "graduates" of the thymus can consistently recognize foreign molecules and then go to the lymph tissues as functioning "T" cells.

Dr. McKean's laboratory is interested in understanding the role in thymocyte development of a family of molecules known as "co-stimulators." Certain costimulators have the ability to produce multiple effects in thymoctyes: they can stimulate thymocyte development into proper "T" cells—and they also can initiate death for thymocytes that recognize self and could cause auto-immune disease.

Knowing how co-stimulatory molecules communicate these opposite messages might one day give researchers the ability to control these messages. If they could do this, they could selectively and therapeutically send the message to fortify recognition of nonself—and in the process, create a more aggressive immune response. Says Dr. McKean: "Our work in the laboratory is fundamental to the new treatments that will one day arrive in the clinic."

Lymph 12: A Potent Mediator of Immune Function

In Dr. Pease's lab, researchers have developed a powerful human antibody that has shown promising results in animal experiments as a potential immunotherapeutic agent. It derives from a source that is unique to the Mayo Clinic: stored blood serum from donated patient samples.

"This kind of bank, coupled with the extensive Mayo Clinic patient base from which to take samples, is just one of the many examples of the kind of resources that help make Mayo Clinic research the best of its kind," says Dr. Pease. "If my colleagues hadn't been keeping these serum samples, we wouldn't be where we are today with this research."

The antibody is formally known as sHIgM12. Its lab nickname is Lymph12. Researchers are excited about the newly discovered interesting and important biologic effects it has when it binds to dendritic cells. Dendritic cells initiate immunity. They are the cells that identify and select which T cells are suited for attacking a given pathogen, and then mobilize them to attack invaders.

In animal experiments Lymph 12 has been shown to enhance the ability of the dendritic cells to:

1. Engulf, drink or otherwise take up antigens.
2. Travel to the lymph nodes.
3. Stimulate "T" cells.

All three of these steps are key components of an effective immune response. More importantly, all three of these steps are NOT activated by a cancer tumor cell—which gives cancer an advantage. Says Dr. Pease: "Unfortunately, the body doesn't consider cancer cells an infection; they are part of your self, so this three-step immune process isn't begun by cancer tumor cells."

But, if the laboratory results of Lymph 12 hold up in humans, the findings would suggest that doctors could jumpstart the dendritic cells with Lymph 12. This would "turn-on"the three-step immune response outlined above to boost immunity.

The fact that this antibody is a human antibody is vitally important to its value in immunotherapy research. The reason: all other avenues of immunotherapy antibody production rely on some form of animal-produced antibody. Animal-origin marks it for detection in human immune systems—and causes an undesirable immune response. Says Dr. Pease: "To me, the most exciting part is that it's a human antibody, because that means it can much more quickly be developed as an effective immunotherapeutic agent."