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June 8, 2001

Development of Important Immune Cells Relies on More Complicated Influences than Scientists Had Thought

Research by Penn Cancer Center's Abramson Family Cancer Research Institute Shows It Isn't all 'Nurture' in the Nature Vs. Nurture Debate About How Cells Develop

Researchers studying the way immune cells differentiate have discovered that an important family of white blood cells divides into separate identities in a much more complicated fashion than current scientific theory has held.

Led by Steven L. Reiner, MD, of the Leonard & Madlyn Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center, the researchers have overturned existing scientific belief that helper T cells are programmed to differentiate only by outside signals.

Instead, the researchers have shown that Th1 and Th2 cells -- which are involved in inflammatory and allergic responses, respectively -- develop in a delicate chronological pattern, and in response to both internal and external influences.

The finding, which will be published in the June 8 issue of the journal Science, clears a new path for inquiry in the development of drugs that can create reinforcements for the body's army of immune cells.

"The cell isn't just a tabula rasa -- a blank slate completely open to outside instructions. The cell is actively making decisions on its own that are sometimes hard for us to see," said Reiner, an Associate Investigator for the Abramson Institute and an Associate Professor in Penn's Department of Medicine.

Establishing how these white blood cells develop will someday help scientists to manipulate their production, increasing the supply of Th1 cells to fight against
some parasite-caused illnesses or intracellular bacterial infections such as tuberculosis, or pumping up the supply of Th2 cells to combat autoimmune diseases and extracellular microbes such as intestinal worms.

In their work, Reiner and his colleagues scrutinized the cascade of events that follow when uncommitted cells are exposed to a protein factor called interleukin 12 (IL-12). It is well known that, when IL-12 is present, Th1 cells predominate. Common scientific thinking has held that this results because IL-12 'instructs' undecided cells to become Th1 cells.

Reiner and his team challenged the prevailing opinion in order to establish how
the process really operates. "That 'instructive' model makes sense intuitively," Reiner said, "But an alternative hypothesis -- which seemed to make more sense the more we learned -- is that development from uncommitted cells to Th1 cells takes place spontaneously, almost imperceptibly, and that IL-12 performs a separate function. Instead, it looks like IL-12 promotes the growth of the cell once it has spontaneously altered."

That happens, Reiner says, because "part of adopting the new fate of Th1 cells includes a special ability to grow in response to the IL-12 protein.

"For many scientists, the therapeutic objective is to change the fate of a cell," Reiner said. "Now we know it isn't all 'nurture' in the 'nature versus nurture' question. The cell has some say in the decision, and understanding that brings us closer to our goal."

Reiner was assisted in the study by Alan C. Mullen, Frances A. High, Anne S. Hutchins, Hubert W. Lee and Alejandro V. Villarino, all of the Abramson Institute; David M. Livingston, PhD, and Andrew L. Kung, MD, PhD, both of the Dana Farber Cancer Institute; Nezih Cereb, MD, of Histogenetics, Inc. and the Center for Genetic Polymorphism; Tso-Pang Yao, PhD, of Duke University, and Soo Y. Yang, PhD, also of Histogenetics and the Center for Genetic Polymorphism.

Their work was funded by the National Institutes of Health.


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