National Jewish Health
Dr. Kappler is also a member of the Department of Biomedical Research at National Jewish Health, Denver, and a distinguished professor in the Departments of Immunology/Microbiology and Pharmacology and a member of the Biomolecular Structure Program at the University of Colorado Health Sciences Center. He also holds an appointment in the Basic and Translational Research Division of the Barbara Davis Center for Childhood Diabetes.
John Kappler says he was the kind of youngster who would break appliances apart to see how all the pieces inside might work together. That curiosity first led him to pursue engineering as an undergraduate at Lehigh University. But after being inspired by a professor, he switched to biochemistry and eventually obtained a Ph.D. from Brandeis University in the field.
He happened upon immunology by moving to California. Having had enough of living on the East Coast, he decided to do a postdoctoral fellowship at the University of California in San Diego under Richard Dutton. "Dutton [at the time] had developed a lot of in vitro ways of studying the immune system," Kappler said. "I thought his work was really original and it would let me be in Southern California in 1969, a very exciting time there, politically, socially, and musically. What could be better than that?"
It turned out, it did get better. Soon after he arrived in Dutton's lab, another postdoctoral fellow—Philippa Marrack—showed up. She had come from the prestigious British Medical Council's Laboratory of Molecular Biology in Cambridge. In 1973, the two married, set up a laboratory together at the University of Rochester, and have collaborated ever since. In 1979, they came to Denver, where they have appointments at both the University of Colorado Health Sciences Center and National Jewish Health.
Over the years, Kappler and Marrack together have elucidated various important aspects of the biology of T cells and their role in the immune response. T cells are white blood cells produced by the thymus that mediate the body's cellular response against infection from viruses and bacteria and provide immunity against repeated exposure from foreign invaders. In 1983, Kappler and Marrack were the first to characterize the T cell receptor—the molecule T cells use to recognize an antigen, a molecule that can elicit an immune response. By 1987, they figured out why T cells don't attack intrinsic antigens within the body.
More recently, they have worked out the molecular detail behind T cell receptor recognition of self- and foreign antigens, and how the body eliminates, for the most part, those T cells that bind to self-antigens. If our bodies did not remove self-reacting T cells, such T cells would constantly be attacking our tissues and we would never survive. Autoimmune diseases, such as diabetes and rheumatoid arthritis, occur because some self-reacting T cells slip out of the thymus and mount an immune response against particular molecules inside the body.
Although Kappler and Marrack continue to collaborate extensively, the two also pursue independent projects. For the past five years, for example, Kappler has been researching the causes of autoimmune diseases and why some people are hypersensitive to the metals beryllium and nickel. Scientists do not know the antigen or protein inside the body that causes these inappropriate immune responses. Proteins in the connective tissue of the joints may be the culprits in rheumatoid arthritis; but no one knows for sure. Which proteins elicit the metal sensitivity also is unknown.
To attempt to find the antigens responsible for rheumatoid arthritis, Kappler created a molecular library that contains approximately 10 million peptides linked to the particular MHC molecule, which people with the disease are more likely to have on their cells. T cells become stimulated by binding pieces of a protein, or a peptide, bound to the MHC carrier molecule on the outside of cells.
Kappler scans the library with T cell receptors of T cells collected from patients with rheumatoid arthritis, with the expectation that some of their T cells should react with a subset of the peptides. If the T cells from different patients with rheumatoid arthritis recognize the same subset of peptides, then he should be able to find the corresponding protein or proteins from which the peptides were derived. Once the proteins are found, new diagnostics and drugs for rheumatoid arthritis could be developed. Kappler also has developed a similar screening system to find the self-antigens that bind metals and make them immunoreactive. Both projects are ongoing.
Even with the research they do autonomously, the husband and wife always consult about their respective work. The two of them have been able to work so well together over the years, because they agreed from the beginning to share credit equally for their research findings. "By sharing credit we didn't have to compete," Kappler said. "Most of our conversations at the breakfast, lunch, and dinner table are about the experiments we are doing. Who is to say where any of the ideas came from?"
For the past three decades, those conversations have led to a better understanding of the T cell, a key component in our body's ability to distinguish molecular friends from foes and to respond appropriately to survive.