Immunology was the focus of the 2011 Nobel Prize for Physiology or Medicine with the October 3 announcement that the award will be shared by three whose work has been seminal in the understanding of immune system function. Half the award will go to Drs. Jules A. Hoffmann and Bruce A. Beutler for their discoveries concerning the activation of innate immunity, and the other half will go to the estate of Dr. Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity.
Innate immunity refers to the body’s first line of defense against infection. When a pathogen enters the body, the body must recognize that a foreign body has entered, then mount an immune response that will destroy the pathogen. Hoffman, working in fruit flies, identified a gene called Toll that was required for innate immunity. He found that the product of the Toll gene helped detect the presence of pathogenic microorganisms and that Toll activation was required for successful defense against them.
In parallel, Beutler was searching for a receptor that would recognize the bacterial product lipopolysaccharide (LPS), which can cause septic shock. The gene for the LPS receptor that he identified turned out to have a high degree of homology to the fruit fly Toll gene. He went on to show that this Toll-like receptor activated inflammatory responses after binding LPS. Other researchers have identified around a dozen different Toll-like receptors in humans and mice, each of which recognizes certain molecules common in microorganisms. Individuals with certain mutations in these receptors carry an increased risk of infections while other genetic variants of Toll-like receptors are associated with an increased risk for chronic inflammatory diseases.
Adaptive immunity refers to ability of the immune system to acquire a long-term memory of pathogens it has seen before, allowing a more rapid and stronger activation of the immune system the next time that pathogen is encountered. Steinman is honored for his discovery of the dendritic cell, an important intermediary in the development of adaptive immunity. Work by Steinman and others showed that dendritic cells capture and present antigens and can powerfully activate T-cells. Dendritic cells also play an important role in the control of tolerance and immunity, processes by which the body differentiates “self” from others.
The understanding of the immune system embodied by this work has laid the foundation for new therapies that attempt to harness the immune system to fight diseases such as cancer, and for new strategies for vaccine development. As an example, Dendreon’s cell-based therapy Provenge for prostate cancer takes a patient’s own dendritic cells, cultures them, then re-introduces them into to the patient to reinforce the immune response to the cancer cells.
Sadly, Steinman passed away on September 30, 2011, days before the announcement of the prize. The Nobel committee was unaware of his death at the time of the announcement. Although the Nobel Prize is not granted posthumously, the committee has decided to nevertheless award the prize to Steinman, because he was alive at the time of the selection. Steinman was suffering from pancreatic cancer, and was being treated with a therapy based on his own discoveries of dendritic cell activation.