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DURHAM, N.C. -- Duke University Medical Center immunologists have pinpointed how a widely used treatment for non Hodgkin's lymphoma attacks abnormal immune cells, called B cells. They believe that their discovery in mice of how the antibody rituximab kills B cells will lead to improved treatments. Such improvement is critically important, since the drug is currently effective in only about half of lymphoma patients, and virtually all patients experience eventual relapse and cease responding to the drug. The drug also has similar drawbacks in its use as a treatment for autoimmune diseases such as rheumatoid arthritis, in which abnormal B cells attack the body's own tissues.

Led by Thomas Tedder, Ph. D., professor and chair of immunology, the researchers published their findings June 21, 2004, in the advanced online version of the Journal of Experimental Medicine. The research was supported by the National Institutes of Health, The Arthritis Foundation and The Alliance for Lupus Research.

Rituximab is a monoclonal antibody that recognizes and binds to a receptor protein called CD20 on the surface of B cells. Such B cells are the immune system's armamentarium, producing antibodies that recognize and attach to invading microorganisms and other foreign substances. Although rituximab is known to cause death of B cells, according to Tedder determining its precise mechanism of action has not been possible.

"A major problem is that in vitro studies with human cells don't really reflect the action of the drug or the complex nature of B cell behavior in the body," said Tedder. Also, he said, the low concentrations of B cells in the blood prevent direct clinical studies, and ethical issues preclude the kinds of invasive physiological studies of B cell action in body organs that would be necessary in humans.

Thus, Tedder and his colleagues created a mouse model in which they developed a dozen anti-CD20 antibodies that enable them to explore the mechanism of anti-CD20 action on the four different known "isotypes" of immunoglobulin antibodies.

In their study, the researchers also used genetically-altered mice to explore the central question of the mechanism of action of the anti-CD20 antibodies. Multiple such mechanisms had been proposed, based only on in vitro studies of B cells. However, in their experiments with the in vivo mouse model, Tedder and his colleagues concluded that the antibodies triggered the killing of B cells only by activating immune cells called monocytes to attack the B cells. These monocytes include macrophages, which detect, engulf and destroy targeted cells.

"We were quite surprised by this finding, because everyone anticipated that other immune cells and mechanisms would mediate the effect," said Tedder. The finding has important and immediate treatment implications, he said. "When anti-CD20 therapy is being given to cancer patients undergoing chemotherapy, their monocytes have been largely wiped out in many cases, which may severely compromise their response to the therapy. In fact, there is anecdotal evidence that giving such patients anti-CD20 therapy before chemotherapy works much better."

Thus, said Tedder, clinical studies should clarify the role of monocyte levels in treatment success. And, monitoring of monocyte levels will likely become a standard practice in such patients. More importantly, treatments that increase monocyte levels could well enhance patients' response to anti-CD20 therapy, he emphasized. The same necessity for adequate monocyte levels also holds for use of anti-CD20 therapy for autoimmune disorders, said Tedder.

The mouse model is now enabling the researchers to explore genetic differences among B-cell lymphomas that will affect their sensitivity to anti-CD20 antibodies, said Tedder. Understanding such genetic differences, as well as the detailed mechanism by which the antibodies interact with B cell receptors, will lead to greatly improved therapies for both lymphomas and autoimmune diseases, said Tedder. These findings will enable Tedder and his colleagues to design and develop new therapies in his laboratory and apply them commercially, as well as aiding other laboratories and companies in developing and using these therapeutics.

Joint lead authors on the paper were Junji Uchida and Yasuhito Hamaguchi in the Tedder laboratory. Other authors were Julie Oliver, Jonathan Poe and Karen Haas in the Tedder laboratory, and Jeffrey Ravetch of The Rockefeller University.