UI researchers advance potential, potent way to stimulate human immune system

[Editor's note: To receive a copy of the research article mentioned in this news release, please call David Schneier, media assistant, at the National Academy of Sciences at 202-334-2138. To interview Arthur Krieg, M.D., before Aug. 4, please contact Becky Soglin. From Aug. 4 - 6 Dr. Krieg can be reached in the evenings at the Swissotel in Boston, Mass., at 617-451-2600.]

IOWA CITY, Iowa -- Dendritic cells are the master control cells of the human immune system, but they aren't always successfully activated to help lead the charge against cancer or infectious disease. It may now be possible to use a kind of bacterial DNA called CpG DNA to stimulate human dendritic cells for powerful therapeutic purposes, according to University of Iowa Health Care findings published in the Aug. 3 issue of the Proceedings of the National Academy of Sciences.

"Previous studies, including UI research, showed that CpG DNA activates the immune system in mice," said Arthur M. Krieg, M.D., UI professor of internal medicine. "Now, using human cell cultures, we have demonstrated there is a very potent way to use the bacterial DNA to activate certain groups of human dendritic cells." Krieg led the research team, which also included Gunther Hartmann, M.D., a UI postdoctoral research associate from the Division of Pharmacology, Medizinische Klinik, University of Munich, and George J. Weiner, M.D., director of the UI Cancer Center and UI associate professor of internal medicine.

Krieg said the findings may lead to improved vaccines and immune therapies for cancer. Human trials using CpG DNA to enhance a vaccine against Hepatitis B have started in Canada, and other clinical trials are planned for treating patients with lymphoma at the UI beginning within a few months.

Dendritic cells, a type of white blood cell, link the primitive arms of the immune system with the more sophisticated acquired immune system by producing chemical signals that activate other immune cells and "tell" them what to fight. The research team evaluated the effects of CpG alone and in combination with a glycoprotein, known as granulocyte-macrophage colony-stimulating factor, on different types of dendritic cells. Previous research has shown that without this growth factor, dendritic precursor cells die within two days.

"We found that the CpG DNA was much better than the growth factor in activating dendritic cells and fostering their survival," Krieg said. "In addition, when used in combination, the CpG and growth factor were far better than either agent alone."

The team also discovered that dendritic cells normally circulating in the blood showed a greater response to the CpG DNA than other types of dendritic cells did. Krieg said that finding suggests that therapy with CpG DNA might activate immune function throughout the entire body.

Dendritic cells that circulate in the blood are key to activating T cells, which kill off infected or malignant cells, thus limiting damage from infection or tumors. CpG DNA-treated dendritic cells were found to be much more effective than "resting" dendritic cells at activating the types of T cells most important to immune response function. Researchers hope the specially-treated dendritic cells can be used for both improved vaccinations and treatment of cancer and allergic and autoimmune diseases.

"For enhanced immunization, CpG DNA is simply added to a vaccine," Krieg said. The dendritic cells respond positively because they are "tricked" into recognizing the synthetic CpG DNA as a sign of infection, although it does not actually cause harm. The CpG sequence consists of two bases normally found in DNA, cystosine and guanine, in a combination that is much rarer in humans and other vertebrates than in bacteria and viruses. In addition, human CpG DNA is always modified by a kind of "crown" called a methyl group. The human immune system recognizes viral or bacterial DNA because this methyl group on the CpG sequence is absent.

Dendritic cells can also be present in and around a tumor, but they normally consider a tumor to be part of the body and leave it alone. However, the discovery suggests that it may be possible to use CpG DNA to activate the dendritic cells, which can then instigate T cells to mount an effective anti-tumor attack. Krieg said this strategy has already led to cures of established tumors in mice.

"Our latest discovery provides an exciting new approach to harness the remarkable power of the immune system for therapeutic purposes," Krieg said. "Other scientific groups in the United States, Canada, Germany and elsewhere have confirmed the immune-stimulating properties of CpG DNA, and additional clinical trials in infectious diseases, cancer and allergy are expected to begin before the end of the year."

The researchers' funding included grants from the Deutsche Forschungsgemeinschaft (a government agency in Germany), the U.S. Department of Veterans Affairs, and the National Institutes of Health (NIH). CpG ImmunoPharmaceuticals in Wellesely, Mass., and Hilden, Germany, also provided support. Additional services were provided by the UI Diabetes and Endocrinology Center, which receives grant support from the NIH.