April 2, 2009

Scientists Hope Immune Function Can Improve Old TB Vaccine

A once widely-used vaccine against tuberculosis, bacillus Calmette-Gu©rin, or BCG, provides only partial protection against the ancient disease that kills more than 1 million people each year.

Now researchers at Baylor College of Medicine and The University of Texas Medical School at Houston hope that they can harness an immune function called autophagy to make the vaccine more effective for longer periods of time. A report on their work appears in a recent issue of the journal Nature Medicine.

"This study breaks new ground for the prevention of tuberculosis using vaccine," said N. Tony Eissa, M.D. professor of medicine "“ pulmonary at BCM and senior author of the report. "It is the first to provide in vivo (in animals) evidence that autophagy can be manipulated to enhance a vaccine. Similar strategies could be used in other kinds of vaccines as well."

Lingering health threat
Tuberculosis remains a major health threat with more than 1.7 million people dying of the disease worldwide in 2006. Treating the disease is a long and more difficult process. An even worse and difficult public health issue is the fact that one-third of the world population is infected with the mycobacteria that causes TB. This latent or silent infection can go on for years before it develops into an active disease. Eradicating the latent infection in these cases is a much more difficult process.

"BCG is a live attenuated form of Mycobacterium bovis, the pathogen of cattle tuberculosis and is used widely as a vaccine in developing nations," said Eissa. "It provides partial protection in children, but it is not as effective in adults. People no longer use it in the United States."

Autophagy as immune booster
Eissa has long been interested in autophagy, an ancient immune function that promotes the degradation of invading pathogens and encourages cells to digest parts of themselves when stressed or starved. The TB organism is difficult to kill because it is sequestered in parts of the cells, where it is hidden from the cell's clean-up mechanisms. In an earlier study, Eissa and colleagues showed that stimulating autophagy in cells by faking a different kind of infection encouraged cells to produce engulfing autophagosomes to kill the TB mycobacteria.

"In this study, we used autophagy to make sure that the vaccine got into the lysosomes," said Chinnaswamy Jagannath, Ph.D., associate professor of pathology and laboratory medicine at UT Medical School and first author of the paper. He and Eissa are co-leaders of the project. "That makes sure that the mycobacteria is broken down better."

"When the mycobacteria are destroyed, peptides are presented by macrophages and dendritic cells to the immune system soldiers the T-lymphocytes," said Eissa. "If we can increase this process, then the effect of the T-lymphocytes in the immune system is enhanced."

Testing their theory
In the laboratory, they tested their theory in cultured macrophages and dendritic cells. These cells go to the site of infection and then take samples back to the lymph nodes where they "tell" the lymphocytes what kind of infection they are facing.

"Then they can bring back an army of infection fighting machines," said Eissa. "If we stimulate autophagy, we can enhance this process of presenting the antigens samples taken by the dendritic cells." That results in improved infection-fighting, he said.

In fact, they found that the antigen Ag85B found in Mycobacterium tuberculosis can stimulate autophagy when it is expressed at high levels in an engineered form of BCG vaccine. The latter modified BCG enhances protection against the mycobacteria. This proved true in studies in the laboratory and mice.

Using more antigens in the future
If one antigen works this well, Jagannath thinks that increasing the level of expression of others might help. "If we could hyperexpress two or three antigens, it should become increasingly better," he said.

"We can put it in the mouse and see how to achieve the best and longest lasting protection," he said.

Others who took part in this research include Yi Xu of BCM, Devin R Lindsey and Robert L Hunter, Jr. of UT Houston and Subramanian Dhandayuthapani of The University of Texas Health Science Center at San Antonio.

Funding for this work came from the National Institute of Allergy and Infectious diseases and the National Heart, Lung and Blood Institute.


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