Protein may play key role for patients with damaged immune systems


In a promising new advance in vaccine development, scientists have identified a protein fragment that is exceptionally potent in eliciting an immune response against infected cells and cancer cells. When scientists injected a vaccine containing this fragment into mice lacking a healthy immune system, the animals were able to mount a cellular immune response despite their compromised immune systems.

"If this recombinant vaccine behaves the same way in humans, the findings will have profound implications for developing safe vaccines to immunize similarly immunocom-promised humans such as AIDS patients," said Dr. Richard Young, professor of biology and a member of the Whitehead Institute for Biomedical Research.

Results from the study were published in the January 17 issue of the Journal of Experimental Medicine.

When germs enter the body, the immune system responds in two ways. One arm of the immune system, led by immune cells called B cells, works mainly by secreting antibodies into the body's fluids. These antibodies seek and destroy the germs circulating in the bloodstream. However, antibodies are useless when it comes to penetrating cells. The task of attacking cells infected by viruses or deformed by cancer falls to the second arm of the immune system, led by T cells. The T cells that home in on infected cells or cancer cells and destroy them are called cytotoxic T cells or CTLs.

Until now, researchers had thought that CTLs could only be activated when another class of T cells called CD4 T cells is present. Immunocompromised patients such as AIDS patients lack the critical CD4 cells.

"Our study shows that so called 'stress proteins' are potent stimulators of the immune system, even when CD4 T cells are not present, so this strategy holds great promise for immunizing not only patients with normal immune systems, but also patients lacking a healthy immune system," said Professor Young.

The fragment with this potent immune stimulatory property was derived from a heat-shock protein. Heat-shock proteins, or stress proteins, are a family of proteins that cells produce in response to stress from heat, injury, germs or toxins. Normally they act as molecular chaperones, binding to other proteins and ferrying them to and from various compartments of the cell. A few years ago, immunologists noticed that heat-shock proteins are particularly abundant in bacteria and are responsible for flagging the T cells and triggering the CTLs to attack.

Professor Young and his colleagues found that heat-shock proteins (hsp) from the tuberculosis bacterium could elicit powerful immune responses and could be used as an immune system booster. The special properties of hsp proteins prompted the researchers to investigate whether soluble hsp proteins could be fused with bacterial or viral proteins of interest to elicit the desired type of immune response.

"This study shows that the heat-shock proteins can function as vehicles to deliver viral proteins to a critical immune system pathway and elicit a CTL response. The fusion technology can also be used against cancer cells. We know that these heat-shock proteins, when fused to a tumor protein, can cause the immune system to mount a CTL immune response capable of killing cancer cells in animals," said Professor Young. Clinical trials are now underway to determine if heat-shock fusion proteins can be used to treat human cancers.

The goal of vaccine development is to produce a full-blown immune response without causing full-blown disease. However, when vaccines containing soluble proteins from the microorganisms are used to produce an immune response, the CTLs are rarely activated.

For decades, vaccine development experts have sought to find a simple and practical way to activate the killer cells or CTLs using soluble proteins, but finding a method that works has been a challenge.

"We were able to solve this problem by taking advantage of the observation that... heat-shock proteins are exceptions to the rule that soluble proteins are unable to stimulate CTL responses. In fact, heat-shock proteins are extremely potent in stimulating a CTL immune response," said Professor Young.

The work reported in the Journal of Experimental Medicine paper was supported in part by the National Institutes of Health and StressGen Biotechnologies.

Other authors of the paper were Qian Huang and Joan Richmond, postdoctoral associates in Professor Young's lab at Whitehead; Kimiko Suzue, a graduate student in the Harvard-MIT Division of Health Sciences and Technology; and Professor Emeritus Herman N. Eisen of the Department of Biology and the Center for Cancer Research.

A version of this article appeared in MIT Tech Talk on January 26, 2000.


Topics: Health sciences and technology

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