Recombinant Protein Immunizes Mice, Promises New Strategy Against Infection And Cancer

November 25, 1997

Solving a long-standing problem in vaccine development, scientists have crafted a new way to deliver foreign proteins into the body such that the immune system is primed to attack virus-infected cells and cancer cells. Because this kind of an immune response is key to vaccine development, the findings have profound implications for developing safe vaccines to immunize against AIDS and other infectious diseases, and for creating new cancer therapies. Results from the study, led by Dr. Richard Young, Member of the Whitehead Institute for Biomedical Research, will be published in the November 25 issue of the Proceedings of the National Academy of Sciences.

In the study, scientists created a new, recombinant protein by fusing together a special type of protein called a 'heat shock protein,' isolated from the tuberculosis bacterium, and a protein called ovalbumin, long used by immunologists to study immune function. When scientists injected the recombinant protein into mice, the animals mounted an immune response against ovalbumin and developed immunity against cancer cells that make ovalbumin. These ovalbumin-producing cancer cells normally kill unimmunized mice.

"These results have led us to use the same heat shock fusion technology to develop vaccine candidates against AIDS and other infectious diseases," says Dr. Young, who now leads a consortium of scientists from Harvard University and the Massachusetts Institute of Technology to develop a vaccine against AIDS. Dr. Young and his colleagues are creating a recombinant monkey vaccine consisting of the heat shock protein fused to a protein from the Simian Immunodeficiency Virus (SIV). Researchers plan to test the efficacy of this vaccine in macaques.

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 immune cells called T cells. T cells orchestrate a multi-pronged attack, and if appropriate, turn into 'killer cells,' called cytotoxic T cells or CTLs, that home in on infected cells and destroy them.

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 a class of proteins, called 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," says Dr. Young.

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, these proteins 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 present on the surface of bacteria and are responsible for flagging the T cells and triggering the CTLs to attack.

Dr. Young and his colleagues found one particular protein from the tuberculosis bacterium, called hsp70, that could elicit powerful immune responses and could be used as an immune system booster. The special properties of hsp70 prompted the researchers to investigate whether soluble hsp70 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 the right immune system pathway and elicit a CTL response. The fusion technology can also be used against cancer cells. Microbial stress proteins could be introduced into tumor cells to act as red flags that attract a CTL immune response," says Dr. Young. The work reported in the PNAS paper was supported by the National Institutes of Health.

The title of the PNAS paper is "Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway."

The authors are:

Kimiko Suzue, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology.

Xianzheng Zhou, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology.

Herman N. Eisen, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology.

Richard Young, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology.

Whitehead Institute for Biomedical Research

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