Recombinant Protein May Play Key Role in Treating Immunocompromised Patients

January 17, 2000

Tags: Young LabCancerImmune SystemProtein Function

CAMBRIDGE, Mass. (Jan. 17, 2000) –– 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 system.

"If this recombinant vaccine behaves the same way in humans, the findings will have profound implications for developing safe vaccines to immunize similarly immunocompromised humans such as AIDS patients," says Dr. Richard Young, Member of the Whitehead Institute for Biomedical Research.

Results from the study will be 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 immune cells called 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, however, researchers had thought that CTLs could only be activated when another class of T cells called CD4 T cells are present. However, immunocompromised patients, such as AIDS patients, lack the critical CD4 cells.

"Our study shows that 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," says Dr. 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, 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 particularly abundant in bacteria and are responsible for flagging the T cells and triggering the CTLs to attack.

Dr. 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," says Dr. Young. Clinical trials are now underway to determine if heat shock fusion proteins can be used in treatment of 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 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.

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

The title of the Journal of Experimental Medicine paper is "In Vivo Cytotoxic T Lymphocyte Elicitation by Mycobacterial Heat Shock Protein 70 Fusion Proteins Maps to a Discreet Domain and is CD4+ T Cell Independent." The authors are:

Qian Huang, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology

Joan Richmond, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology

Kimiko Suzue, Whitehead Institute for Biomedical Research and 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


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