Wistar researchers invigorate 'exhausted' immune cells

Sep 15, 2008

In battles against chronic infections, the body's key immune cells often become exhausted and ineffective. Researchers at The Wistar Institute have found a way to restore vigor to these killer T cells by blocking a key receptor on their surface, findings that may advance the development of new therapies for diseases such as HIV, hepatitis B and C, and cancer.

In their study, published online September 15 in the Proceedings of the National Academy of Sciences (PNAS), Wistar Institute investigators and colleagues report that using an antibody to block the receptor, known as programmed death-1 (PD-1), dramatically restored immunity in chronically infected mice. Furthermore, they discovered a method to distinguish between T cells that can be revitalized in this way and those that can't.

The findings will help researchers develop PD-1 blocking agents, and also provide a way to select patients who may benefit most from such novel drugs, says the study's lead author E. John Wherry, Ph.D., an assistant professor in Wistar's Immunology Program.

"Blocking PD-1 may provide a novel tool to fight chronic infection as well as some cancers, like melanoma, that are susceptible to destruction by the immune system," Wherry said. Examples of infections that often result in T-cell exhaustion are HIV, hepatitis B, and hepatitis C, he says.

Wherry's continuing research on PD-1 has provided the groundwork for developing antibody therapies that inhibit the receptor. Wherry says he knows of a pharmaceutical company preparing to test one of these agents in patients with hepatitis C.

Researchers have known that T cells – white blood cells capable of inducing the death of infected or cancerous cells – become progressively less functional over time. In earlier studies, Wherry and his colleagues found that, during the course of a chronic infection, gene expression in killer T cells changed dramatically as the cells became exhausted and immune response to a pathogen slowed down. Wistar investigators then identified one gene that played a central role in this tamping down of immune response – PD-1, which produces PD-1 protein receptors that stud the surface of these T cells.

In follow-up experiments, they found that if they blocked PD-1 receptors in cell cultures using an antibody made up of one of the protein's natural binding ligands they could alleviate T-cell exhaustion. This demonstrated that PD-1 serves as a "brake" on T-cell function.

Wherry suspects that this reaction is designed to protect a body against the ravages that a chronically over-stimulated immune system can wreak. "The immune system can cause a lot of damage in an effort to control an infection. If you can't clear an infection and are making yourself sick trying to do so, it may be better off to live with the infection than die from the immune-mediated collateral damage," he said.

In the current study, Wherry and colleagues tested in mice infected with lymphocytic choriomeningitis virus the effect of plugging the PD-1 receptor with the antibody, thus releasing the "brake" on the immune system. And they studied two different subsets of killer T cells: those with the highest expression of PD-1 receptors and ones with an "intermediate" expression. Researchers theorized that those T cells with the highest PD-1 expression, signifying the deepest exhaustion, would benefit most from an antibody to PD-1.

To their surprise, that is not what they found. They implanted these two different subsets of cells into infected mice, and then gave the mice a PD-1 antibody. Those mice implanted with T cells with intermediate expression of PD-1 recovered their vigor, while mice with the highest PD-1 expression did not. "It may be the killer T cells expressing a lot more PD-1 are already committed to cell death," Wherry said.

Knowing which subset of T cells will respond to an antibody drug will help physicians identify patients who could respond, if these novel agents reach extensive clinical testing, Wherry says. "We can optimize the promise of such a medical tool and minimize wasteful treatment," he said.

Source: The Wistar Institute

Explore further: First vital step in fertilization between sperm and egg discovered

add to favorites email to friend print save as pdf

Related Stories

Bristol-Myers pitches its cancer medicine pipeline

Jun 06, 2011

(AP) -- Bristol-Myers Squibb Co. executives said Monday they have more than a half-dozen drugs in testing against different cancers and could get important data on them and possibly a couple of approvals this year.

Recommended for you

Bionic ankle 'emulates nature'

4 hours ago

These days, Hugh Herr, an associate professor of media arts and sciences at MIT, gets about 100 emails daily from people across the world interested in his bionic limbs.

Firm targets 3D printing synthetic tissues, organs

6 hours ago

(Medical Xpress)—A University of Oxford spin-out, OxSyBio, will develop 3D printing techniques to produce tissue-like synthetic materials for wound healing and drug delivery. In the longer term the company ...

User comments : 2

Adjust slider to filter visible comments by rank

Display comments: newest first

mattytheory
1 / 5 (1) Sep 15, 2008
perhaps the "brake" on t-cell function evolved for a reason. i certainly hope the researchers have considered this before they go tampering with ways to circumvent this natural process...
holmstar
not rated yet Sep 16, 2008
I'm sure the effect is temporary... But one would certainly want to exercise caution with this technique. An immune system run-amuk can easily be deadly.

More news stories

Unraveling the 'black ribbon' around lung cancer

It's not uncommon these days to find a colored ribbon representing a disease. A pink ribbon is well known to signify breast cancer. But what color ribbon does one think of with lung cancer?

Classifying cognitive styles across disciplines

Educators have tried to boost learning by focusing on differences in learning styles. Management consultants tout the impact that different decision-making styles have on productivity. Various fields have ...

Tiny power plants hold promise for nuclear energy

Small underground nuclear power plants that could be cheaper to build than their behemoth counterparts may herald the future for an energy industry under intense scrutiny since the Fukushima disaster, the ...

Hand out money with my mobile? I think I'm ready

A service is soon to launch in the UK that will enable us to transfer money to other people using just their name and mobile number. Paym is being hailed as a revolution in banking because you can pay peopl ...