Immune System’s Bare Essentials Used to Speedily Detect Drug Targets

Scientists at Johns Hopkins have taken a less-is-more approach to designing effective drug treatments that are precisely tailored to disease-causing pathogens, such as viruses and bacteria, and cancer cells, any of which can trigger the body’s immune system defenses.

In a report to be published in the latest issue of Nature Medicine online Oct. 31, researchers describe a new “epitope-mapping” laboratory test that within three weeks can pinpoint the unique binding site – or epitope – from any antigen where immune system T cells can most securely attach and attack invading germs or errant cells.

Knowing exactly where the best antigen-T-cell fit occurs – at sites where short stretches of proteins, called peptides, bind and are displayed on the surface of antigen-processing immune system cells – is a prerequisite for designing effective and targeted drug therapies, researchers say.

Identifying the best binding site, they say, should speed up cancer vaccine development, lead to new diagnostic tests that detect the first appearance of cancer cells, well before tumors develop, and sort out disorders that are difficult to diagnose, such as Lyme disease.

“Our new, simplified system reproduces what happens in the cells of the immune system when antigens from a pathogen first enter the body and need to be broken down into peptides to become visible to T cells, one of the two immune defender cell types,” says immunologist Scheherazade Sadegh-Nasseri, Ph.D., an associate professor of pathology, biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine. “Once T cells recognize an antigen, they latch on, become activated, and call for other immune system cells to enter the fight,” adds Sadegh-Nasseri, the senior study investigator for the team of scientists who developed the new epitope-mapping process.

Sadegh-Nasseri says the team’s new lab test takes a fraction of the time involved in current methods, which rely on sequencing, or identifying every single peptide in the antigen’s make-up, one after another. Such sequencing can take months, or even years, to identify possible T cell binding sites.

“The added beauty of our system is that the entire process can be done in the lab, so we do not have to perform tests in people,” says Sadegh-Nasseri, who has a patent pending for the new test.

The Johns Hopkins team, including co-lead investigators AeRyon Kim, Ph.D., and Isamu Hartman, Ph.D., also immunologists, based their test on nearly 20 years of the team’s previous research into how immune system cells selectively process antigens and the maze of possible protein combinations inside. That cumulative research led them to narrow their search to five essential and well-described proteins involved in antigen processing by immune system cells.

In their latest series of experiments, the team tested a mix of the selected immune system proteins to see if it could accurately detect two already known epitopes, those of the Texas strain of the influenza virus and type II collagen, both widely used experimental antigens. Then, they used the mix to find unknown epitopes for portions of the influenza virus that causes avian flu and for the parasite involved in malaria.