Gold-Metal Results: Compounds block immune proteins

Metals such as platinum and gold keep certain proteins from stimulating the body’s immune response, a study finds. The results suggest how some metal-based drugs might ease autoimmune symptoms, the researchers say.

They were screening compounds in search of a chemical that would blunt the action of a set of immunological proteins that usually bind to protein fragments, or peptides, from foreign objects such as viruses and bacteria. These class II major histocompatibility complex (MHC) proteins present the peptides to immune cells called helper T cells, which coordinate the body’s response. The cells initiate inflammation and the production of antibodies.

As part of the natural regulation of the immune system, the body uses a catalyst to make class II MHC proteins release a temporary cargo before presenting a peptide.

In an autoimmune disease, the proteins present peptides from a person’s own body, leading to a self-attack.

Brian S. DeDecker of Harvard Medical School in Boston and his colleagues were attempting to find a compound that would “knock the peptide out” of the immune proteins’ grasp, thereby reducing an autoimmune response, DeDecker says.

Out of 28,000 compounds examined, the team found only two that interacted with the class II MHC proteins in test tubes. Both compounds contained a soluble, oxidized form of platinum. Initial tests indicated that one of these compounds, a drug called cisplatin, caused the MHC proteins to let go of a tightly bound flu-virus peptide.

The researchers then tested the speed with which cisplatin caused the release. Cisplatin was five times as fast at stripping class II MHC proteins of their peptides as the body’s own catalyst was.

“There is a developing understanding that how tightly MHC binds its peptide determines whether you get a T cell response,” says team member Lawrence J. Stern of the University of Massachusetts Medical School in Worcester.

The researchers also conducted two test-tube experiments with live T cells. They exposed one group of cells to cisplatin and another to a gold compound not in the initial screening. In both cases, the metals inhibited the T cells’ response, the researchers report in the April Nature Chemical Biology, suggesting that the compounds disrupt peptide presentation.

The work could lead to new ways to study the mechanism of peptide release, says immunologist Gerald T. Nepom of the Benaroya Research Institute at Virginia Mason in Seattle. “There are all kinds of reasons that you would want to be able to control or fine-tune the [release] of peptides in the binding pocket of the MHC molecules,” he says.

But to lead to new therapies, the effect would have to be reversible, he says. “You want to help the arthritis, but you don’t want to leave [the patient] susceptible to the flu.”