Gold Shows Mettle Against Rheumatoid Arthritis

Discovery Could Lead to Less Toxic, More Effective Gold-based Therapies

From ancient times, gold has been the most prized of metals, yet in the medical realm, it endured a lowly status. Though occasionally used to treat ailments such as heart disease, syphilis, and alcoholism, most physicians deemed gold useless—except perhaps to “soothe an itchy palm” or as “an antidote to poverty.” The metal gained some scientific luster in 1929, when a dashing young Frenchman, Jacques Forestier, began giving gold salts to his rheumatoid arthritis patients. News spread of the therapy’s success. Twenty years later, he arrived in New York to present his findings at an international congress, only to be upstaged by a researcher reporting on his pioneering, and it would later turn out, Nobel Prize–winning work on the use of cortisone in rheumatoid arthritis.

Photo by Graham Ramsay

Brian DeDecker (above), Stephen De Wall, and colleagues found that gold therapy works by freeing autoimmune-provoking peptides from MHC class II proteins.

Gold fell out of favor, overshadowed by the more famous—and less toxic—hormone treatment. Forestier’s therapy had something else going against it. Though his results were replicated in clinical trials in the 1930s, and his treatment was successfully used in clinics all over Europe, no one had been able to figure out how exactly gold works to alleviate rheumatoid arthritis.

Now, Brian DeDecker, Stephen De Wall, and their colleagues report in the Feb. 27 Nature Chemical Biology that they have found an answer, one that could enhance gold’s reputation in medicine. More than that, the discovery could lead to a safer, more effective version of gold therapy, which is still in use in developing countries.

“Gold is still widely used in some countries, such as India. It works. The main problem is side effects,” said Timothy Mitchison, the Hasib Sabbagh professor of systems biology, and a co-author on the study. “Given our new hypothesis for a gold mechanism, it might be possible to do something about the side effects.”

Raising the Gold Standard
Like other autoimmune diseases, rheumatoid arthritis occurs when the cells of the immune system begin attacking the body’s own tissues, in this case the delicate synovial membrane lining the joints. Researchers still do not know what exactly provokes this attack, but it is thought to involve the MHC class II proteins. Normally, these proteins sit on the surface of a special class of immune cell, holding bits of foreign protein in their grip. This MHC class II–peptide complex is seen by other immune cells, which then launch an attack on cells bearing that same complex. DeDecker and De Wall, HMS research fellows in cell biology, and their colleagues found that gold, along with other precious metals such as platinum, frees peptides from the grip of the MHC class II proteins, essentially disarming the immune response. “Gold and these other metals potently rip the peptide from MHC class II,” said DeDecker.

In their experiments, the researchers used human leukocyte antigen to test gold and other metals’ effects. It is not clear what peptides might be pushed out by gold therapy in actual rheumatoid arthritis patients, in large part because of the mystery surrounding the disease. One possibility is that they are blood-borne bacterial or viral antigens that have become trapped in the joint. Another is that they are foreign antigens that closely mimic host peptides, confusing the immune system and turning it against those native antigens.

Nor is it clear how, exactly, gold frees the putative antigen from MHC class II’s grip. The researchers, who carried out their experiments at the Institute of Chemistry and Cell Biology (ICCB ), have evidence that it may work by subtly changing the MHC class II proteins’ shape in an allosteric fashion rather than by simply usurping the peptide’s spot on the MHC protein. “It is not replacing the peptide as a competitive inhibitor, it is doing something else to actively kick it out,” DeDecker said.

DeDecker and De Wall were not looking for gold when they began their study. What they were doing was chasing the dream of the late Harvard University structural biologist Don Wiley. In 1989, Wiley made the first crystal structure of an MHC class II–peptide complex. “Ever since that day, I am sure he had in his head, let’s knock those peptides out,” said DeDecker. Wiley invited DeDecker and De Wall, both of whom had experience developing high-throughput assays, to help him. “Which was a crazy idea because MHC class II holds peptides with a very, very high affinity,” said DeDecker.

Screening on Faith
The researchers spent the next eight months setting up the cleanest assay they could devise and were about to embark on a screen. Right around that time, Wiley tragically passed away. “At that point, Tim [Mitchison] took over support for the project and kept us going,” DeDecker said. With help also from Stephen Harrison, HMS professor of biological chemistry and molecular pharmacology, he and De Wall began screening tens of thousands of compounds in the library of the ICCB. They got no hits. “It required a good deal of faith to continue,” said Mitchison. The pair decided to screen a plate of about 600 FDA-approved drugs and got two solid hits—a pair of anticancer drugs, cisplatin and carboplatin, which happen to be metals.

At first, DeDecker was disappointed. Trained as a crystallographer, he viewed metals as a means to an end—to solve crystal structures—rather than long-sought quarry. De Wall, who now works at a clinical diagnostics company, tried to cheer him up. “Steve said, ‘Look, these things are used for rheumatoid arthritis therapy.’ My first reaction was, ‘Like in medieval times? Still today?’” DeDecker said. The pair decided to test the drugs’ mettle. Normally, MHC class II proteins exchange peptides with the aid of a catalyst, HLA-DM. In their original screen, they had included HLA-DM along with MHC class II and the human leukocyte antigen. This time, they left HLA-DM out. The platinum-based drugs still knocked the peptide off. “That gave us the hint that there was a conformational change going on—there was something more fun, more exciting than a competitive inhibitor,” DeDecker said.

They decided to expand their screen to include a whole panel of metals. Only gold and paladium exhibited the same peptide-releasing powers as platinum. To test their hunch that the metals were not simply outcompeting the peptide, they took peptide-free MHC class II protein, added metal, and purified the complex. Then they added the peptide. The peptide did not bind. Meanwhile, at the University of Massachusetts Medical School, Lawrence Stern and colleagues had created an antibody for peptide-free MHC class II protein. It turned out the metal–MHC complex bound the antibody, suggesting that rather than usurping the peptide’s spot, the metal was keeping MHC class II free of peptide.

Up to this point, their experiments had been conducted in test tubes. To see what effect metals might have on actual immune cells, Stern and colleagues performed a classic assay. In it, B cells are pulsed with peptide, which they take up and present to T cells. The B cells then activate T cells, which secrete cytokines that can be measured. When they treated the B cells with metal, cytokine levels were very low, suggesting the immune response had been thwarted due to lack of peptide. “That is the closest we get to biology,” DeDecker said.

Is it close enough? Could the discovery lead to a revival of gold’s use in medicine and even to less toxic, more effective gold therapies? “I hope so,” said Mitchison. “Steve and Brian certainly got a lot of interest from academic and industry groups when they presented their work, so I am cautiously optimistic.”

As for the toxicity issue, there is some evidence that gold adducts may trigger an immune response. “It might be possible to design gold compounds with ligands that prevent cell entry and/or prevent an immune response,” Mitchison explained. “All that said, we do have to be cautious. Gold may well have other targets.”

—Misia Landau

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