Synthetic Protein Eases Arthritis Symptoms In Mice

"This study opens a new research avenue to better understand and,perhaps, to treat rheumatoid arthritis, a condition that causessuffering in more than two million Americans," says NIAID DirectorAnthony S. Fauci, M.D.

Investigators from NIAID's Laboratory of Immunology, led by MichaelLenardo, M.D., published their findings in the October issue of NatureMedicine, now available online. The idea that the protein, calledpre-ligand assembly domain protein or PLAD, might play a role inthwarting the joint inflammation characteristic of rheumatoidarthritis--one of the most common autoimmune diseases--grew out oftheir research on a very rare autoimmune disease called autoimmunelymphoproliferative syndrome (ALPS).

Previously, Dr. Lenardo and his colleagues showed that in ALPS a formof PLAD blocks a cell surface receptor and prevents a needed chemicalsignaling pathway from functioning correctly. In ALPS, the signalpathway interrupted by PLAD leads to disease symptoms. But, thescientists reasoned, PLAD might also be able to block a related cellsurface receptor--one involved in passing signals that lead toinflammation. In theory, inhibiting this pathway might benefit peoplewith rheumatoid arthritis, who suffer from excessive inflammation.

A key promoter of inflammation is a chemical called tumornecrosis factor alpha (TNF-alpha). TNF-alpha starts a chemical chainreaction leading to inflammation by binding to two cell surfacereceptors, TNFR-1 and TNFR-2. Naturally occurring PLAD helps both formsof TNFR assemble and prepare to receive TNF-alpha. Synthetic PLAD, thescientists hypothesized, would bind to its natural counterpart andprevent it from performing its usual task.

The scientists used a variety of techniques (including injection ofTNF-alpha) to induce arthritis symptoms in mice. Researchers alsoinjected some of the animals with lab-made PLAD (P60 PLAD). "We foundthat P60 PLAD protein powerfully inhibited the symptoms ofTNF-alpha-induced arthritis," says Dr. Lenardo. P60 PLAD also lessenedthe effects of arthritis induced by other means. Moreover, he adds, P60PLAD appeared to inhibit disease symptoms in mice with established aswell as acute arthritis. The scientists did not detect any obvioustoxicity in the PLAD-treated mice.

"We're very hopeful that this could be good news for arthritissufferers," says Dr. Lenardo. In particular, the researchers areintrigued by P60 PLAD's apparent specificity: it seems to block thebinding of TNF-alpha to TNFR-1, while allowing TNFR-2 to continue tofunction. This is important, notes Dr. Lenardo, because it mayrepresent an advantage over some currently used arthritis drugs, whichdirectly block TNF-alpha by binding to both TNFRs and thereby inhibitbeneficial actions mediated by TNFR-2.

The scientists next aim to develop a more stable form of P60 PLAD. Ultimately, they hope to test the protein in clinical trials.

The research was also supported by the National Institute of General Medical Sciences, part of the NIH.

NIAID is a component of the National Institutes of Health, an agency ofthe U.S. Department of Health and Human Services. NIAID supports basicand applied research to prevent, diagnose and treat infectious diseasessuch as HIV/AIDS and other sexually transmitted infections, influenza,tuberculosis, malaria and illness from potential agents ofbioterrorism. NIAID also supports research on transplantation andimmune-related illnesses, including autoimmune disorders, asthma andallergies.

Reference: G-M Deng et al. Amelioration of inflammatoryarthritis by targeting the pre-ligand assembly domain (PLAD) of tumornecrosis factor receptors. Nature Medicine. Published online September18, 2005. DOI: 10.1038/nm1304.

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