|Synthetic Protein Eases Arthritis Symptoms in Mice
A lab-made version of a human protein alleviates symptoms of both acute and
chronic arthritis in mice and could be the basis for a new arthritis drug for
people, report scientists from the National Institute of Allergy and Infectious
Disease (NIAID), part of the National Institutes of Health (NIH). The protein
prevents the assembly of a cell surface receptor, thus blocking transmission
of chemical signals that lead to arthritis symptoms.
“This study opens a new research avenue to better understand and, perhaps,
to treat rheumatoid arthritis, a condition that causes suffering in more than
two million Americans,” says NIAID Director Anthony S. Fauci, M.D.
Investigators from NIAID’s Laboratory of Immunology, led by Michael Lenardo,
M.D., published their findings in the October issue of Nature Medicine, now available
online. The idea that the protein, called pre-ligand assembly domain protein
or PLAD, might play a role in thwarting the joint inflammation characteristic
of rheumatoid arthritis — one of the most common autoimmune diseases — grew out of
their research on a very rare autoimmune disease called autoimmune lymphoproliferative
Previously, Dr. Lenardo and his colleagues showed that in ALPS a form of PLAD
blocks a cell surface receptor and prevents a needed chemical signaling pathway
from functioning correctly. In ALPS, the signal pathway interrupted by PLAD leads
to disease symptoms. But, the scientists reasoned, PLAD might also be able to
block a related cell surface receptor — one involved in passing signals that lead
to inflammation. In theory, inhibiting this pathway might benefit people with
rheumatoid arthritis, who suffer from excessive inflammation.
A key promoter of inflammation is a chemical called tumor necrosis factor alpha
(TNF-alpha). TNF-alpha starts a chemical chain reaction leading to inflammation
by binding to two cell surface receptors, TNFR-1 and TNFR-2. Naturally occurring
PLAD helps both forms of TNFR assemble and prepare to receive TNF-alpha. Synthetic
PLAD, the scientists hypothesized, would bind to its natural counterpart and
prevent it from performing its usual task.
The scientists used a variety of techniques (including injection of TNF-alpha)
to induce arthritis symptoms in mice. Researchers also injected some of the animals
with lab-made PLAD (P60 PLAD). “We found that P60 PLAD protein powerfully inhibited
the symptoms of TNF-alpha-induced arthritis,” says Dr. Lenardo. P60 PLAD also
lessened the effects of arthritis induced by other means. Moreover, he adds,
P60 PLAD appeared to inhibit disease symptoms in mice with established as well
as acute arthritis. The scientists did not detect any obvious toxicity in the
“We’re very hopeful that this could be good news for arthritis sufferers,” says
Dr. Lenardo. In particular, the researchers are intrigued by P60 PLAD’s apparent
specificity: it seems to block the binding of TNF-alpha to TNFR-1, while allowing
TNFR-2 to continue to function. This is important, notes Dr. Lenardo, because
it may represent an advantage over some currently used arthritis drugs, which
directly block TNF-alpha by binding to both TNFRs and thereby inhibit beneficial
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 of
the U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on transplantation and immune-related illnesses, including autoimmune
disorders, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.