New strategy prevents rheumatoid arthritis in mice

February 8, 2013

Dana-Farber Cancer Institute scientists have demonstrated a new strategy for treating autoimmune disease that successfully blocked the development of rheumatoid arthritis in a mouse model. They say it holds promise for improved treatment of arthritis and other autoimmune disorders in people.

The scientists report in the that infusing a highly specific type of cell that regulates immune responses into arthritis-prone mice shut down the cascade of inflammation that damages tissues and joints.

The method worked best when the infusions of CD8+ Treg were given at the same time that the animals were injected with a protein that triggered the arthritis-causing autoimmune reaction. "We found we could almost completely inhibit the disease in this setting," said Harvey Cantor, MD, chair of the Department of and AIDS at Dana-Farber and the study's senior author.

Even when administered weeks after the disease was initiated, CD8+ Treg infusions combined with low doses of methotrexate – a commonly used drug for – were able to significantly slow the arthritis process, the scientists reported.

The new strategy also blocked when the scientists injected peptide antigens to expand the rodents' own pool of CD8+ Tregs, rather than infusing them from outside. Overall, the results "suggest that [these] strategies represent a promising to ," the researchers wrote.

The is a network of cells, tissues, and organs that, when functioning normally, attacks and destroys infections, viruses, parasites, and other foreign "invaders."

In autoimmune disorders, however, parts of the immune system attack the individual's own healthy cells and tissues – the result of the immune forces failing to recognize "self" identifying tags on the body's cells.

An estimated 50 million American suffer from autoimmune disorders, which include rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, and celiac disease. At least 100 different have been identified, and are more common among women. The incidence of these diseases is rising in the United States for unknown reasons.

Rheumatoid arthritis is caused by inflammation throughout the body, attacking many tissues, especially the joints, frequently causing painful and deformed fingers and hands. About 1.5 million Americans are afflicted with rheumatoid arthritis. Drugs of several types, including corticosteroids, are given to reduce inflammation and slow the disease. The newest treatments are biologic agents, which block secreted chemicals called cytokines that carry out the misguided attacks. However, even with these agents – which can have serious side effects – rheumatoid arthritis treatment is often not optimal, said Cantor.

In contrast to these "downstream" players in the complex autoimmune cascade, the strategy described in the new report is aimed "upstream," where the attacks begins with overactive immune fighters, called T follicular , that mistakenly respond to "self" markers on healthy cells. These T cells can become chronically overactivated, spurring a continuous attack by antibodies on the body's tissues.

"Current treatment strategies that inhibit cytokines such as TNF or IL-1 production spare the upstream initiating events that continuously induce new effector T cells and cytokine secretion," noted Cantor. "We believe that targeting the CD4 T cells that initiate this cascade may be a more effective approach to rheumatoid arthritis therapy."

T regulatory cells, or Tregs, play an important role in turning off an immune response when it's no longer needed, such as after the body has repelled viral or bacterial invaders. Cantor previously found that certain Tregs, known as CD8+ Tregs, can recognize and eliminate overactive CD4 T helper cells that display a marker called Qa-1 in mice; the human equivalent is HLA-E.

In the new experiments, Cantor's team showed that these Qa-1-recognizing CD8+ Tregs could be recruited to kill off the subset of the harmful T helper cells causing arthritis "and exert strong inhibitory effects on disease progression." They found that CD8+ Tregs that recognized an Hsp60 molecule on the Qa-1 T helper cells were the most effective in eliminating the overreacting T cells. The researchers showed that administering the Hsp60 antigen to the mice triggered expansion of the CD8+ Tregs already present in the animals and slowed or stopped disease development.

Moving closer to clinical relevance, the researchers will test this approach in mice carrying human immune cells that provoke an autoimmune response.

Cantor said they are also studying the possibility of using nanoparticles coated with Qa-1/Hsp60 molecules to expand CD8+ Tregs as a more practical method that might be used someday for human therapeutic tests.

Explore further: Regulatory immune cell diversity tempers autoimmunity in rheumatoid arthritis

More information: Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T-cells, J Clin Invest. doi:10.1172/JCI66938.

Related Stories

Regulatory immune cell diversity tempers autoimmunity in rheumatoid arthritis

May 8, 2012
Untangling the root cause of rheumatoid arthritis has been a difficult task for immunologists, as decades of research has pointed to multiple culprits in our immune system, with contradictory lines of evidence. Now, researchers ...

Researchers uncover gene's role in rheumatoid arthritis, findings pave way for new treatments

January 24, 2013
University of Michigan research sheds new light on why certain people are more likely to suffer from rheumatoid arthritis – paving the way to explore new treatments for both arthritis and other autoimmune diseases.

Self-regulation of the immune system suppresses defense against cancer

December 21, 2011
Regulatory T cells, which are part of the body's immune system, downregulate the activity of other immune cells, thus preventing the development of autoimmune diseases or allergies. Scientists at the German Cancer Research ...

Recommended for you

Fluid in the knee holds clues for why osteoarthritis is more common in females

June 26, 2017
Researchers have more evidence that males and females are different, this time in the fluid that helps protect the cartilage in their knee joints.

Biologics before triple therapy not cost effective for rheumatoid arthritis

May 29, 2017
Stepping up to biologic therapy when methotrexate monotherapy fails offers minimal incremental benefit over using a combination of drugs known as triple therapy, yet incurs large costs for treating rheumatoid arthritis (RA). ...

Drug for refractory psoriatic arthritis shows promise in clinical trial

May 24, 2017
In a pivotal phase-3 clinical trial led by a Stanford University School of Medicine investigator, patients with psoriatic arthritis for whom standard-of-care pharmaceutical treatments have provided no lasting relief experienced ...

Cross-species links identified for osteoarthritis

May 17, 2017
New research from the University of Liverpool, published today in the journal npj Systems Biology and Applications, has identified 'cell messages' that could help identify the early stages of osteoarthritis (OA).

Osteoarthritis could be prevented with good diet and exercise

May 12, 2017
Osteoarthritis can potentially be prevented with a good diet and regular exercise, a new expert review published in the Nature Reviews Rheumatology reports.

Rodents with trouble walking reveal potential treatment approach for most common joint disease

May 11, 2017
Maintaining the supply of a molecule that helps to nourish cartilage prevented osteoarthritis in animal models of the disease, according to a report published in Nature Communications online May 11.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.