LONDON - The discovery that a monoclonal antibody can prevent and treat rheumatoid arthritis developing in a mouse model of the disease may lead to a new generation of therapies for this disabling and costly condition.
The finding also is likely to interest researchers trying to develop therapies to treat other diseases with an autoimmune component, such as diabetes, multiple sclerosis and inflammatory bowel disease.
The result came as a surprise because the agonistic monoclonal antibody concerned, which binds to the CD40 molecule found on cells of the immune system, has previously been evaluated for its effect in boosting the immune response in patients with cancer, for example.
Researchers from The Kennedy Institute of Rheumatology at Imperial College School of Medicine in London report their results in the June 2000 issue of Nature Medicine in a paper titled, "Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process."
Marco Londei, professor of medicine at the Kennedy Institute, told BioWorld International, "This study suggests to us that CD40 is like a double-edged sword. Until now, there has been a large body of evidence suggesting that CD40 was able to boost an immune response. Our report suggests that there is another side to CD40, that it may block an immune response."
Londei said the study may, once the basic mechanism of action of anti-CD40 therapy has been clarified, pave the way toward new therapies to treat diseases that involve chronic inflammatory processes, including rheumatoid arthritis.
CD40 is found on many different cells, including antigen-presenting cells such as monocytes, macrophages and dendritic cells, and B lymphocytes. Studies have shown that, normally, CD40 must bind to its ligand in order to trigger an immune response or an inflammatory process. The ligand of CD40, until recently known as CD40L, but now called CD154, is found mainly on activated T cells.
Londei and colleagues Claudia Mauri and Lennart Mars were studying how different monoclonal antibodies affect the evolution of arthritis in a new animal model of chronic rheumatoid arthritis. In this model, the disease develops in the animal following immunization with collagen type II.
The researchers found that if they gave an agonistic monoclonal antibody against CD40 after immunizing the mice with collagen type II, including after the onset of the disease, the symptoms did not develop as expected. The monoclonal antibody had no effect, however, if given before the immunization, and only a slight effect if given at the same time as the immunization.
Londei said, "This result was very surprising because we would have expected that this monoclonal antibody would make the disease worse." New data from more recent unpublished studies will shed light on why this was happening, he said.
"Although I cannot discuss these unpublished studies," Londei added, "the results from our current paper lead us to believe that one possible mechanism to explain the finding is that we are forcing the antigen to be presented by B cells. This may change the function and characteristics of T cells and transform the immune response into the TH2 type." In simplistic terms, the TH1 response is considered to be a pro-inflammatory immune response, while the TH2 response is anti-inflammatory and may protect against autoimmune processes. Most immunizations result in a TH1 response.
"Our results also show," Londei said, "that if you give the antibody before the immunization, it does not work. It has to be given when the disease has already started. It appears to be a question of timing." More studies will have to be conducted to eliminate the potential risks of using anti-CD40 monoclonal antibodies to treat patients with autoimmune diseases, he said.
He and his colleagues are planning further studies examining the use of monoclonal antibodies against CD40 in other animal models of rheumatoid arthritis.
Commenting on the paper in a News & Views article in the same issue of Nature Medicine, Eric Zanelli and Rene Toes, of Leiden University Medical Center in Leiden, the Netherlands, said the manipulation of the interaction between B and T cells through CD40 and CD154 could be beneficial to arthritis patients.
Their article, titled "A dual function for CD40 agonists," concludes, however, that "the risks associated with the use of agonistic antibodies against CD40 to treat autoimmune disorders are, at present, unacceptably high. Therefore, much more needs to be learned of the delicate balance of CD154-CD40 interactions . . . in autoimmune diseases." Eventually, they add, new therapeutic strategies for autoimmune diseases could result.