Two new targets for drugs to control lupus have been identified, and may provide a breakthrough in the treatment of the disease.
The study by investigators at Hospital for Special Surgery further enables patients to control the disease with fewer side effects, provided that drugs that can work specifically on these sites are developed by companies.
AdvertisementLupus is an autoimmune disease affecting many parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. The main feature of this disease is inflammation that is characterized by pain, heat, redness, swelling and loss of function.
However, in majority of the people, this disease influences only a few organs with mild symptoms, but in others, lupus can lead to serious and critical problems.
If the statistics of the Lupus Foundation of America are believed, an estimated 16,000 Americans develop lupus each year.
The study was led by Lionel Ivashkiv, M.D., director of Basic Research at Hospital for Special Surgery in New York City.
"The study identifies very good therapeutic targets, and what needs to be done is identify better candidate drugs," Nature Immunology quoted Dr. Ivashkiv.
The drugs developed by researchers are mainly aimed at blocking interferon as extraordinarily high levels of interferon-alpha may lead to lupus.
However, these drugs have immunosuppressive side effects making patients susceptible to a number of illnesses and infections, of which some can prove to be deadly.
At present, these drugs are undergoing testing in clinical trials. If researchers succeed in developing drugs for these newly identified drug targets, it will be possible for the patients to avert these immunosuppressive effects.
Two major functions are performed by Interferons. Firstly, they protect against viruses and second, they regulate immune responses, strengthening immune responses and playing a role in autoimmunity.
The two functions of IFN are governed by different proteins which are known as STATs. STAT1 mediates the autoimmune and inflammatory functions, and STAT2 mediates the virus protection function.
"What we were interested in understanding is how you can regulate the balance between activating the inflammatory effects and the antiviral effects," said Dr. Ivashkiv.
He added: "We thought if we could control the functions of the interferons, that would lead to new therapeutic approaches where you could block specifically some of their functions, but not others."
It was discovered that calcium distinctively boosts activation of STAT1 by interferons, and therefore the investigators were focusing attention on calcium.
It was tested if two kinase enzymes in the calcium-signaling pathway, CAMK and Pyk2, could be manipulated to control STAT1.
The investigators demonstrated in the studies involving mice, that if these calcium-signaling pathways were blocked using the drug called KN-93 it regulated the amount of STAT1, but not STAT2 activation.
"What we found was that these kinases that are regulated by calcium actually regulate the strength of activation of STAT1 by the interferons, but they do not regulate the strength of activation of STAT2," said Dr. Ivashkiv.
He added: "The idea was if you block these signaling pathways, would you block the STAT1 part, which controls the inflammatory/deleterious effects and preserve the antiviral part. We tested that in an animal model of lupus and we were able to show, in vivo, that you can suppress STAT1 activation by inhibiting the calcium-dependent kinases."
In the opinion of the researchers, their work has acknowledged a new therapeutic approach for attacking lupus.
"What the companies are trying to develop are, basically, antibodies against the interferons. The concern there is that if you block the interferon completely, patients may become very immunosuppressed and unable to handle viral infections," said Dr. Ivashkiv.
"Our idea is that if you block these calcium pathways, you could block the deleterious effects of the interferon, but maintain the antiviral effects," he added.
The study was published online in Nature Immunology recently and will appear in print in February.
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