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Discovery May Lead to Novel Treatments for Autoimmune and Chronic Inflammatory Diseases

NEW YORK, NY—January 25, 2007

By pinpointing the mechanism through which intravenous therapy combats chronic inflammatory diseases, researchers have discovered that they may be able to replace the time-consuming infusion therapy with an injection that could be given during a quick office visit. Investigators at Hospital for Special Surgery in New York City have discovered that intravenous immune globulin (IVIG) or antibody therapy works, in part, by attaching to a receptor known as FcgRIII and blocking the function of interferon gamma, a major inflammatory factor. Only a small component of the IVIG solution, 0.5%, is responsible for blocking this receptor.

“The study suggests that it’s not the whole preparation itself, but the immune complexes within the preparation that are causing the therapeutic effect,” said Lionel Ivashkiv, M.D., Director of Basic Research at Hospital for Special Surgery (HSS) who led the study. Instead of using IVIG, which is pooled from thousands of blood donors, clinicians may be able to use small amounts of so-called immune complexes, or even design synthetic drugs that will avoid problems, such as potential exposure to infectious agents, that are associated with using blood products.

The study appears in the January issue of the journal Immunity.

For years, doctors have used IVIG to treat patients with autoimmune and chronic inflammatory diseases, such as dermatomyositis, Kawasaki disease, multiple sclerosis, lupus, chronic lymphocytic leukemia, and idiopathic thrombocytopenic purpura, but just how the therapy works has remained a mystery. Some  researchers have shown that IVIG works, in part, by activating a receptor known as FcgRIIb, which then suppresses auto-antibody-mediated inflammation. HSS researchers wondered whether an immune system protein called interferon gamma (IFN-g) could be involved—many chronic inflammatory and autoimmune diseases are caused or exacerbated by an overexpression of this protein.

To test their theory, the investigators turned to macrophages, immune cells that engulf bacteria and are stimulated to kill their prey by IFN-g. The researchers found that in test tube studies of macrophages, IVIG could inhibit the action of IFN-g signaling.

Next, they tested the effects of IVIG in mice infected with Listeria monocytogenes, a bacteria that is usually controlled by IFN-g. They found that mice treated with IVIG, because of the suppression of IFN-g, had much more severe infections than mice treated with saline. Experiments in a mouse model of immune thrombocytopenic purpura also revealed that immune globulin inhibited IFN-g. IVIG sparks this inhibition by docking on a receptor called FcgRIII.

In another experiment, researchers turned their focus to a different question—which component of IVIG is responsible for its therapeutic effects. IVIG is composed of 99.5% monomeric IgG and 0.5% so-called immune complexes. The researchers cultured macrophages with the different IVIG components and discovered that the immune complexes were responsible for the suppression of IFN-g.

“This study suggests that we can move away from using these IVIG preparations and generate very defined (synthetic) immune complexes, which have the potential to work better, be easier to deliver, and have fewer problems in terms of the infusion part of the therapy,” Dr. Ivashkiv said.

Usually, patients must receive IVIG infusions in the hospital setting, which can involve three to four hours per day, for three consecutive days.  “IVIG is time intensive, it’s somewhat expensive, and there are sometimes shortages, because it’s a human product,” Dr. Ivashkiv explained. “A lot of the limitations of the therapy is just the volume and the quantity of the material that is used. Some people get volume overload or severe allergic reactions.”

If clinicians can deliver only the active agent of IVIG and/or design immune complexes with recombinant materials, they may be able to avoid many of these problems, say researchers. “It could be done as an injection, as part of an office visit,” commented Dr. Ivashkiv.
 
In addition to HSS researchers, investigators from the Weill Medical College of Cornell University and Weill Graduate School of Medicine, Memorial Sloan-Kettering Cancer Center, Beth Israel Deaconess Medical Center, the British Columbia Cancer Agency in Vancouver, and the Walter and Eliza Hall Institute of Medical Research in Australia contributed to the study.  A Cancer Research Institute Fellowship and the National Institutes of Health supported their work.

 

About HSS | Hospital for Special Surgery
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the eighth consecutive year) and No. 3 in rheumatology by U.S. News & World Report (2017-2018). Founded in 1863, the Hospital has one of the lowest infection rates in the country and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In 2017 HSS provided care to 135,000 patients and performed more than 32,000 surgical procedures. People from all 50 U.S. states and 80 countries travelled to receive care at HSS. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The culture of innovation is accelerating at HSS as 130 new idea submissions were made to the Global Innovation Institute in 2017 (almost 3x the submissions in 2015). The HSS Education Institute is the world’s leading provider of education on the topic on musculoskeletal health, with its online learning platform offering more than 600 courses to more than 21,000 medical professional members worldwide. Through HSS Global Ventures, the institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.

 

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