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.