Discovery May Lead To Novel Treatments For Autoimmune And Chronic Inflammatory Diseases

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By pinpointing the mechanism through which an

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 Fc³RIII 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 Fc³RIIb, which then suppresses auto-antibody-mediated inflammation. HSS researchers wondered whether an immune system protein

called interferon gamma (IFN-³) 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-³. The researchers found that in test tube studies of

macrophages, IVIG could inhibit the action of IFN-³ signaling.

Next,

they tested the effects of IVIG in mice infected with Listeria

monocytogenes, a bacteria that is usually controlled

by IFN-³. They found that mice treated with IVIG,

because of the suppression of IFN-³, 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-³. IVIG sparks this

inhibition by docking on a receptor called Fc³RIII.

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-³.

" 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. 

 Note: This story has been adapted from a news

release issued by Hospital For Special Surgery.