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Scientists trick immune system to treat autoimmune disease in mice


January 9, 2012

Left: Natural control mechanism blocks the enzyme's zinc active site Right: Novel antibody works as effectively as the natural control mechanism (Image: Weizmann Institute of Science)

Left: Natural control mechanism blocks the enzyme's zinc active site Right: Novel antibody works as effectively as the natural control mechanism (Image: Weizmann Institute of Science)

Researchers of Israel's Weizmann Institute of Science have achieved a significant new development which may have far reaching implications for the treatment of autoimmune diseases such as Crohn's and rheumatoid arthritis.

The immune system of those affected by these and similar ailments attack the body's own tissue by mistake. Weizmann Institute scientists have managed to convince the immune systems of mice to instead attack an enzyme known as matrix metallopeptidase 9 (MMP9). This enzyme is known to be significant to the body's autoimmune process.

The MMP enzymes perform important tasks within the body, such as allowing cells to mobilize and proliferate and they are also highly important within the process of wound healing. Yet problems arise when the enzymes, especially MMP9, operate unchecked by the body's MMP inhibitors, known as tissue inhibitors of metalloproteinases (TIMPS) .

The research group of Professor Irit Sagi of the Institute's Biological Regulation Department have invested a considerable amount of time exploring possible means to block these enzymes, as this process may lead to new effective disease treatments.

Earlier approaches explored by Sagi and other researchers had focused on drugs to target MMPS directly. However, this approach had clear limitations, notably severe side effects, so the research team began the complex process of producing synthetic molecules to be injected into mice which would cause the production of antibodies similar to TIMPS, which the team dubbed "metallobodies". The advantage over synthetic drugs being that TIMPS target the MMP enzymes in a highly precise fashion: an "arm" on each TIMP able to block a cleft on the enzyme in which the active material shelters.

Sagi's team, together with Professor Shanzer of the institute's Organic Chemistry Department were able to create an artificial version of the enzyme's active material, a metal zinc ion surrounded by three histidine peptides. The presence of this synthetic material resulted in the production of the "metallobodies" which were observed to function in a similar fashion to TIMPS.

This alternative approach to drugs that directly attack MMP enzymes begun with the work of Doctor Netta Sela-Passwell, then an undergraduate student in Sabi's lab and continued through her work as a doctoral candidate. Professor Sabi and Doctor Sela-Passwell decided that it may be possible to coax the immune system into targeting the MMP enzymes. Their experiments appear to have validated this approach. The research team induced a similar condition to Crohn's in mice, of which the symptoms were prevented in mice that had undergone the experimental treatment. The Wiezmann Institute's technology transfer arm, Yeda, has applied for patents of the synthetic immunization molecules as well as the generated "metallobodies".

The research was published in Nature Medicine last month.

Source: Weizmann Institute of Science


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observations suggest that an orally active therapeutic, used in conjunction with antiretroviral therapy, be designed to both block gut-derived microbial translocation and stimulate restitution of the gut epithelium. The hope would be to restore immunological integrity of the intestinal mucosal barrier, thereby controlling immune activation, both locally, in the gut mucosa, and systemically by suppressing cellular targets distal to the gut that may directly contribute to the progression of AIDS. The design for such an orally active therapeutic may be found in the complex formula of bovine colostrum and "immune milk," which has long been recognized to offer passive protection from a broad number of enteric bacterial and viral pathogens, primarily via the transfer of immunoglobulins and suppression of gut-associated inflammation with promotion of mucosal repair and regeneration.

Alex Edwards
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