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Unique Vaccination Creates 'Metallobodies' Against Autoimmune Activity

  [ 40 votes ]   [ Discuss This Article ] • December 28, 2011

The team is excited not just by this ‘vaccination’ method's potential for treating Crohn’s disease in humans, but by its potential application in treatment of many other diseases as well.

After years of work on the problem, researchers at Israel’s Weizmann Institute believe they’ve found a way to “turn the tables” on autoimmune disorders such as rheumatoid arthritis and Crohn’s disease. These disorders turn the immune system against the body's own tissues.

In an animal model of Crohn’s disease, Prof. Irit Sagi, PhD, and her research group have tricked the immune systems of mice into targeting a key villain in the autoimmune process - an enzyme known as MMP9 (a member of the matrix metalloproteinase family).

As outlined in their report, published Dec 25 by Nature Medicine, MMPs can cut through collagen and other support materials in the body. And, when working normally they are crucial for cellular mobilization, proliferation, wound healing, and other jobs. But when some members of the family – especially MMP9 – get out of control, they can "aid and abet" autoimmune disease and cancer metastasis.

The team therefore focused on finding ways to block these proteins in hopes of finding effective treatments for a number of diseases.

Originally, Dr. Sagi and others had designed synthetic drug molecules to directly target MMPs. But these drugs proved to be fairly crude tools that had extremely severe side effects.

• The body normally produces its own MMP inhibitors, known as TIMPs, as part of its tight regulation program for keeping these enzymes in line.

• But as opposed to the synthetic drugs, these natural inhibitors work in a highly selective manner.

• An arm on each TIMP is precisely constructed to reach into a cleft in the enzyme that shelters the active bit – a metal zinc ion surrounded by three histidine peptides – closing it off like a snug cork.

• “Unfortunately,” says Dr. Sagi, “it is quite difficult to reproduce this precision synthetically.”

Getting the Immune System to Create MMP-9 Antibodies

Then co-author Dr. Netta Sela-Passwell began working on an alternative approach as a student and later a PhD researcher in Dr. Sagi’s lab. She and Dr. Sagi decided that, rather than attempting to design a synthetic molecule to directly attack MMPs, they would try coaxing the immune system into targeting MMP-9 through immunization.

Just as immunization with a killed virus induces the immune system to create antibodies that then attack live viruses, an MMP immunization would trick the body into creating antibodies that block the enzyme at its active site.

Together with Prof. Abraham Shanzer of the Organic Chemistry Department, they created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site. They then injected these small, synthetic molecules into mice and afterward checked the mice’s blood for signs of immune activity against the MMPs.

The antibodies they found, which they dubbed “metallobodies,” were similar but not identical to TIMPS, and a detailed analysis of their atomic structure suggested they work in a similar way – reaching into the enzyme’s cleft and blocking the active site.

The metallobodies were selective for just two members of the MMP family – MMP2 and 9 – and they bound tightly to both the mouse versions of these enzymes and the human ones.

As the team hoped, when they had induced an inflammatory condition that mimics Crohn's disease in mice, the symptoms were prevented when mice were treated with metallobodies. “We are excited not only by the potential of this method to treat Crohn’s,” says Dr. Sagi, but by the potential of using this approach to explore novel treatments for many other diseases.”

Yeda, the technology transfer arm of the Weizmann Institute, has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies. Millions of autoimmune disease sufferers can only hope that human trials of this promising 'vaccination' concept will proceed soon.

Source: Based on Weizmann Institute News Release, Dec 26, 2011

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