Research article Crohn's from Crohn's & Colitis Foundation

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Research - The Latest News

Third Quarter, 2007

Dear friends,

In recent months, we've gained additional important

insights into the specifics of how Crohn's disease

develops. Having identified many of the genes, immune

factors, and bacteria that combine to cause the

disease, we're now beginning to understand how these

" disease partners " actually work.

Let's look at this emerging picture from several

viewpoints:

Bacteria: Normally, the colon and the lower portion of

the small intestine are " colonized " by a complex

variety of bacteria, viruses, and fungi—collectively

called the microbiota. Most of these are harmless, but

occasionally, a bacterium can undergo a change and

become virulent. Researchers are beginning to

understand precisely how a common bug like E. coli can

turn aggressive, and how it manages to attach itself

to and invade the cells lining the small intestine

where it can trigger Crohn's disease in genetically

susceptible people.

Immune Dysfunction: Once virulent bacteria invade the

intestinal cells, the immune system typically kicks in

and mounts an attack to clear them. That's what

happens if you're healthy. But if you're genetically

predisposed to Crohn's disease, your immune system may

get its signals crossed and overreact, leading to

uncontrolled inflammation, or conversely, fail to kill

the invader, leading to persistent infection.

As we've recently come to understand it, the immune

dysfunction seen in Crohn's disease may manifest

itself as:

1. a decrease in a person's ability to kill bacteria;

2. an overactive T cell response to bacteria and

bacterial antigens;

3. an inability to tolerate the presence of commonly

tolerated bacteria; or

3. changes in the intestinal cells that make it easier

for bacteria to attach to them.

Genetics: Interestingly, the most recent gene to be

implicated in Crohn's disease is ATG16L1, which codes

for a protein involved in a process known as

autophagy. The word " autophagy " literally means

" eating oneself. " In biology, it can be understood as

the digestion within a cell of materials produced by

that cell or from a bacterium engulfed by the cell. In

people who have an abnormal variant of ATG16L1, the

immune cells responsible for killing bacteria may not

be up to the job, and bacteria may resist being

destroyed.

The discovery of ATG16L1 fits almost uncannily with

recent insights into what goes awry in at least some

types of Crohn's disease. A defect in ATG16L1 may lead

to problems with autophagy, while a defect in NOD2—the

first Crohn's susceptibility gene to be discovered, in

2001—may impair the ability to kill bacteria through

another route: by causing a deficit in the secretion

of defensins, proteins that specialize in bacterial

killing. These two genetic defects correlate with two

different routes into the development of Crohn's

disease, and with the new molecular insights described

above.

It is hoped that a more detailed picture of the

biology of Crohn's disease and ulcerative colitis will

shape the search for improved therapies. The more we

understand about the many factors that lead to the

uncontrolled inflammation seen in these diseases, the

more we can target " upstream, " pre-inflammatory

processes for treatment and nip inflammation in the

bud.

Clinical News: One highly promising treatment for

Crohn's disease, called natalizumab, has received

preliminary endorsement by the FDA's advisory panel

and is awaiting final approval. Natalizumab is an

antibody against alpha-4 integrin, a protein involved

with the recruitment of immune cells to the site of

inflammation. Natalizumab blocks that recruitment

process, thus short-circuiting the inflammatory

response.

If approved, the new drug could be a welcome

alternative for people who have not responded well to

anti-TNF agents. Currently approved for the treatment

of multiple sclerosis (MS), natalizumab was briefly

taken off the market because three people developed

progressive multifocal leukoencephalopathy (PML), a

rare brain infection, while taking the drug. For this

reason, natalizumab is being used in a very select

group of patients with MS who are being monitored very

closely for side effects. It will be used similarly in

people with Crohn's disease if it receives final FDA

approval.

The drug's safety issues have drawn attention to a far

broader problem: the anti-inflammatory therapeutic

strategy itself. By damping down inflammation, a key

function of the immune system, the medications used to

treat inflammatory diseases may put patients at risk

for infection. The risk may be small, but we should

and can do better.

All in all, the news is encouraging. We've already got

the big picture, and now we're homing in on the

details. And the details are what we need to more

fully understand if we're going to find our way to

better treatments and, perhaps sooner rather than

later, a cure. Please continue to support our efforts

to the greatest extent you can. The quality of life

of millions of people depends on it.

R. Balfour Sartor, M.D.

Chief Medical Advisor

Crohn's & Colitis Foundation