Friday, November 02, 2007

HDAC drugs for autoimmune diseases

Initially it may come as a surprise, but it turns out that some powerful cancer drugs also are useful against autoimmune diseases as well. A good example is the monoclonal antibody rituximab.

In this case the reason is that as a monoclonal antibody, rituximab binds to the protein CD20, which is widely expressed on B cell lymphocytes of the immune system. Once it has bound to the CD20 of a B cell, it may lead to cell death by apoptosis, which is helpful in the case of of B cell cancers such as non-Hodgkin lymphoma and B cell leukemia.

The general pattern here is that some kinds of cancer and some autoimmune diseases both involve the overactivity and proliferation of certain types of immune system cells. A drug that counteracts such pathology may be useful for treating both the associated cancers and autoimmune diseases.

T cells are another large and important class of immune system cells, which we've discussed before (see here). T cells can also be involved in cancer, such as another form of non-Hodgkin lymphoma called cutaneous T cell lymphoma.

There is an FDA-approved drug for this cancer, called vorinostat, also known as suberoylanilide hydroxamic acid (SAHA). We have also mentioned this before, because the compound is a histone deacetylase (HDAC) enzyme inhibitor. HDAC enzymes have the effect of turning off genes, so an inhibitor of a particular HDAC enzyme has the effect of allowing the genes to remain turned on. Some cancers develop because they cause the overexpression of a HDAC enzyme that then turns off genes which would otherwise suppress the cancer. So an inhibitor of the approriate HDAC enzyme boosts the expression of the affected cancer-fighting genes. This is how vorinostat works.

Certain types of T cells can also cause various autoimmune diseases if they get out of control. Normally these T cells should be kept under control by messaging molecules (such as Foxp3) produced by a special type of T cell called a regulatory T cell (Treg cells). So when a condition develops where there is excessive and harmful activity of T cells, it it may be possible to counteract this by boosting the number or activity of Treg cells.

And this is precisely what SAHA is apparently able to do – by inhibiting a HDAC enzyme, it raises Treg cell activity to control the overactivity of other types of T cells, as found in inflammatory bowel disease and various kinds of transplant rejections.

New cancer drugs could help in autoimmune disease
A new class of drugs used to treat cancer might be effective at suppressing overactive immune systems in patients with autoimmune diseases like Crohn's disease, U.S. researchers said on Sunday.

"What we would be proposing would be a therapy that would enhance the body's own immune system's ability to regulate itself," said Wayne Hancock of Children's Hospital of Philadelphia, whose study appears in the journal Nature Medicine.

Hancock said drugs known as histone deacetylases inhibitors, or HDACs, which affect compounds involved in the growth and death of cancer cells, bolstered the production of cells that regulate the immune system in mice.

In one study, the drug helped reverse and prevent inflammatory bowel disease. It also prevented the rejection of heart transplants in other mice. And it stopped rejection of pancreatic cell transplants in other mice.

It's possible that SAHA (i. e. vorinostat, which is distributed commercially by Merck under the name Zolinza) could also work to treat other autoimmune diseases like rheumatoid arthritis. And who knows what other cancer drugs might also have such dual uses?

More: Cancer drugs could fight autoimmune disease

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Anonymous Czes Kulvis said...

Look: any autoimmune disease is reaction of de-regulated and overactive immune system against host body.

So what really means 'drugs against autoimmune disease'?

All I can imagine is: Drugs to suppress immune system.

7/16/2008 07:39:00 PM  
Blogger Charles Daney said...

Look: any autoimmune disease is reaction of de-regulated and overactive immune system against host body.

So what really means 'drugs against autoimmune disease'?

All I can imagine is: Drugs to suppress immune system.

Think of it this way. The immune system consists of a rather large number of independent processes.

A drug to "regulate" only the process which is not working right may be all that is needed.

Such a drug might, for example, alter the amount of some messenger protein that controls the malfunctioning process.

The analogous situation in cancer is that certain cells are dividing when they shouldn't, because some particular mechanism isn't working right in those cells. A drug that treats that cancer would need only to affect the particular type of cells, and the particular process in those cells, that is malfunctioning.

In fact, some autoimmune diseases are similar to cancer, in that there are too many immune system cells of a particular type. This is why anti-cancer drugs can also be effective for treating autoimmune diseases.

7/16/2008 08:18:00 PM  

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