Natural Immune-control System May Aid Treatment Of Autoimmune Disease & Tissue Rejection

[Guest guest]

Source:

Dana-Farber Cancer Institute

Date:

May 17, 2007

Natural

Immune-control System May Aid Treatment Of Autoimmune

Disease And Tissue Rejection

The

immune system's ability to police itself may offer a new method of arresting

the cells responsible for autoimmune diseases such as multiple sclerosis and

for the rejection of transplanted organs and tissues, scientists at Dana-Farber

Cancer Institute report in a study in the May issue of the journal Immunity.

Because

the technique utilizes the body's own mechanism for controlling the immune

system, it may prove more effective and less prone to side effects than current

therapies, which take a less direct approach, the study authors indicate. Although the research was done in mouse cells, it is

likely to apply to humans because of strong similarities between mouse and

human immune cells.

" We

found that when we block a key interaction between two types of immune system

cells, one of those types -- which is often associated with autoimmune disease

and tissue rejection -- is attacked and dies, " says senior author Harvey

Cantor, MD, of Dana-Farber. " The fact that this

approach uses the body's natural system for regulating the immune response

encourages us that it can be the basis of an effective therapy for a variety of

immunological conditions. "

Autoimmune

disease and tissue rejection pose a complex challenge to scientists. Both problems result from an attack by immune system cells

-- which are trained to detect and destroy infected or diseased tissue -- on

parts of the body where it isn't wanted. In the case

of rejection, they recognize transplanted tissue as foreign and mount an

assault on it. In autoimmune diseases, they attack the

body's own tissue as through it were foreign.

Conventional

therapies for these conditions can have serious drawbacks. Many

of them rely on natural substances called antibodies, which wedge inside

" receptors " on immune system T cells. The

coupling blindfolds T cells to the presence of foreign or diseased tissue,

blunting their ability to spark an immune attack.

Antibody-based

treatments fall short for a variety of reasons: the antibodies often fail to

fit securely inside T cells receptors, so the immune response is only slightly

reduced; or the antibodies succeed in blocking the receptor, but that

inadvertently causes the T cells to launch a more ferocious attack. In other cases, antibodies work too well, suppressing the

entire immune system, rather than just a portion of it, leaving patients

susceptible to dangerous infections.

To

overcome these problems, researchers have tried to harness the body's natural

system for quieting the immune response. One

intriguing approach involves the immune system's " natural killer, " or

NK, cells. Scientists have long known that some NK

cells can kill a class of T cells -- known as CD4 T cells -- that have been

activated to fight infection, but that NK cells are often restrained from doing

so.

Cantor and

his colleagues theorized that when a tiny hook, or ligand,

called Qa-1--Qdm on activated CD4 T cells latches

onto the NKG2A receptor on NK cells, the T cells are protected from destruction. To test this, they produced activated T cells that either

lacked the Qa-1--Qdm receptor or had a faulty version

of it, preventing them from binding to the NKG2A receptor. The

result was that the T cells became vulnerable to attack from a set of NK cells. Using an antibody to block the connection between Qa-1--Qdm and NKG2A had the same result.

" Our

findings suggest that it is possible to use antibodies to trigger the body's

own mechanism for suppressing the immune response, " Cantor remarks. " The results serve as a proof of principle that this

approach can be applied to the treatment of conditions characterized by an

excessive or unwanted immune response. "

While the

work was done with mouse cells, the Qa-1--Qdm ligand has the same shape and structure in human and mouse

T cells, raising hopes that the approach will prove effective in humans as

well, adds Cantor, who is also a professor of pathology at Harvard

Medical School.

The

research was supported by grants from the National Institutes of Health, the

National Multiple Sclerosis Society, the Barr Foundation, and a

fellowship from Taiho Pharmaceuticals of Japan.

The lead

author of the study is Linrong Lu, PhD, of

Dana-Farber. Co-authors include Koichi Ikizawa, PhD, Dan Hu, PhD, Miriam

Werneck, and Kai Wucherpfennig,

MD, PhD, all of Dana-Farber.

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