NK killer cell, canser

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NEWLY DISCOVERED KILLER CELL FIGHTS CANCER; A mouse immune cell that

plays dual roles as both assassin and messenger, normally the job of

two separate cells, has been discovered by an international team of

researchers from the United States and France. The discovery has

triggered a race among scientists to find a human equivalent of the

multitasking cell, which could one day be a target for therapies that

seek out and destroy cancer. " In the same way that intelligence and

law enforcement agencies can face deadly threats together instead of

separately, this one cell combines the ability to kill foreign

pathogens and distribute information about that experience, " says

Drew Pardoll, M.D., Ph.D., the Seraph Professor of Oncology at the

s Hopkins Kimmel Cancer Center. " We think this hybrid cell speeds

up immune reactions and makes the system more efficient, " adds

Pardoll, whose findings are reported in the February issue of Nature

Medicine.The Hopkins investigators speculate that the hybrid,

dubbed " IKDC " for interferon-producing killer dendritic cell, has

been missed by cancer biologists because it is rare, making up one-

tenth of cells in the spleen with similar features, such as other

dendritic cells, according to Housseau, Ph.D., research

associate at Hopkins' Kimmel Cancer Center and member of Pardoll's

immunology laboratory.Most of the immune system typically works

through a web of cross-talk and signaling among a variety of cells.

One of the first immune cells that invading bacteria or cancer cells -

both of which carry antigens that alert the immune system - may

encounter is a natural killer (NK) cell. As its name implies, NK

cells deliver a deadly blow by poking holes in the invader's outer

membrane. Then, NK cells secrete molecules that reach other immune

cells, including dendritic cells, known as the main messenger for the

immune system. Dendritic cells spread " look here " information about

foreign invaders to other immune cells, but do not actually kill the

invaders.It was while investigating a particular type of dendritic

cell that Housseau noticed the outer membranes of these cells were

studded with what were supposed to be hallmarks of NK cells, akin to

finding feathers on a dog. " We thought we were looking at dendritic

cells, but we were wrong - they were some type of NK-dendritic cell

blend, " says Housseau. The blended cell turned out to be a newly

identified actor on the immune system stage that retains all the

molecular characteristics of both NK and dendritic cells.Probing

further, Housseau scoured the surface of IKDCs to create a sketch of

its molecular profile. He found that it produces both types of

interferon proteins, normally secreted independently by NK and

dendritic cells. He also found both NK and dendriticlike molecules on

the surface of IKDCs. Housseau calculated that they account for about

10 percent of conventional dendritic cells in the spleen.IKDCs begin

their lives behaving like an NK cell. After the cell encounters a

pathogen, the cell switches roles from killer to dendriticlike

messenger, and, according to the researchers, the swap occurs only

once. Then, the cell dies and is replenished by the bone marrow. " When

an IKDC cell switches to its messenger function, the transformation

is quite astonishing, " says Pardoll. The cell sprouts long, hairy

tentacles called dendrites. It uses its " arms " to increase the amount

of surface area it reaches to communicate and interact with other

immune cells.In the next step of their investigation, the scientists

tracked the location of fluorescent-tagged IKDCs and their

corresponding stage of transformation after infecting mice with

bacteria called listeria. In assassin-mode, the IKDCs were found in

the blood, lining of the gut, liver and other organs - all areas

where there is close contact with environmental pathogens. " Here,

IKDCs are ready to sense invaders and spring into action, " says

Housseau.Then, the group tracked the cells to the main messenger

center of the immune system - the lymph nodes. Here, they found

approximately 35 percent of the original group of IKDCs now secreting

communication molecules signaling a switch to messenger-mode.

Simultaneously, Housseau's colleagues in France, led by ce

Zitvogel at the Institut Gustave Roussy, tested whether IKDCs are

culprits in killing cancer by injecting mice with a cancer drug

called Gleevec, which blocks an abnormal protein produced by cancer

cells, and a growth factor for NK cells. The drug-growth factor combo

served as a lure, leading the IKDCs to tumors implanted in the mice.

The results were that tumors shrunk in mice, which received

injections of IKDCs, but not in those receiving conventional NK cells

only. Evidence from the shrunken tumors revealed certain " cell-

killing " proteins that could be traced to IKDCs. These results are

published separately in Nature Medicine.Housseau's group is

conducting further studies to verify the role of IKDC cells in

infection and cancer. Meanwhile, the group is profiling IKDC genes to

find a specific marker that could help them identify a human

counterpart.The Hopkins research was funded by the National

Institutes of Health, the Janney Fund and Seraph Foundation, and

gifts from Bill and Betty Topecer and Dorothy Needle.Participants in

the research include Camie W. Chan, Crafton, Hong-Ni Fan,

Flook, Kiyoshi Yoshimura, Skarica, and F. Stins from

s Hopkins; Dirk Brockstedt and W. Dubensky from Cerus

Corporation; and L. Lanier from the University of California

San Francisco. " Interferon-producing killer dendritic cells provide a

link between innate and adaptive immunity. " Nature Medicine 12, 167 -

168 (2006).Video Footage Available: IKDC cell killing a cancer

cell. & nbsp; Courtesy of the Institut Gustave Roussy.On the

Web: " http://www.hopkinskimmelcancercenter.org "

www.hopkinskimmelcancercenter.org