Natural
Killer Cells Are Made, Not Born !!
Natural
killer cells are made, not born
February 2, 2004
Natural killer cells are made, not born
First evidence of immune cell's activation potential in infection, tumor control
In pursuit of natural killers: Guido Ferlazzo,
Ph.D. (left), and Christian Münz, Ph.D., are proving that
natural killers, a type of immune system cell, can be the body's
new gun for hire in tumor and infection control therapies.
Münz became assistant professor and head of the Laboratory
of Viral Immunology in December 2003.
Call it the immune system's version of nature versus nurture.
For years, scientists regarded natural killer
cells as a blunt instrument of the body's immune defense system.
Born to kill, these cells were thought to travel straight from
the bone marrow, where they are manufactured, to the blood,
circulating there and infiltrating the sites of early tumors
or infectious agents in the body.
Now, Rockefeller University scientists, led by
Christian Münz, Ph.D., have learned otherwise. Natural
killer cells, Münz and his colleagues say, have to be
nurtured. Their ability to destroy tumor and infected cells
is not present at birth.
This new insight paves the road to changes in
bone marrow and stem cell transplant procedures and will enable
scientists to pursue research into activating natural killer
cells to help the body fight emerging infections and tumors.
In two separate papers in the February issue
of The Journal of Immunology, Münz, postdoctoral associate
Guido Ferlazzo, Ph.D., and their colleagues show that natural
killer cells accumulate mostly in "secondary lymphoid
tissues" - the tonsils, lymph nodes and spleen - after
emerging from the bone marrow. There, the natural killer cells
await activation (probably after stimulation by sentinel dendritic
cells) before they react in two distinct modes. In one mode,
they promptly secrete cytokines, chemical messenger proteins,
which modulate emerging T and B immune cell responses. In the
other, they become potent killers of tumors and virus-infected
cells. While natural killer cells do provide a crucial first
defense against many infectious agents and tumor cells, they
do so with more discrimination than raw determination.
"Natural killer cells burst forth from the
the tonsils, lymph nodes and spleen, and destroy infected and
cancerous cells while the immune system's T and B cells are
still mobilizing," says Münz. "Without natural
killer cells, threatening conditions can get a strong foothold
before the adaptive immune response kicks in."
Leading oncologists treating human leukemias
and lymphomas already track natural killer cell activities
after bone marrow and stem cell transplants. James Young, M.D.,
a researcher at Rockefeller's neighboring Memorial Sloan-Kettering
Cancer Center's Allogenic Bone Marrow and Stem Cell Transplant
Service, is one of them. "The emerging data on the activation
of natural killer cells, their distinct functions in the body
and their cellular targets, are helping to move the study of
natural killer cells in transplantation and cancer from conjecture
to sound hypotheses," he says.
The findings by Münz and his colleagues
not only explain why a natural killer burst is important -
the burst likely results from mobilization of natural killer
cells from lymphoid tissues, and these activated immune cells
are discriminating enough to recognize, through a full repertoire
of surface receptors, virus-infected and tumor cells - it also
affirms a potential strategic change in bone marrow or stem
cell donor matching.
Bone marrow donors are selected based on the
similarity of their white blood cell profiles: the closer the
match to the patient, the better. But that's likely less important
when doctors can harness the donor's natural killer cells to
fight both residual cancer cells and residual immune system
cells of the patient. Certain mismatches between donor and
recipient can actually encourage the donor's natural killer
cells to deliver an extra punch to the cancer and the threatening
graft-versus-host disease, the updated logic goes.
Münz and his colleagues did not develop
the bone marrow donor match strategy, but part of their aim
in understanding where and how natural killers hang out, was
to determine how the cells are recruited to combat cancer and
other emerging diseases in the body. The Rockefeller scientists
are in close contact with clinicians interested in tailoring
immune cells - such as natural killers - in treating human
leukemias.
The current Journal of Immunology publications
also contribute to strategies for dealing with the viral menace
known as Epstein-Barr virus, a member of the herpes family
of viruses. Though most infections are latent, active Epstein-Barr
is the source of infectious mononucleosis in many teenagers.
Epstein-Barr also is a human cancer-causing virus.
The virus hijacks the immune system's B cells in an elaborate
chemical signaling mimicry of normal B cells. The result often
is B cell tumors like Hodgkin's disease and Burkitt's lymphoma.
Münz and his colleagues know that the natural killer cell
response, or burst, is important in establishing immune control
against the cancer causing Epstein-Barr virus.
"We have seen that Epstein-Barr virus transformation
of B cells can be delayed by a strong natural killer cell burst," says
Münz. "Now we are studying how this herpes virus
may be targeted by natural killer cell responses." By
learning both what molecular signals activate natural killer
cells in their dialogue with dendritic cells and how viruses
can be targeted by natural killer cells, Münz and his
colleagues may be able to artificially stimulate natural killer
cells to heighten their effect and ward off emerging Epstein-Barr
virus associated malignancies.
"We're trying to get a sum of all signals
that activate natural killer cells against viruses and tumors
and do not cause harm to healthy human tissues," says
Münz. "In the past five years, we've learned enough
about these cells to extend hopes of their eventual usefulness
in medical treatments."
This research was funded by the Leukemia & Lymphoma
Society and the New York Academy of Medicine.
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