ROLF ZINKERNAGEL, a Nobel laureate at the University Hospital, Zurich,
believes a geographical view of the immune system will be essential to modern
vaccine research. 鈥淚f you stick a vaccine into your big toe nothing will happen,
but if you stick it into your lymph node, then puff, off it goes,鈥� says
Zinkernagel. He hopes to discover why vaccines work better in some parts of the
body than others.
The lymph nodes in the neck and groin swell during illness, emphasising their
importance to immune defence. Crucial to this function is the unique arrangement
of their cells, which exchange signals either by direct contact or by releasing
hormone-like substances. The signals help killer T cells recognise a substance
in the body as friend or foe. On receiving the signal, T cells exit the lymph
node and patrol the rest of the body, looking for infected cells or tumour cells
to destroy.
Killer T cells are particularly important for fighting pathogens that invade
parts of the body that antibodies can鈥檛 easily reach, such as the lungs and
liver. Antibodies are most effective against infections with cell-destroying
viruses such as measles, influenza and polio, because the pathogens float freely
in the blood. They also work well against free-roaming bacteria such as those
causing cholera or diptheria, and can block the effects of their toxins. So far,
the most successful vaccines have been targeted at these diseases because they
have generally been good at activating antibodies, but very poor at stimulating
T cells. At least part of the reason, says Zinkernagel, is that researchers are
failing to target the lymph nodes and cannot maintain enough vaccine in the body
for long periods.
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Zinkernagel has already shown that getting the vaccine into the lymph nodes
is the most effective way to immunise against skin or muscle tumours. His team
has successfully protected animals against the growth of solid tumours beneath
the skin by vaccinating them with live tumour cells of the same type. The
vaccine will only work, however, if the tumour cells stay alive long enough to
move into the lymph nodes. Of course, injecting tumour cells ultimately spreads
cancer. So for treating human patients Zinkernagel wants to mimic the effects of
this kind of vaccination without injecting live cells.
Currently his team is working with patients who have malignant melanoma. They
are injecting fragments of tumour cell proteins directly into the lymph nodes.
Although the study is not yet complete, the preliminary results look
promising.
Another experimental option that may pan out, says Zinkernagel, is to
inoculate patients with DNA that encodes the tumour cell proteins. The hope is
that cells will take up the DNA, manufacture the proteins, and display them on
their surface. When such DNA-vaccinated cells reached the lymph nodes, they
would serve the same purpose as injecting live tumour cells, without any of the
risks.
DNA vaccines should also help solve another problem with current vaccines:
how to maintain immunity over long periods of time. The current tuberculosis
vaccine, for example, only gives a partial, short-lived protection, because it
contains attenuated bacteria, and these don鈥檛 stay in the body for more than one
to three years. A better alternative would be to use something that persists in
the host for an entire lifetime, as the TB bacterium does. A DNA vaccine might
produce cells that make the desired antigenic protein for a long time. Provided
these cells can spread to the lymph nodes, they should generate nearly permanent
immunity.
One of the world鈥檚 most effective vaccines, the Sabin poilo vaccine, works on
this same principle. It consists of live but weakened virus that can infect our
bodies for a few days but which does not cause disease. This ensures high levels
of antibodies against polio infection for at least five to ten years.
Deciding where in the body the DNA should be placed will require a sound
understanding of anatomy and physiology. 鈥淚鈥檓 confident that these aspects of
systems physiology will come back and will be applied,鈥� says Zinkernagel.
鈥淥therwise you鈥檇 beat your head against the wall.鈥�
