Brain Tumors Paralyze The Immune System - First Preclinical Trails With RNA-Interference To Lift Blockage

Gliomas are extremely malignant and fast growing tumors. Not only do
they secrete molecules to secure their blood supply by generating new
blood vessels, they are also able to secrete messenger molecules to
protect themselves against attacks by the immune system.


Professor Michael Weller, Medical Director of the General Neurology at
the University Clinic in T?bingen, applied the RNA-interference
technique to block the gene of one important representative of this
group of messengers, the Transforming Growth Factor-beta (TGF-
beta). When the TGF-beta gene is switched off and the blockage of the
immune system lifted, brain tumors can be attacked by the immune
system.


In all of the mice in which the researchers had switched off the TGF-
beta gene, the tumors were completely decomposed. "These results
could open the way for vaccinations against brain tumors, because
only an immune system which is working faultlessly is able to react to a
vaccination with an adequate immune response, Professor Weller said
at the Brain Tumor Conference 2006 held by the Max Delbr?ck Center
for Molecular Medicine (MDC) and the Helios Klinikum in Berlin-Buch,
Germany.


Tumors in the brain are attacked less often by the immune system
than tumors in other parts of the body. The reason for this is, amongst
others, that the blood-brain barrier protects the brain from the
pathogens transported in the blood vessels. However, this also means
that the brain is simultaneously less accessible to the immune system
than are other parts of the body. Therefore, researchers thought for a
long time that the immune system was not active in the brain at all.


Yet, in recent years, researchers were able to demonstrate immune
reactions in the brain. Multiple sclerosis, for example, is caused by an
extreme immune reaction likewise in the brain. Furthermore,
researchers could show that the brain tumor cells indeed defend
themselves against attacks by the immune system. These cells
produce messenger molecules that block the immune system of the
patient. A multitude of such molecules had already been identified by
scientists. For example, substances with complicated names such as
Transforming Growth Factor-beta (TGF-beta), Regeneration and
Tolerance Factor (RTF), and the soluble surface antigen HLA-G.


Since 1994, Professor Weller has been working on a mechanism to
switch off the messenger TGF-beta directly so that the immune system
will be able to recognize and attack tumor cells. In experiments with
mice and rats, he blocked the gene for TGF-beta with the help of the
so called RNA interference (RNAi) method. RNA stands for
"ribonucleic acid", a molecule which translates the genetic code found
in the DNA into the language of proteins (amino acids). The RNAi is a
strand of antisense RNA that binds and blocks the RNA strand of the
TGF-beta gene switched on in the tumor. Thus, the RNAi prevents the
translation of the TGF-beta gene into its corresponding protein. In
other words, the gene is quasi silenced and no TGF-beta protein is
produced.


Furthermore, Professor Weller could show that certain cells of the
immune system, like lymphocytes and natural killer cells, are able to
recognize and destroy the tumor. To prevent a recurrence of the tumor,
the researchers additionally vaccinated the mice with dead tumor cells.
"These dead cells cannot proliferate anymore. Therefore, they are not
dangerous for the organism", Professor Weller pointed out. But their
cell surface characteristics are the same as "regular" tumor cells and,
therefore, they can stimulate the immune system. Only when the
immune system is no longer blocked by TGF-beta can an effective
immune response be provoked by these vaccinations. "At this time,
such strategies are merely experimental as we did all our research on
animals. These methods cannot yet be transferred to human patients",
Professor Weller emphasized.


Max Delbr?ck Center for Molecular Medicine (MDC) Berlin-Buch