| December 21,
Pump Up The Volume (of Immune Cells)
to Fight HIV
Transfusions of Self-Donated CD4 T Cells Boost Resistance
PA) - For patients suffering from HIV, a virus that
specifically targets white blood cells, the best donors
of new CD4 T cells just might be themselves. In the
January 2002 issue of Nature Medicine, researchers at
the University of Pennsylvania Medical Center
report the first autologous - or self-donated - transfusions
of pure CD4 cells, in eight HIV-positive volunteers.
The infused cells were resistant to re-infection with
both a laboratory strain of HIV and the volunteer's
own HIV strain.
"Basically, we took a volunteer's own T cells,
engineered the cells to mimic a genetic lesion that
renders some people resistant to HIV infection, grew
them in large amounts, and then transferred them back
to the volunteer," said Bruce L. Levine, PhD,
a researcher in the Leonard & Madlyn Abramson
Family Cancer Research Institute at the Penn
Cancer Center. As a result, the volunteers showed
a sustained resurgence of their active CD4 cells. "The
technique not only holds promise for people who are
HIV positive, but also for those suffering from the
various types of cancers that suppress the immune system."
Although the technique is not yet ready for FDA approval,
the article outlines how Levine, Carl June, MD,
Professor at the Abramson Institute, and colleagues
at Bethesda Naval Hospital and the Walter Reed Army
Medical Center demonstrated the safety and feasibility
of boosting the immune system through large-scale transfusions
of activated immune cells.
The researchers enrolled HIV positive active duty or
retired military personnel into the study. Their blood
was drawn and CD4 cells were purified and exposed to
tiny metal beads coated with antibodies for CD28, a
receptor on the surface of T cells. Once 'activated'
by these antibodies, the cells were grown in culture
for two weeks. The researchers then removed the beads
with a magnet and washed the cells, readying up to 30
billion cells to be infused back into the volunteers.
The researchers repeated this process up to six more
times over an interval of six to eight weeks. Each of
the volunteers experienced an increase in CD4 cells
and, most interestingly, the ratio of CD4 cells to other
T cells rose to near-normal levels.
"Considering that we only gave each volunteer a
dose equal to about 10% of the CD4 cells in their body,
it indicates that rise is due to cell growth and replication
and not just the influx of new cells," said Levine.
"Just as importantly, we also see a marked decline
in the HIV receptor CCR5 on CD4 cells, which shows that
the cells are resistant to infection."
Like most cells, the surface of T cells are covered
in receptors, sensor molecules that react when they
encounter specific molecules, such as antibodies. Each
receptor is like a button that starts a different process
in the machinery within the cell. HIV infects CD4 cells
by attaching to a number of receptors on the surface
of the cell, including a critical receptor called CCR5.
Previously Levine and June have shown that, by activating
the CD28 receptor, T cells are stimulated to multiply
and become resistant to HIV.
"There is a certain portion of the population that
is resistant to HIV infection because they lack a working
CCR5 receptor," explained Levine. "Here, we
copy that effect by stimulating the CD28 receptor, which
apparently acts like a switch, turning off the production
of CCR5 receptors within the CD4 cells."
Of course, safety was the primary concern of Levine
and his colleagues. Since HIV attacks CD4 cells, the
researchers feared that an influx of new CD4 cells would
only serve to add fuel to the fire. Although preclinical
results had shown that activated CD4 cells were resistant
to HIV, volunteers remained on their prescribed therapies.
Since the first cohort of volunteers began the study
in 1996, before the widespread use of anti-retroviral
'cocktails,' the researchers were able to note that
the infusions did not appear to interfere with drug
therapy. The researchers observed no severe side effects
or significant problems stemming from the infusions.
This technology is being further evaluated in several
clinical trials in HIV and various cancers. In cancer,
the goal is to use this approach to more quickly reconstitute
the immune system of patients who have received chemotherapy
and to augment the immune response to any residual cancer
"This report is important to the field because
it demonstrates the practicality of augmenting CD4 T
cells in HIV infection," said Levine. "Since
functioning CD4 T cells are absolutely essential in
controlling a number of chronic viral infections and
cancers, our results here encourage our confidence in
the potential of this technology."
This study was funded through Army contract DAMD17-93-V-3004
and the generosity of the Leonard & Madlyn Abramson
Family Cancer Research Institute.
The current HIV trial is for Department of Defense
active duty and retired personnel ONLY. Physician contact:
COL Naomi Aronson, MD, Walter Reed Army Medical Center,
# # #
Under the guidance of Carl H. June, MD, the translational
research program at the Leonard and Madlyn Abramson
Family Cancer Research Institute seeks to accelerate
the transfer of laboratory discoveries into clinical
treatments. Currently, June's group is developing cancer
vaccines for clinical trials at specialized facilities
created by the Abramson Institute.