THE ROLE OF NK CELLS AND THE IMPORTANCE OF

IMMUNOTHERAPY IN THE TREATMENT OF PATIENTS

WITH CANCER:

The natural killer cells (NK cells) are our body's natural defense
against cancer cells. They circulate through our body, seeking Excellence in TCM and
cells that have unusual molecules on their surface which indicate Integrated Medical Services;
that the cell is either a tumor cell or it is infected with a virus.

When such a cell is found, the NK cell opens up and extends a The World Health
tentacle to the ailing cell and engages the "Killer Activating Organization (WHO) list of
Receptor" in preparation to destroy the cell. Another tentacle illnesses and medical
reaches out to seek another spot in the cell, the "Killer Inhibitory conditions for which
Receptor". If this spot is not found, the NK cell blasts the sick cell acupuncture can be an
with particles that punch holes in the bad cell wall and pumps effective option:
venom into it that surges in and out of the cell until it breaks out.
The National Institute of
This event is enacted 10,000 times a day in a healthy person's Health (NIH) Consensus on
body as tumor cells are routinely destroyed when they are formed. Acupuncture, 1997;
Natural Killer (NK) Cell,
Belowpaling
shows a picture of a Natural Killer cell in its normal state
agresif diantara seluruh jajaran sel sistem imun,
as it patrols the body.
beredar keseluruh tubuh, mencari sel yang memiliki
molekul unik di permukaannya, petanda sel tumor atau
sel terinfeksi virus.
Natural Natural killer cells (NK cells) are the most aggressive
Bila ditemukan, maka NK Cell akan mengeluarkan dua
fighters of allyaitu
tentacle cells in Activating
Killer the immune system.
Receptor They are the first line of
dan Killer
defense against
Inhibitory mutant
Receptos; and
yang virus infected
selanjutnya cells like Severe Acute
akan menentukan
apakah suatu sel akan dihancurkan dengan tembakan zat
Respiratory Syndrome (SARS) or West Nile that threaten one's
kimia atau dibiarkan hidup.
health. They are lymphocytes with no immunological memory and
are part of your innate immune system. NK cells make up about 5
to 16 percent of the total lymphocyte population. Their main
function is to destroy infected and cancerous cells.

NK cells do not kill indiscriminately. They look for a banner

flown by normal cells. If the NK cell sees this banner, it receives a
signal to spare that cell. This signal overrides the NK cell's urge to
kill. If this banner is absent on the target cell the NK cell proceeds
with its attack. It attaches to the target and releases a lethal burst
of chemicals that penetrate the cell wall. Fluids begin to leak in
and out and eventually the cell breaks out.

Besides their role in controlling of infections, NK cells help in the

regulation of other aspects of the immune system which effects
our general health. Today modern science has identified the
players and the mechanism by which the immune system
works. However, Traditional Chinese Medicine has thousands of
years of continued practice, and through accumulated experience
of trials and errors, Chinese herbalists have successfully
identified, processed, and used herbs, and herb derivatives in the
treatment of diseases. Traditional Chinese pharmacology stands
alone like no other medical system in producing strong, effective,
and harmless herbal formulas to boost the immune system.

The clinical effectiveness of immunotherapy with Immuno

SG;has been well documented. The active ingredients in this Is your doctor critical of
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been scientifically studied and demonstrate to highly elevate the Traditional Chinese
body's production and activity of NK cells, T cells, B
Medicine in your
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knowledge of the immune system expands.

Observe the heavy section of the cell wall at the top of the first
picture, which contains the tentacles and venom sacs and how
they are now deployed outside the cell wall on the right side of the
cell in the second picture.

NK Cell Destroying a Tumor Cell:

You can see the two tentacles, the one with the venom sacs and the
"Killer Activating Receptor" and the other that didn't find the site
to inform the NK cell to stop the killing operation with the ."Killer
Inhibitory receptor" and the MHC-1 cells.

Exposition of the killing action and mechanism of NK cells:

The Fab portion of the antibody binds to epitopes on the "foreign"

cell. The NK cell then binds to the Fc portion of the antibody. The
NK cell is then able to contact the cell and release pore-forming
proteins called perforins, proteolytic enzymes called granzymes,
and chemokines. Granzymes pass through the pores and activate
the enzymes that lead to apoptosis of the infected cell by means of
destruction of its structural cytoskeleton proteins and by
chromosomal degradation. As a result, the cell breaks into
fragments that are subsequently removed by phagocytes. Perforins
can also sometimes result in cell lysis.

Cell Apoptosis Induced by NK Cells:

The NK cell releases pore-forming proteins called perforins,

proteolytic enzymes called granzymes, and chemokines.
Granzymes pass through the pores and activate the enzymes that
lead to apoptosis of the infected cell by means of destruction of its
structural cytoskeleton proteins and by chromosomal degradation.
As a result, the cell breaks into fragments that are subsequently
removed by phagocytes. Perforins can also sometimes result in
cell lysis.

Following is a scientific report by Jerry T. Thornthwaite,

Ph.D. describing his discovery of the NK cells in 1972.

Advances in Cancer Detection

"My Discovery of the Natural Killer Cell", by Jerry T.
Thornthwaite, Ph.D.

In 1972, I presented a poster session with my major Professor, Dr.

Bob Leif, at the annual Reticuloendothelial Society Meeting. On
my poster, I presented on very unusual cells from the spleen (and
later from the lymph nodes) of non-immunized mice that
destroyed sheep red blood cells (SRBC) on contact. I came very
close to publishing the article in Science which took some time
and effort, but the conclusion was that it was more suitable for the
immunology journals. The papers were accepted in the Journal of
Immunology. I did not know the proper name for these cells but
was able to develop a way of enumerating them, determine their
density and enrichment in linear bovine serum albumin gradients
and study their morphology utilizing light, scanning electron and
transmission electron microscopy. Many years later, I developed a
clinical application by in vitro enriching natural killer cells for
infusion into patients.

Currently, I am investigating natural substances that are supposed

to increase the natural killer cell response. Unlike complement
mediated IgM antibody destruction of SRBC, which showed lyses
of "plaques" of SRBC appearing as deflated balloons (Fig. 1), the
complete destruction of the SRBC did not require prior
immunization with SRBC or complement (Fig. 2). Thus, I gave
them the name "complement independent plaque-forming cells"
(CIPFC) or "rough lymphocyte plaque-forming cells" when I was
able to perform scanning electron microscopy (SEM). Later,
Heberman (1973) and Oldham (1973) used the term "Natural
Killer Cell".
Figures 1 and 2. Two IgM antibody-complement plaques showing
the deflated SRBC in the plaque area (left) and the "rough
surfaced" "complement independent-nonimmunized" plaques
(right).

In 1973, I developed a technique using alcian blue to stain cells

that were dead prior to glutaraldehyde fixation. Viable cells, prior
to glutaraldehyde fixation, did not stain. I used this technique to
locate the CIPFC destroying target tumor cells. The killed tumor
cells were also easy to see at the later stages by the blebbing of the
membranes of the tumor cells (Fig. 3 and 4).
Figures 3 and 4 showing Nomarski optics of the binding of
complement independent cells (left) and cytoplasmic "blebbing"
of the target mouse P815 plasmocytoma cells from lymph nodes
of non-immunized mice.

Working with Marilyn Cayer, we were able to section en face the

alcian blue areas and perform electron microscopy.

Figure 5. CIPFC (Natural Killer Cell) destroying a target tumor

cell.

Natural Killer Lymphocytes:

Natural killer (NK) cells are antigen nonspecific lymphocytes
which recognize foreign cells of many different antigenic types.
These cells are an important first line of defense against newly
malignant cells and cells infected with viruses, bacteria, and
protozoa (Natural Killer Cells). About 5 to 16 percent of the total
lymphocyte population contains natural killer cells. NK cells have
the ability to attack foreign cells without first having to recognize
specific antigens; a characteristic lacking in CD4+ lymphocytes
(Stine, 1997). Similarities in development, morphology, lytic
mechanism and cell-surface phenotype indicate that NK cells and
cytotoxic T cells are closely related lineages. The effector
functions of both types of cells are controlled by MHC class I
glycoproteins, and both express receptors that bind these
glycoprotein molecules. The main difference between the two
cells is that cytotoxic T-cells recognize infected cells by the
peptides their MHC class I molecule present, while NK cells look
for the absence of MHC class I molecules. It has been proposed
that NK cells complement cytotoxic T-cells by taking charge in
situations where MHC class I expression is hindered through the
effects of virus infection (Nature, 1995).

NK cells have evolved a mechanism for mediating host defense

against infection with viruses by having the ability to distinguish
infected from uninfected cells. Although the exact mechanism is
not clear at the present time, one possible mechanism may be that
NK cells selectively kill target cells bearing low levels of MHC
class I molecules on their surface. Natural killer cells have two
types of surface receptor which aid in distinguishing infected from
uninfected cells. The first receptor, NKR-P1, recognizes a wide
variety of carbohydrate ligands found on many cells. The
activation of NK cells to kill normal cells displaying these ligands
is prevented by a second receptor, a C-type lectin, which binds to
MHC class I molecules and inhibits NK activity (Janeway-
Travers, 1996). NK cells kill target cells by releasing perforin
which damages the target cell membrane and results in death of
the cell. Inducing apoptosis in the target cell is another mechanism
NK cells utilize to kill infected cells (Natural Killer Cells). If the
specific functions of NK cells malfunction or are killed
themselves, an important component of the immune attack is
destroyed.

Most of the studies related to the immune system and HIV

concentrate on T lymphocytes, B lymphocytes, and antigen-
presenting cells. However, studies reported so far have found that
NK cells can be lethally infected by HIV, and NK cell cytotoxic
functions are impaired during the course of infection (Dissection).
In 1989, a researcher by the name of Paolo Lusso discovered that
infection with herpesvirus-6 can cause a decline in the body's
natural killer cell response. This was the first time researchers
have shown that natural killer cells were vulnerable to any kind of
viral attack. It was also the first real evidence that infection with
this herpesvirus might play a role in AIDS. In the same year,
Lusso's team also showed that herpesvirus-6 attacks
CD4+lymphocytes (Science News, 1993). As mentioned earlier,
CD4+lymphocytes are the primary targets of HIV.

Although natural killer cells do not normally produce the CD4

molecule and are typically resistant to HIV's attack, herpes-
infected natural killer cells were found to manufacture the CD4
receptor molecule that provides an entrance for HIV. Experiments
have shown that when HIV was added to cultures of herpes-
infected natural killer cells, HIV was able to infect those cells
(Science News, 1993). So although NK cells cannot be infected by
HIV as a normal functioning cell, once it is infected with
herpesvirus-6 it manufactures the CD4 receptor which makes it a
primary target of HIV. The consequence of NK cells becoming
infected with HIV results in an increase in malfunctioning NK
cells along with a decline in the natural killer cell response;
rapidly leading to the development of AIDS.

These cells are sometimes called large granular lymphocytes

(LGL's). NK cells have some surface markers in common with T
cells, and they are also functionally similar to cytotoxic T
lymphocytes (CTL's). Like CTL's, NK cells are particularly
important in the killing of cellular targets (usually tumor cells).
Unlike CTL's, however, the killing by NK cells is nonspecific,
they do not need to recognize antigen/MHC on the target cell. NK
cells do not have a T cell receptor and are not T cells.

An NK cell kills a target cell by releasing perforin (and other

molecules) which damages the target cell membrane leading to
death. NK cells also cause death by inducing apoptosis in the
target. The cytokine TNF alpha is released by the NK cells and
may be involved in this process.

Natural killer (NK) cells are well known for their ability to kill
certain tumors. However, it is now recognized that NK cells have
a significant role in host defense against invading pathogens,
particularly intracellular organisms, and are capable of in
fluencing the specific, acquired immune response. The ultimate
goal of our work is to elucidate the function of NK cells in normal
and abnormal immune responses and to derive targeted
therapeutic interventions that influence these innate effector cells.

Immune System & NK Cells

"Research has shown that low Natural Killer cell activity is

present in nearly all illness." Dr. Jesse Stoff

In The Ultimate Nutrient, Dr. Stoff states the following:

"In recent years the immunological community has begun to

recognize and study special cells that are a part of our immune
system called Natural Killer (NK) cells. These cells contain a
large array of armaments...

In my studies I have become aware of the severe deficiency that

exists in our NK cell reserves. Studies indicate that at one time we
carried high levels of NK cell activity. Current measurements
indicate we are about 10-20% of those levels today. The
implications of this fact are staggering."

Dr. Stoff isn't the only researcher to pay attention to NK cells and
the immune system. Scientific reaerch on this subject have also
taken place in China, Japan, South Korea, and other countries.
And, in the United States, there are many others, among them is
the Pittsburgh Cancer Institute, Department of Pathology.
This is mainstream medical research. In 1994, the Pittsburgh
Cancer Institute produced an 11 page study on NK cells. They
demonstrated a correlation between low NK cell activity and
cancer, viral and bacterial diseases and autoimmune diseases.
They state the following:

 The correlation between low NK cell activity and serious

viral infection has been well documented.
 In general, patients with low NK cell activity appear to be
at higher risk for infections.
 Patients with autoimmune diseases may have
abnormalities in NK cell activity...
 Impaired NK cell function has been reported in patients
with connective tissue diseases including lupus and
rheumatoid arthritis.
 In cancer, NK cells are thought to be the first line of host
defense against blood-borne metastases.
 It is clear that chronically low levels of NK cell number or
activity in patients with cancer or other diseases may be
associated with more severe symptoms or increased risk of
disease progression."

What do NK cells do that make them so important?

NK cells are one of many interactive components of the immune
system, however, they have some very special qualities. NK cells
are in the T cell family and know "self" from "non-self" like other
T cells. NK cells focus on killing virally infected cells and cancer,
but will kill bacteria, parasites and fungi. What's really special
about them is that they have a completely different way of
recognizing invaders. They specialize in killing virus and cancer
cells that other parts of the immune system no longer "see"
for whatever reason. Any cell that is "hiding" is vulnerable to
attack by NK cells if they are capable enough to respond. This is
routine for them as cancer and virus cells have a tendency to to
"hide". However, when other parts of the immune system becomes
overwhelmed so as to slow or stop their function, NK cells are the
last line of defense a person has.

Decreased NK cell activity means that either the person is sick or

will be. On the other hand, chronic or severe illness could indicate
low NK cell activity among other compromised immune system
factors. Measurement of natural killer cells activity is a very
useful evaluation of the immune function status. I want
to schedule an NK cells evaluation test;

Immuno SG; is a powerful herbal medicine specifically

formulated to boost the body's production of NK cells and NK
cells activity. TCM Pharmacy;
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CIPFC (Natural Killer Cell) destroying a target tumor cell.

Two natural killer cells attack a cancer cell - Graphic
www.drugabuse.gov/NIDA_notes/NNv...ine.html
A natural killer cell (yellow) attacks a cancer cell (red).
www.biotechnologie.de/BIO/Naviga...derPrint

Natural killer cells attacking an infected cell (Image: Jerry G Johnson from

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natural killer cell (yellow) attacking a cancer cell (red)

Natural killer cell (green) attacks a cancer cell (blue).

This stained blood smear shows a blood monocyte staining purple and red

Monocyte
polconsultant.com/conteduc/immun...ders.htm
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Human neutrophyl.