Patty Clements
Impact Your Health
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Experts in the Field
by:  Jim Bischoff, M.D.

Human Natural Killer Cells in Health and Disease:  Biology and Therapeutic Potential
by:  Theresa L. Whiteside & Ronald B. Herbrman

Experts in the field
Clinician of the Month
Jim Bischoff, M.D.

Natural Killer Cells: Your First Line of Defense Against Disease

JLML:  Dr. Bischoff, how did you first get interested in Natural Killer cells?

JB: NK Cells are a critical part of the immune system, and specifically they’re a type of T-cell. We all have hundreds of millions of NK cells, made from stem cells in the bone marrow. Their job is to your first line of defense against invaders or pathogens in your body. This includes viruses, bacteria, fungi and malignant tumor cells. They can detect an invader within minutes and go to work destroying it.

NK cells produce a number of substances called cytotoxins, which are toxic to bacteria, viruses and malignant cells. They seek and destroy. They travel around the body, and when they find, for example, and unfriendly bacteria; they drill a hole in the cell’s membrane, inject it with cytotoxin, and blow it up. And then they can reload and go on and kill another one and another one. One NK cell can kill hundreds of bacteria or viruses.

NK Cells make interferon’s and interluekins, which are part of the immune system, and tumor necrosis factor, which eats tumors. NK cells participate in immune regulation, hematopoiesis  [the production and maturation of blood cells from primitive stem cells in the bone marrow], reproduction, and neuroendocrine interaction.

JLML:  What happens in the body when NK cell activity is low?

JB:  Low or absent NK cell activity is associated with a spectrum of human diseases, and a lowered ability to deal with stressful events. Everyone I’ve tested with those diseases has had a low NK cell activity. Families with a familial history of cancer tend to test low as a family. Families with no cancer tend to run high.

People with herpes, Epstein-Barr virus, chronic colds and flues, Candida overgrowth, auto-immune disease and cancer all tend to have very low NK cell activity. People who have chronic low or border line low chronic anemia also have low NK cell activity. For example, I had a patient whose NK cell activity was 2, which is extremely low, and her hemoglobin was 5, also low, and when we got her NK cell activity up to 56 her hemoglobin came up to 14 in a fairly short period of time. This is because active NK cells stimulate the bone marrow to make red blood cells.

JLML: What can you tell us about NK cell activity and auto-immune diseases such as lupus, multiple sclerosis and rheumatoid arthritis?

JB: An Active NK cell produces chemical messengers that control and program the immune system. If your immune system is attacking our body, and a rheumatoid arthritis, the NK cells will calm them down. People with autoimmune diseases almost always have low levels of NK cell activity.

JLML: How is NK cell activity measured?

JB: What I didn’t realize when I started studying NK cells is that the usual test doctors do is an NK cell count. You can count them because they’re a T-cell, and T-cells count got to be popular because of HIV. However, most of us have a normal count regardless of our health, unless you have HIV or AIDS, were born with immune deficiency disease, or have had chemotherapy or radiation—which kills NK cells.

The relevant test is of NK cell activity.We’ve been able to test the activity of NK cells for 22 years, but it’s much more complicated than doing a simple count. A radioactive isotope of chromium is used to test. Whether your NK cells are active or inactive, functional or nonfunctional. With the count you just use flow cytometry, and every lab has a cytometer. Radioactive material has much stricter regulations, increases the cost, and is less available. The activity test hasn’t been promote or become widely available, yet it’s far more clinically relevant and helpful.

JLML: What are the ranges to look for in a NK cell activity test?

 JB: We’ve learned that almost all people with cancer are low—o to 10 or 20. Then they have chemotherapy and radiation, which kills all NK cells, and suppresses their activity for many months and even years afterwards.

 The Lancet published an 11-year prospective study just over year ago, the measured the NK cell activity of 3,625 healthy people with no known disease. After 11 years they looked at who got cancer and who didn’t. People with a high NK level had a dramatically lower risk of getting cancer, and those who a low level had a significantly increased risk of cancer.

JLML: Yes, that was a very interesting study. They also reported that higher NK cell activity was associated with keeping body weight closer to the standard, not smoking, increased intake of green vegetables, and moderate alcohol consumption.

JB: Stress, insomnia and depression also lower NK cell activity. NK cells are closely linked to the regulation of stress hormones such as norepinephrine, and when those are low we tend to be depressed. I’m not sure which comes first, the depression or the low NK cell activity. I suspect they go hand in hand. All corticosteriods and all immunosuppressive drugs such as methotrexate suppress NK cell activity. Interferon shots will raise NK cell activity, but they’re very expensive and they tend to create steeps peaks and valleys in the levels.

JLML: What do you use with your patients to raise their NK cell levels?

JB: I use a special type of bovine colostrums called Biomune that comes from dairy cows and goes through a dialysis process that filters out the larger molecules that block absorption. It’s generic name is dialyzable bovine colostrums extract. I’ve done baseline measurement of NK cell activity on many patients, given them this colostrums product, and measured their activity against and have found great success in raising levels and resolving many types of disease.

JLML: What do you find that it works best for?

JB: Any type of chronic infection, from bladder infection to colds, and allergies. I’ve also seen it work well for patients with chronic fatigue, and had some success with auto-immune diseases. Dr. Jesse Stoff of Tucson, Arizona did a clinical of 107 patients who had chronic fatigue, Epstein-Barr virus, staph infections, many types of cancer, and other diseases. He treated them with the Biomune for anywhere from 1.5 to 59 months, and saw a positive response in all of those he treated, and very significant positive responses in the majority of them.

References:

Whiteside TL et al, “Human Natural Killer Cells in Health and Disease,” Clin Diagn Lab Immunol 1994 Mar;1(2):125-33.

Imai K et al, “Natural cytotoxic activity of peripheralblood lymphocytes and cancer incidence: an 11-year follow-up study of a general population,” Lancet2000 Nov 25;356(9244):1795-9.            

Human Natural Killer Cells in Health and Disease:
Biology and therapeutic Potential
by: Theresa L. Whiteside and Ronald B. Herberman
 from the Pittsburgh Cancer Institute, the Dept. of Pathology,
 Dept. of Otolaryngology, and the Dept. of Medicine at the University of Pittsburgh.

The Following quotes are from the Immunological Basis of Disease, a landmark study published in the journal: Clinical Immunotherapy.

1.)    In the Summary the authors conclude: “ Natural killer (NK) cells mediate a variety of functions that are important in human health and disease. Defective or absent NK cell activity is associated with a spectrum of human diseases. Immunotherapy to augment (Increase) Natural Killer cell activity is now available.”

2.)     “NK cells mainly circulate in the blood, where they account for about 5-15% of circulating lymphocytes. In some organs, such as the liver, NK cells represent up to 45% of the lymphocytes. NK cells have important biological functions. It has been realized that NK cells participate either directly or indirectly in multiple networks relating to the development, regulation, and communication within the immune system. “

3.)    “The ability to spontaneously lyse (disintegrate) a broad range of virally infected cells or tumor cells is the basis of the name ‘Natural Killer’ cell. NK cells are selective killers that do not harm normal ‘Self’, but eliminate susceptible targets (without the need for antigen presentation by MHC molecules.) The NK cell survives the lytic event, and it can ‘recirculate’ i.e. bind to another target and kill it.”

4.)   “While the ability of the Natural Killer cell to recognize and kill it’s target is widely known, other functions of NK cells may be biologically and physiologically even more important. Activated NK cells produce a spectrum of cytokines; including interferons, interleukins, transfer factors, tumor necrosis factors, hematopoietic cell growth factors, transforming growth factors, and other growth factors.

5.)   “Chronically low levels of NK cell activity occur in association with a variety of diseases including cancer, acquired or congenital immune deficiencies, severe life threatening viral infections, autoimmune diseases, and behavioral disorders.”

6.)   “In patients with cancer, low NK cell activity may have prognostic value in predicting relapse, response to treatment, and survival time without metastasis.”   “Only activated Natural Killer cells kill fresh tumor cells.”

7.)   “In cancer, NK cells are thought to be the first line of defense against metastasis.”  “Evidence that low NK activity may precede the development of cancer comes from studies of familial cancers. A highly significant relationship was observed between high familial incidence of cancer and low NK cell activity. Patients maintained on immunosuppressive therapy or whose NK cell activity is depressed or absent have a high incidence of cancer. Thus, low NK activity may be a risk factor for malignancy.”

8.)   “Chronic Fatigue Syndrome (Fibromylagia) has repeatedly been associated with depressed levels of Natural Killer cell activity.”  “ Patients with Autoimmune Diseases may have abnormalities in Natural Killer cell activity.”

9.)   “The rols of NK cells in viral diseases has been known for a long time. The correlation between low NK cell activity and serious viral infections has been well documented. There is evidence that NK cells participate in eliminating cells infected by fungi of by bacteria.. and in their ability to kill Candida Albicans.”

10.) Biological roles of Natural Killer Cells include:

          A.) Antiviral and Antibacterial Activity (Viricidial and                               Bactericidal Actions)
          B.) Anti-Tumor effects and elimination of metastasis                                 (Cytotoxic Effects)
          C.) Regulation of Hematopoiesis (The Production of Red                         Blood Cells)
          D.) Immune Regulation (Immune Programming,                                         Communication, and Control)
          E.) Effects on Reproduction
          F.) Interactions with Neuroendocrine System (Nervous and                     Hormonal systems)

11.) “The relationship between stress and low NK cell activity has been documented in many studies. The roll of NK cells in modulatin behavioral changes that accompany stressful life events is supported by numerous reports that the inability to handle stress in otherwise healthy individuals is associated with low NK cell activity.

12.) “The level of NK cell activity varies substantially among normal individuals. In our laboratory the, the normal range of NK cell activity is 55 to 350. This is based on assays performed with many of hundreds of healthy volunteers. In general, NK cell activity is a stable trait for a given individual. Normal individuals fall into categories with low, moderate, or high NK cell activity based on repeated measurements.”

13.) “ A considerable amount of evidence has accumulated to the substantiate the involvement of NK cells in many human diseases. Patients with low NK cell activity appear to be at higher risk for infections, have more prolonged disease, or experience more severe symptoms that those whose NK cell activity remains normal.”

14.)“From the evidence reviewed, it is clear that chronically low levels of NK cell activity in patients with cancer or other diseases may be associated with more severe symptoms or increased risk of disease progression. It may therefore be advantageous for patients with cancer, or immunodeficiency diseases to receive therapy aimed at augmenting (increasing) NK cell activity. Such therapy is available today.

15.) Conclusions: “Natural Killer cells play an important role in human health and disease. Strong correlative evidence linking disease and persistent low Natural Killer cell activity has accumulated.”

16.) “In summary, the frequent association of chronically low NK cell activity with disease implies that NK cells may be involved in the Immune surveillance system and immunoregulatory functions.   It also implies that increasing Natural Killer cell activity in disease may be beneficial to the patient.”

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