Natural Killer Cells and Their Use in Treatment

It is known that natural killers (NK-cells) are a special population of cells of the innate immune system that play an important role in the antitumor and antiviral immunity. NK-cells are able to exert direct cytolytic effect on transformed or infected cells. They are involved in the regulation of the immune response through cytokine production.

The number of normal killers (NK-cells) in the body (peripheral blood lymphocytes) is about 5%. Location of genes with phenotype CD3-CD16 + CD56 + CD94 + is suitable for typical NK. As we can see, the normal killers do not have markers of B- and T-cells, although they are lymphoid cells.

It is assumed that the normal structure of the killers is able to recognize high-glycoprotein expressed on the membranes of virus-infected cells. Convergence to the target cell and its recognition is possible by receptors on NK. Activation of normal killers is possible when the space outside the cells releases granule contents.

It is believed that the main role in this process belongs to the cytolysin (perforin) that has some structural similarities to the item compliment C9 (perforin antibody inhibited the destruction outside the cell). Incorporating into the membrane of target cells, perforin forms transmembrane pores, resulting in cell death, because their contents follow through these pores. Besides the granules, normal killers present two kinds of serine protein kinase that can act as a cytolytic factor, but its effect on the NK-dependent lysis is not fully understood. The scientists revealed the presence of a NK-resistant protein kinase A-chondroitin sulfate proteoglycan that can protect cells from autolizisys. It is found that by recognizing the target, NK-cell produces recognition as “positive” and “negative” (Whiteside & Herberman 1990).

NK-cells have receptors that suppress cytotoxicity, which distinguishes them from T-killers. If not recognized, these receptors interact in the target cell with MHC class I. Then, an infected cell receives a signal to the inhibition of cytotoxic activity. To reach positive results in case of lack of recognition on target cells expressing molecules MHC and the interaction of infected cells with NK-cells, there should be participation of specific NK-cell receptors, such as CD69 and CD2, or antibodies associated with them through the receptor for Fc – CD16.

The process of linking with normal killers formed on the surface of target cells + antigen immune complexes with antibodies is interpreted as manifestations of the killer cell activity. In other words, it is antibody-dependent cellular cytotoxicity. For example, the herpes virus is trying to avoid detection of T-killer, having to suppress the expression of MHC class I molecules on the surface of infected cells. In such cases, the virus recognizes NK-cell.

The exact nature of the origin of normal killers is not clear until now. They are usually associated with the genesis of the BGL (large granular lymphocytes). Although NK-cell morphologically resembles lymphoblasts or lymphocytes, its histogenetic connection with B-or T-cells is not defined. A characteristic feature is the presence of normal killers Fc-receptors.

NKT-cells are a unique subclass of T-cells, which are characterized by phenotypic features of both T-cells and NK-cells. NKT bears a T cell receptor (TCR) and NK-cell markers (CD16, CD56, CD161) on its surface. Feature of the “classical” invariant NKT (iNKT) is the expression of an invariant TCR (Vα24-JαQ, Vβ11), which recognizes glycolipid antigen in a complex with the nonclassical MHC I molecules class – CD1d. “Non-classical” invariant NKT can be singled out, which can recognize CD1d, but other versions express the TCR. According to Robertson (1990), both CD4-CD8-, CD4 + CD8 and CD4-CD8 +-NKT-cells occur among NKT

NK cells play a very important role in the body, so the decrease in their activity may develop the most serious diseases, such as cancer, acquired or congenital immunodeficiency, severe or life-threatening viral infections, autoimmune diseases and even behavioral disorders. Recognizing cancer, killer cells secrete interferon-gamma and then destroy the cancer cells.

In addition, special studies have shown that NK cells play an important role in the human body in protecting against HIV, herpes, hepatitis B and C and other viral infections. Impairment of NK cells is also associated with a number of genetic disorders, chronic and infectious diseases (Kimura & Yamaguchi, 1989).

The NK-cell count has dropped by 38% over the past 15 years and has steadily decreased by about 3% per year.

According to the study, 3,624 adults over age 40 were surveyed. The following relationship was revealed: high activity of NK cells contributed to the low risk of developing cancer in the next 11 years, while low activity of NK cells led to the increased risk of cancer (Robertson & Ritz, 1990). In addition, the activity of NK cells is directly related to the diet and lifestyle (Whiteside & Herberman 1994).

The body of a child, an elderly person or a body in a state of stress is much more vulnerable to the development of immunological disorders. Increased activity of NK cells can significantly enhance immunity in these populations.

Numerous studies around the world have confirmed that there is a direct correlation between the activity of NK-cells and health. Moreover, the majority of the U.S. population has such indicators of activity of NK-cells as weak immune system, chronic diseases, and high susceptibility to viral infections.

American professor Stoff studied the relationship of a broad population of the U.S. population. He examined more than 3,000 people. As a result of this research, he found the following (Stoff, 2012):

Poor– bad condition: the content of NK is 0 – 20 lytic units.

People, who have such indicators of activity of NK-cells, have cancer or serious chronic illness.

Average (main population of Americans) – 20 – 50 lytic units.

Fair – satisfactory (tolerable) indicators – 50 – 150 lytic units.

Good (good results – a healthy population) – NK 150-230 lytic units.

Excellent (excellent performance – excellent health) – NK 230-300 lytic units.

Perfect health. NK-cell activity of 230-270 is considered a norm.

The knowledge gained by a group of scientists from the Institute of Ragon (USA) can provide the basis for an effective AIDS vaccine. The experts calculated the gene responsible for the formation of the body immune T-cells, which “recognize” more fragments of the protein of HIV. This can kill the virus more effectively.

For a person infected with HIV, if there is no medication treatment. The development of AIDS is only a matter of time. However, in a small number of people exposed to immunodeficiency virus AIDS develops very slowly or is not developed at all (Sauer, et al. 2012).

Back in the late 1990s, studies have shown that a very high percentage of people with natural immunity against HIV (and their number is about 1 in 200 infected) are carriers of the gene HLA B57.

A group of scientists from the Institute Ragon in Charleston (USA) continued research in this area. The result has revealed the ability of this gene to activate the body’s defenses and resist HIV infection.

However, the new study found that the organism carrying the gene HLA B57 produces a greater number of T-killer cells, which also are cross-reactive. It means that they can recognize more than one “enemy” protein and thereby destroy the mutated virus.

Prof. Chakraborty said: “At people without the gene HLA B57, cross-reactive T-killer cells are also present, but in much smaller quantities. Findings give hope for a vaccine that could increase their number” (Finke, et al. 2009).

Chakraborty and colleagues had previously developed a computational model of T-killer cells in the thymus (thymus), where they are selected, aiming at screening as too “weak” cells, badly identified threat, and too ”aggressive” ganging up on healthy cells .

This effect allows to control HIV infection (and any other rapidly developing virus), but on the other hand, makes gene carriers more susceptible to autoimmune diseases (rheumatic fever, systemic lupus erythematosus, gout).

In the thymus (lymphoid organs, in which the maturation, differentiation and immunological “training” of T-cells is going), T-killer cells interact with native peptide of the human body and, depending on the response to these peptides, successfully pass the “check the aggressiveness” or die.

The type and number of custom peptides, faced by T-killer cells, is determined by the genes HLA. Scientists have shown that HLA B57, along with HLA B27 (whose carriers also demonstrate the presence of immunity against HIV), provides the minimum number of custom peptides, resulting in a T-killer simply stand “test”.

In the end, T-cells are leaving the thymus, with a higher cross-reactivity and ability to destroy a larger number of forms of HIV, but at the same time more dangerous for healthy cells. This model also explains the reason for the increased risk of autoimmune disease in carriers of the gene HLA B57.

The knowledge gained in the study may help scientists to develop vaccines that cause the same response to HIV, which makes the gene HLA B57 develop independently. The most extensive studies of killer cells are conducted in the context of the fight against cancer.

NK activity can be significantly increased under the influence of cytokines, such as erleykina-2 (IL-2) and interferon-y (IFN-y) (Bryceson et al, 2006). Lymphokine-activated killer (LAK), which has a high cytotoxicity against the transformed cells, can be generated from some components of peripheral blood, spleen, or tumor in the presence of exudate grakorporalno IL-2. Mechanism of action of LAK is to direct cytotoxic injury autologous tumor cells as well as to synthesize and release biologically active substances, such as cytokines, which have a regulatory effect on other effectors of antitumor immunity.

Introduction of IL-2/LAK-immunotherapy into clinical practice is expanding the limits of cancer treatment. However, despite the progress that has been made in recent decades in clinical practice, there is still the problem of lack of efficacy of immunotherapy, due to the formation of the phenomenon of peripheral tolerance. The ability of the tumor to “escape” from immune surveillance (the absence of specific antigen, a high rate of division malignantly transformed cells, the secretion of suppressor factors and low bioavailability) is the key problem of immunotherapy (Grimm, et al., 2010).

To improve the effectiveness of immunotherapy, it is necessary to activate effector cells (NK, helper and cytotoxic T-lymphocyte) to prevent the development of the processes of immune tolerance and, if necessary, to level state of immunosuppression, developing on the background of tumor progression. Therefore, to enhance the cytotoxicity of NK LAC appropriate is selection of enriched killer subpopulations or removal of suppressor cells. The modern methods of immunomagnetic separation, the clinical application of which requires experimental validation, may be used for this.

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