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Micro-immunotherapy is an innovative unique healthcare approach which uses molecules specific to the immune system to regulate immune responses, in order to optimize its function and to alleviate disease symptoms. Immune system, in micro-immunotherapy, is used as a diagnostic tool to detect the pathology and then, it is used as a path way to clear the symptoms of disease. Micro-immunotherapy also offers a new, immunological perspective on pathophysiology, to give a better understanding of the interactions between endogenous and exogenous factors. Micro-immunotherapy offers a therapeutic tool, which incorporates the latest discoveries in the field of Immunogenetics, for general practitioners and for specialists equally. Its effectiveness and usefulness is not only based on the first-hand experience of thousands of doctors in Europe, but also relies on favourable clinical trials conducted and data collected in numerous research projects.

Dr Maurice Jenaer

Dr Maurice Jenaer, an expert clinician, laid the foundations of Micro-immunotherapy in 1970s. Trained micro-immunotherapy practitioners use immunological laboratory tests to monitor the progress of their patients and to gauge the prognosis of the disease symptoms. These tests are used from the onset of the treatment to observe the current condition of immune system, and then compare it with the results obtained after the application of micro-immunotherapy treatment protocol in order to verify its effectiveness.

There are 7 key areas which need to be understood, to fully comprehend the concept of micro-immunotherapy. These are described below in more details.

1. Cytokines;
2. Microdoses;
3. Modulation of dilutions;
4. A multi-objective strategy;
5. Sequential signalling;
6. Specific Nucleic Acids (SNA®);
7. Absorption by the lymphatic system.

Cytokines

In simplest term Cytokines are proteins specialized in communication between the various parts of the immune system.

The way the immune system is organised constantly amazes immunologists. The numerous agents with clearly defined functions include a class of specialized proteins that coordinate communication between the various protective elements of the immune system, such as lymphocytes, macrophages and other cells involved in the immune response to any attack on the body. These specialized proteins are called cytokines.

Cytokines exert their effects both on the cells that produce them (autocrine effect) and on other cells (paracrine effect), as well as acting remotely on target organs or tissues (endocrine effect). They are produced as a result of cell activation and are therefore not generally found in non-activated cells.

The major cytokines identified to date are interleukins (classified from IL-1 to IL-36), interferons (IFNα, β and γ), growth factors (CSF and TGF) and tumour necrosis factors (TNFα and β). Because of their role in signalling, cytokines form the basis of the micro-immunotherapy formulas.

Microdoses

Micro-immunotherapy employs remedial substances within periphysiological range, whereby it is unlikely to produce whole body-effect, yet high enough to allow for immune response to occur where it is needed.

The rationale behind the use of cytokines in microdoses lies in the fact that in physical body cytokines circulate at micro physiological concentrations of the order of 10^-4 M to 10^-14 M.

In micro-immunotherapy, the lowest dilutions of cytokines used are at least equal to the concentration of 10^-6 and may reach or exceed 10^-14. Hence, to communicate directly with the immune system, the dilutions of micro-Immunotherapy are analogous to the physiological concentrations of the immunocompetent substances in the body. Because of its microdoses, micro-­Immunotherapy is well tolerated, and has no known toxicity.

Modulation of Dilutions

• The objective of Micro-Immunotherapy is to tweak and optimize immune responses with the use of microdoses of remedies, which are not alien to immune system;
• In micro-immunotherapy microdoses are intelligently administered with the selection of appropriate potencies to achieve optimal therapeutic effects;
• Selection of potency of a dose partly relies on well-founded scientific phenomenon of Hormesis and partly on the scientific discoveries which tend to underpin the secrets of high dilution technology;
• By using these different dilution levels micro-Immunotherapy is able to simulate, modulate or inhibit the actions of the immune system, depending on the disorder to be treated.

A Multi-Objective Strategy

Micro-Immunotherapy offers a therapeutic approach designed to act at causative level of disease symptoms. Unlike the selective approach that is generally used in conventional immunology, micro-Immunotherapy acts at several levels:

• Modulating the Th1, Th2, Th17 response etc;
• Stimulating or inhibiting the production of cytotoxic chemicals;
• Modulating the production of cytokines linked to cell activity.

It can therefore be said that micro-Immunotherapy offers a therapeutic approach that is not simply based on relieving symptoms but that also acts on causes. For instance, preventive treatment with micro-Immunotherapy would be effective against allergies, causing immediate hypersensitivity (seasonal allergic rhinitis). Micro-Immunotherapy will have a role in symptomatic cases too, to modulate an impaired immune system. This explains why micro-Immunotherapy could be applied both preventively and to treat symptoms.

The following diagram shows functional activity of micro-immunotherapy remedies at various cellular levels.

Schematic view of micro-immunotherapy products at cellular level.

Sequential Signalling

Micro-immunotherapy allows the immune system to recover to normality through a series of remedial chain reactions. The immune response takes place over time. When the immune system recognizes an antigen, it analyses the nature of the intruder and deploys a certain number of immunocompetent cells; this is innate immunity. If the attack persists, new cells will join in and a more elaborate strategy will be set in motion, called acquired immunity. From the first presentation of the antigen to the eradication of the foreign body, a series of cascaded immune reactions take place. This also includes the production of cytokines.

Micro-Immunotherapy formulas reproduce this cascade of cytokines. A micro-Immunotherapy formula therefore involves a specific distribution of cytokines to be taken at given intervals of time. To achieve the suitable distribution of cytokines, the administration of the doses of micro-immunotherapy remedies leads to the sequential doses with respect to the exact potency of the remedy.

This cascade of cytokines gave birth to the term of sequential signalling.

The goal of dosage frequency in defined order of potency, of micro-Immunotherapy remedies, is to direct the immune system to evolve in the direction of normality with the help of a targeted cascade of chain reactions. In this way, the immune system carrying suitable micro-Immunotherapy remedies is attuned to perform optimally.

Specific Nucleic Acids (SNA®)

Along with Cytokines, micro-immunotherapy formulas contain specific nucleic acid (SNA). SNA is a small synthesised oligonucleotide, homologous to a specific gene sequence. Since SNAs are specific nucleic acids, therefore these are used to perform specific tasks in the formulae of micro-Immunotherapy remedies.  When SNAs in the right format are used, they have the capacity to modulate the expression of a specific gene that may cause adverse effects.

SNA®s were patented internationally by Labo’life.

Absorption by the Lymphatic System

The Micro-Immunotherapy product’s message is sent directly to the epicentre of the immunological battle field. The Immune response takes place in the lymphatic network as well as in other parts of the body. In the lymphatic network, lymphocytes are being recruited and mobilized according to the needs of the system. The Mucus membrane of the sublingual region is the primary route for the administration of micro-immunotherapy remedies. In this sublingual area, close to lymphatic system, the micro-Immunotherapy remedy is absorbed containing 40 globules approximately. When globules in a capsule of the micro-immunotherapy product come in contact with the surface of sublingual mucosa, the remedial solution goes straight to the heart of the immune battle in the lymphatic system.

In order to enhance the understanding of readers, an example of one of micro-immunotherapy formula, PAPI formula, is given below.

PAPI formula is used to treat infection caused by Human Papilloma Virus (HPV).

Micro-immunotherapy PAPI Formula

Micro-immunotherapy offers specific formulas containing nucleic acids, cytokines, natural endogenous molecules and other immunomodulatory substances, in highly diluted doses (microdoses) for sublingual absorption, to sequentially modulate mechanisms involved in a particular disease. To illustrate the mode of action of this therapeutic approach, this section describes the synergy of action of 7 key areas described in the beginning of this article, in context with HPV infection.

Composition of the PAPI Formula [1]

Interleukin 1  10-17CH

Interleukin 2  10-17CH

Interferon-α   10-17CH

Cyclosporine A          10-7CH

Cyclosporine A          10-17CH

Ribonucleic acid        10-18CH

Specific nucleic acid   SNA-HLA II 10-16CH

Specific nucleic acid SNA-PAPI      10-16CH.

The PAPI formula is made up of:

• Cytokines such as interleukin-1 (IL-1), interleukin-2 (IL-2) and interferon-α (IFN-α);
• Immunomodulators such as cyclosporine A (CsA);
• Nucleic acids such as ribonucleic acid (RNA);
• Specific nucleic acids:
  • SNA-HLA II
  • SNA-PAPI

All the substances in the PAPI formula are prepared in highly diluted doses by the dilution / succussion method. The efficacy of periphysiological dilutions of endogenous molecules and various immunomodulators has been described extensively in various scientific publications. The composition of the PAPI formula, like all other micro-immunotherapy formulas, is designed in sequences. What is meant by ‘designed in sequence’, is this, in each formula doses of each remedy are organized in certain sequential potency order so that the desired result can be achieved. The sequential structure of the formula has been conceived so that it acts at the level of the cascade of basic mechanisms established by the pathophysiology of the disease. Dr Jenaer, founder of micro-immunotherapy, considered this sequential nature to be one of the key element in micro-immunotherapy system.

The sequential order of the PAPI formula is based on the following points:

• The active substances in a capsule are intended to have their effect on a single pathophysiological mechanism that is essential to HPV infection;
• A sequence of capsules seeks to act on a cascade of basic pathophysiological mechanisms at the onset of HPV disease and as it develops;
• Each capsule interacts with the effects of the contents of previous capsule (transition between capsules), setting up the “domino effect” of the sequence.

In the case of the PAPI formula the remedies sequence is structured at three levels

1. A.    Viral cycle;
2. B.     Immune impairment;
3. Associated Disorder;

At each level, the PAPI formula seeks to specifically modulate a series of events involved in the development and course of HPV infections and related diseases. The objectives of the PAPI formula are described below in stages, together with the mode of action of the substances and the dilutions used at each of these three levels mentioned above.

Mode of Action of Substances and Dilutions used at each of the Three Levels

A. Viral Cycle

At the first level, targeting the HPV viral cycle, the PAPI formula is based on two stages:

Reducing expression of the viral genome and modulating its replication/transcription. 

SNA-PAPI:

Irrespective of their mode of replication, viruses contain at least one ‘parental’ strand of DNA containing their specific genomic information. The viral sequence can become incorporated into human cellular DNA and give rise to various diseases. However, a viral chain can be intercepted by various techniques, leading to the specific inhibition of these viral sequences.

SNA-PAPI is a synthesised oligonucleotide, with a sequence substantially analogous to part of the genomic material bound to HPV. A high inhibitory dilution of SNA-PAPI is aimed at blocking the damaging information introduced by HPV and restoring the normal function of the cell.

Reducing the cell proliferation induced by the virus (HPV).

Cyclosporine A (CsA)

HPV suppresses expression of the p21 protein and CsA stimulates expression of p21, a protein that inhibits cell proliferation. In this phase of the PAPI formula, CsA is found in a modulating dilution, to obtain the effect sought: promoting p21 expression and consequently inhibiting cell proliferation, without stimulating the immunosuppressive effect of CsA.

Interleukin-1 (IL-1)

IL-1 is a pro-inflammatory cytokine that stimulates the mitogenesis of keratinocytes and the cell lines of cervical cancer immortalised by HPV.

In the PAPI formula, IL-1 is found in a high inhibitory dilution form, to combat the effects of that cytokine on the mitogenesis of keratinocytes.

Summary for ‘Viral cycle’: The PAPI formula is designed to block HPV replication and shorten the mitogenesis/proliferation cycle of keratinocytes stimulated by the virus.

B. Immune Impairment

At this level, guided by the immune response associated with HPV, the aim is to develop immunomodulation focused on the specific immune impairment induced by the papillomavirus. At this point, we shall identify two stages in the PAPI formula:

Modulating the immune-inflammatory reaction: NF-kB and pro-inflammatory cytokines 

RNA

Viral and synthetic types of RNA are potent inducers of interferon by stimulating Toll-like receptors. RNA is a ligand for Toll-like receptor. When RNA binds to Toll-like receptor8 this activates factor NF-kB, a factor essential to inflammation. The aberrant activation of NK-kB in the cells infected with HPV is responsible for inhibiting the apoptosis and proliferation of infected cells and their progression to cancer.

In the PAPI formula, RNA is found in a high inhibitory dilution, to counteract the excessive activation of NF-kB.

Reducing immune evasion, immunosuppression and tolerance of the virus: Langerhans cells and CD4+CD25+ Treg.

Cyclosporin A (CsA)

The immunosuppressant drug CsA causes a reduction in the number of Langerhans cells, DNA synthesis and function of antigen-presenting cells (APCs), and inhibits the differentiation of these cells. This sometime adversely effects the epidermis, which partly explains the increased risk of viral disease and skin cancer in long-term patients. In this phase of the PAPI formula, CsA is found in a high inhibitory dilution, to stimulate the production and function of Langerhans cells, which are essential ‘professional APCs’.

Interleukin-2 (IL-2)

IL-2 is a cytokine required for the generation, maintenance and expansion of regulatory T-cells (Treg), cells that lessen the activity of TCD8 lymphocytes. In the PAPI formula, IL-2 is found in a high inhibitory dilution, to counteract the production and function of Treg cells, which are essential for the virus to escape from the immune system and for viral tolerance.

Summary for ‘Immune impairment’: The PAPI formula is designed to reduce excessive inflammation secondary to disproportionate activation of NF-kB factor and to support the immune system against virus evasion mechanisms and virus tolerance.

C. Associated Disorder

Finally, a third level is targeted at diseases associated with HPV infection, such as neoplastic disease. We can identify two fundamental stages in the PAPI formula:

Avoiding the initial events that lead to the onset and development of neoplasms: Genomic instability and clonal selection

Interferon-α (IFN-α)

The endogenous activation of the antiviral response brought about by type I interferon is associated with increased inflammation and expression of the viral proteins E6-E7 in cells containing HPV within their genome. The deregulated expression of E6 and E7 is a factor in predisposition to and progression of cervical cancer. In the PAPI formula, IFN-α is found in a high inhibitory dilution, to neutralize the production of viral oncoproteins, which are involved in the onset and progression of the neoplastic process.

Avoiding events that lead to neoplastic progression: Aberrant expression of the HLA-DR antigen.

SNA-HLA II

HLA-DRs are class-II MHC molecules that act as cell-surface receptors, coded for by the human leukocyte antigen. The primary function of HLA-DR is to present antigens to the immune system in order to induce or suppress T-cell response. Professional APCs such as macrophages, B-cells and dendritic cells are the cells where HLA-DRs are typically found. The over-expression of HLA-DR molecules in non-professional antigen presenting cells (non-professional CPAs) such as keratinocytes, possibly induced by an excess of pro-inflammatory mediators, is related to disorders such as cancer and autoimmune disease. In the case of cervical tumours associated with HPV, the increased expression of HLA-DR in keratinocytes is associated with progression of the disease (CIN).

In the PAPI formula, SNA-HLA II is found in a high inhibitory dilution, to block the appearance of DR-type HLA structures on the surface of “non-professional APCs”.

Summary for “Associated disorder”:  The PAPI formula is designed to reduce the possibility of neoplastic events and/or their progression.

As a final point, it should be noted that globules of PAPI formula are administered sublingually, where they come into contact with the oral and sublingual mucosa so that the signals can reach the immune elements present in those regions such as monocytes, macrophages and Langerhans cells. From there, the information will access Waldeyer’s ring, where several types of immune cells and receptors such as Toll-like receptors, which are present in those areas, can react and produce cytokines and other antiviral substances. Furthermore, the signals of the PAPI formula could also be transmitted to the rest of the system through specific receptors of immune system cells, Jerne’s networks, lymphocyte networks and other immune elements.

As mentioned in the beginning, this is an example to illustrate the synergy between the 7 basic principles of micro-immunotherapy; these principles are to be found in all other Micro-Immunotherapy formulas.

Benefits of Micro-Immunotherapy

• Micro-immunotherapy is an everyday therapeutic tool forming part of any therapeutic strategy;
• Micro-immunotherapy has a specific, precise and a non-toxic action to restore the whole potential of the immune system;
• Micro-immunotherapy does not force or block the function of immune system; it simply supports it, gently and subtly, to restore to normality.

As a therapeutic method, micro-immunotherapy can be combined with other therapies, as a conjugate therapy, such as drug therapy, surgery, hormone therapy, or chemotherapy etc. Its purpose is to act directly on immune system. The unique therapeutic approach of micro-immunotherapy places it within the broad arsenal of therapies offered by modern medicine.

References

1. The 7 tools of micro-immunotherapy. Published by: Institut International de Micro-Immunothérapie at www.3idi.org