Concurrent treatment by fetal precursor cell transplantation and medications prepared by biotechnological methods

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Extracts of cells of various tissues have been used therapeutically for over a century. Among those classified as cytokines, lymphokines and other non-immunoglobulin secretions of activated lymphocytes, and monokines of activated monocytes, have been studied extensively and used in clinical practice during the last 40+ years. Their greatest advantage is an exceptionally high activity even when used in extremely low concentrations. A substance originally called leukocyte dialysate (LcD) belongs to this therapeutic group: it is a unique immunomodulator, very valuable because of its complex therapeutic effects.

The actions of leukocyte dialysate were recognized for the first time in 1942 when Karl Landsteiner (discoverer of human blood group antigens and antibodies, 1900) and M.V. Chase accomplished a transfer of the delayed hypersensitivity response of sensitized guinea pigs to the non-sensitized ones by transplanting live guinea pig leukocytes.

The same experiment was repeated in 1949 when H.S. Lawrence succeded to transfer tuberculin hypersensitivity from sensitized donors to non-sensitized human volunteers. VI.BIBLIOGRAPHY [223] H.S. Lawrence proved in 1955 that such property is retained also by a purified leukocyte extract; and named the effective component of such extract a ‘transfer factor’ (TF).VI.BIBLIOGRAPHY [224] In those days the claims of H.S. Lawrence about the transfer of ability to respond by delayed skin hypersensitivity via a soluble factor of molecular weight lower than 20,000 Da (daltones) were considered a ‘quackery’. The dominant theories of those times declared that all immune reactions, including delayed skin hypersensitivity, were dependent on antibodies (Ab) of a molecular weight at least 150,000 Da. In 1963 H.S. Lawrence discovered that the ability to respond to an immunogen is retained by a leukocyte extract of molecular weight under 10,000 Da.

In 1960 H.S. Lawrence proved that the final effect of TF results from the action of many effector substances included in the leukocyte dialysate, and introduced a term dialysable leukocyte extract(DLE). DLE contains at least 200 components, the most abundant is thymosin VI.BIBLIOGRAPHY [225, 226], and there is a wide spectrum of other biologically active substances, all of molecular weight from 1,000 Da to 20,000 Da, such as oligopeptides, nucleotides, serotonin, bradykinine, nicotine amide, prostaglandins, ascorbate, etc. One of them - with a molecular weight of only 3,000 Da - is an antigen specific transfer factor VI.BIBLIOGRAPHY [227].

Dialyzable leukocyte extract causes the immune system of the recipient to respond to a new antigen as if the immune system have had a memory of previous encounters with that antigen: patient’s ‘virgin’ T-lymphocytes would have been already activated, clonal selection have taken place, even before the first exposure to this new antigen. So when the actual contact with the new antigen is made, a massive proliferation of memory and effector T-cells, as in a typical ‘secondary reaction’, promptly develops.

Importantly, the molecule of dialyzable leukocyte extract is small, its molecular weight is low, so that DLE is non-antigenic, and does not cause any immune reaction in a recipient.

Even though the induction of cell-mediated immunity, i.e. antigen recognition, is dependent upon the identification of MHC of the individual, dialysable leukocyte extract acts as xenogeneic, it means that it ignores any species barriers in its effect, i.e. it is ‘species non-specific’.

The ‘transfer factor’ has been defined as the leukocyte dialysate capable to transfer the antigen-specific T-lymphocyte response VI.BIBLIOGRAPHY [228]. ‘Transfer factors’ are molecules that educate recipients to express cell-mediated immunity, and this effect is antigen-specific. VI.BIBLIOGRAPHY [229]

Transfer factor exhibits a broad range of biological activities: increase of the E-rosette cell count, interferone (IFN) concentration, lymphokines production, antigen-triggered expression of IL-2 receptors on CD4+ lymphocytes, of Ca++ influx into blood monocytes, as well as an accentuation of the delayed hypersensitivity skin reaction, etc.

Transfer factor is thermo-labile, and its biological activity persists for months at temperature range from - 20°C to - 70°C.

A hypothesis about the existence of transfer factor specificity for each antigen was postulated. The specificity of each transfer factor is based on the presence of at least 6 aminoacids in its structure. The structure of individual antigen-specific transfer factors varies in the same way as the binding of individual antigens on hyper-variable regions of immunoglobulins G (IgG). VI.BIBLIOGRAPHY [225]

MEDLINE lists over 1,100 scientific papers describing various uses of dialysable leukocyte extracts for immunotherapy, based on proven facts such as:

- transfer of a specific immunity within 4 - 6 hours,

- long term duration of so transferred immunity,

- absence of an inter-species barrier,

- acceptance of transferred immune responses as ‘self’,

- transfer of immunity by a peroral route.

Since 1992 the transfer factor has been used successfully in clinical practice in the treatment of many diseases, usually in their advanced stages, when other therapies known to modern medicine failed, such as:

- combined severe immunodeficiency, Wiscott-Aldrich syndrome, chronic mucocutaneous candidiasis, chronic fatigue syndrome, isolated T-cell deficiency,

- herpes simplex. herpes zoster, including ocular herpes, mononucleosis, measles, varicella, progressive vaccinia, congenital cytomegalovirus infection,

- tuberculosis of lungs, tuberculosis of bone, sarcoidosis, leprosy, cutaneous leishmaniasis, cryptosporidiosis, cryptococcosis, coccidiomycosis, histoplasmosis,

- AIDS, mycosis fungoides,

- bronchial asthma, chronic obstructive pulmonary disease, interstitial pneumonia,

- chronic hepatitis, Crohn’s disease, recurrent aphthous stomatitis,

- female chronic cystitis, chronic cystitis in children, chronic pyelonephritis,

- agammaglobulinemia, hyperimmunoglobulinemia E, Waldenstrom’s macroglobulinemia,

- epilepsy, autism, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer disease, Guillain-Barre syndrome, subacute sclerosing panencephalitis,

- chron. uveitis, Behcet syndrome, recurrent otitis media,

- psoriasis, discoid lupus erythematosus, lupus vulgaris, hereditary bullous epidermolysis; bullous pemphigoid, pemphigus vegetans, atopic dermatitis, alopetia areata, warts,

- papillomatosis of larynx,

- metastatic cancer of lungs (all histological types), of nasopharynx, bone, kidney, urinary bladder, prostate, liver, colon, uterine cervix, breast, head&neck, as well as osteogenic sarcoma, malignant melanoma in all stages, neuroblastoma, acute leukemia, Hodgkin disease, Burkitt lymphoma,

- juvenile rheumatoid arthritis, adult rheumatoid arthritis.

In all of the diseases which are italicized, fetal precursor cell transplantation is, or should be, used in the treatment, along with transfer factor.

About 30% of publications deals with the use of transfer factor for the treatment of malignancies. The logic behind it has been the concept of F. McFarlane Burnet, presented in 1960, and of L. Thomas of 1970, of host immune surveillance according to which the immune system recognizes and destroys frequently developing immunogenic tumor cells.

Cell-mediated immunity is the most important host response for the control of growth of antigenic tumor cells. Humoral immunity has not been found to be of much value for cancer therapy up until now. T-cells are responsible for direct killing of cancer cells and for activation of other components of the immune system. Natural killer (‘NK’) cells play apparently a significant role in this process as well, but up until now they have remained an enigma to the medical science.

Dialysable leukocyte extract lowers the content of DNA and RNA in cancer cells, and diminishes their protein synthesis. DLE also triggers differentiation of hematopoietic stem cells, that explains its benefit in cancer patients treated by irradiation and chemotherapy.

It is not quite clear at this time why the immune surveillance fails in the first place by allowing growth and spread of cancerous cells, originating from the malignant transformation of a normal cell. The idea to use transfer factor has been based on its ability to transfer the antigen specific T-cell response from a donor to a patient with cancerous cells, stimulating patient’s own T-cells to act more efficiently.

As all cancer cells of a patient are of monoclonal origin, i.e. they originate from a single transformed cell, at least in the earlier stages of cancer growth, the therapeutically most effective type of dialysable leukocyte extract, a transfer factor, is the one prepared from patient’s own cancerous cells, or white blood cells, if the cancer cells from the biopsy or surgical resection specimen are not available. This is what our group has researched and is available as individually for each patient prepared dialysable leukocyte extracts.

At the beginning most dialysable leukocytes extracts used in research and clinical practice were of human origin, which made the process of preparation of DLE’s lengthy, inefficient and expensive. After the lack of inter-species barriers was proven beyond any doubt the donors of DLE became livestock and pigs.

BCRO has used rabbits as donors of lymphocytes for variety of reasons: absence of recognizable retroviruses, i.e. rabbit is the sole laboratory animal today that is so distinguished, absence of slow viral infections, fast reproduction cycles with numerous fetuses from each pregnancy, ease of manipulation during the production process and during the collection of blood and tissue specimens of spleen, lymphnodes, so it is obvious that there is a full compatibility between fetal precursor cell xenotransplants of rabbit origin and transfer factor of rabbit origin.