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TRANSFER FACTOR: AN IMMUNOMODULATOR FOR FIGHTING INFECTIOUS DISEASES*

Dr Dimitri Viza

*This text contains large excerpts from lectures given by Dr Viza at the Xth International Congress on Transfer Factor in Monterrey, and at the Biotecnologia Habana 99 Symposium

Abbreviations: CMI: Cell-Mediated Immunity; CMV: Cytomegalovirus; CTL: Cytotoxic T Lymphocytes; EBV: Epstein Barr Virus; DTH: Delayed Type Hypersensitivity; HIV: Human Immunodeficiency Virus; HHV-6: Human Herpes Virus 6; HHV-8: Human Herpes Virus 8; HSV: Herpes Simplex Virus; LMI: Leukocyte Migration Inhibition; SIV: Simian Immunodeficiency Virus; TF: Transfer Factor.

Summary

Transfer factor (TF) is an immunomodulator of low molecular weight and proteinaceous nature, described for the first time by Lawrence in the early ‘50s and capable of transferring antigen-specific information to T-lymphocytes. It has been used widely and successfully over the past quarter of a century in the treatment of viral, parasitic, and fungal infections, as well as immunodeficiencies, neoplasias and allergic and autoimmune disorders. From the impressive list of maladies, which respond dramatically to transfer factor therapy, one should cite infections due to viruses, especially those of the herpes family, such as labial, genital and ophthalmic herpes, acute CMV and HHV-6 infections, Burkitt’s lymphoma and nasopharyngeal carcinoma caused by the EBV. Similarly, extremely encouraging clinical results have been observed in patients suffering from candidiasis, tuberculosis, and cancers of the lung and prostate.

However, there is more to transfer factor than just being an inexpensive remedy, or one for the rare-syndrome sufferer. Its potential for answering the challenge of unknown pathogenic agents is considerable. And what I call the “black box effect” permits to make specific transfer factor to a new pathogen before it has even been identified. The preventative potential of transfer factor also holds great promise. Indeed, it has been shown that specific TF administered before a viral infection can prevent the development of the disease, TF acting as a vaccine addressing the cell mediated immunity.

Introduction

The first observation postulating the existence and establishing the concept of transfer factor dates from the early 1950s (1), when H.S. Lawrence showed that delayed type hypersensitivity (DTH) to a given antigen could be transferred from one individual to another via acellular extracts obtained from the leucocytes of an immunised donor. He assumed that this adoptive transfer of immunity was due to a molecule, which he named transfer factor (TF) and he surmised that its molecular weight is less than 12,000 Daltons, as it filters through a standard dialysis bag. Since then, all transfer factor preparations have been obtained by disrupting lymphocytes, dialysing the lysates, and using the dialysed material for in vitro tests or in vivo clinical or animal studies.

Over one thousand reports have since confirmed Lawrence’s original observations and established unequivocally that the dialyzable extracts thus obtained are capable of transferring specific immune information in vitro to naïve lymphocytes or in vivo to human patients or experimental animals. This information concerns only cell-mediated, no de novo antibody production has ever been elicited by transfer factor, although it has been reported that it may modulate normal antibody production triggered by conventional immunisation (2,3).

It is now established that cell-mediated immunity (CMI) plays a crucial role in the control of infectious, parasitic, and autoimmune diseases, as well as cancer. It is therefore of no surprise that transfer factor has been used successfully over the past twenty-five years not only in the treatment of viral, parasitic, fungal and myco-bacterial infections, but also as an adjuvant treatment in autoimmune, allergic and malignant disorders.

Although at the molecular level, the mechanism of action of TF remains largely unknown, its activity, in addition to the transfer of immune information, is manifested as a non-specific modulation of the immune response. Indeed, a boosting of the immune defences is obtained when required, e.g. in infectious, malignant or genetically impaired immune disorders, while a suppressing effect may be exerted when a down-regulation of the immune system is desirable, as in autoimmune or allergic pathologies. Moreover, its non-antigen-specific immunomodulating activity, which may also play a role in the regulation of humoral immunity, is due to molecules present in the dialysate, but distinct from those responsible for the transfer of antigen-specific information.

Be that as it may, the total dialysate obtained from peripheral lymphocytes is a quasi-perfect cocktail of molecules with balanced, because sometimes apparently antagonistic effects, which provide immunoregulatory activity, a bonus being the adoptive transfer of a novel antigenic specificity to the immunological memory of the recipient. Hence the qualification of TF as an immunomodulator, or a lymphokine with immunomodulatory activity mediating adoptive immunity, in contrast with the so-called active (induced by immunisation with the corresponding antigen) or passive (mediated by antibody injection) immunity.

Nonetheless, and notwithstanding astounding clinical results, many drawbacks have impeded research in this field and fast advances in understanding the nature and mode of action of this intriguing biological entity.

For many years, the only source of transfer factor was that of pooled leucocytes from blood donors. This limited the supply, whereas the biological potency and specific activity of the extract varied from one preparation to another. Indeed, the precise antigenic specificity of the various batches of TF was practically unknown, but presumably large, since each batch reflected the collective immune experience of several individuals. For this reason, these preparations were, and still are, improperly called “non-specific”, indicating multiple but unknown specificities. Thus, despite extremely encouraging reports in the early 1970’s, the clinical use of transfer factor was curtailed by the dearth of material with standardised and consistent activity. Similarly, biochemical studies were virtually impossible for lack of sufficient raw material for purification.

In 1974, my laboratory reported that human transfer factor with known specificities could be replicated in tissue culture, using a lymphoblastoid cell line (4,5) and in the late 1970’s, we and other investigators presented evidence that specific transfer factor obtained from mammals after immunisation with a given antigen, was active in humans (6,7).

However, in spite the theoretical resolution of the supply problem, the controversy relating to this molecule was to grow. There are several reasons for this, but they pertain mainly to the unusual properties and characteristics of the molecule.

Unusual properties

Nearly fifty years after Lawrence’s original observations, transfer factor remains an elusive and controversial entity, despite enormous laboratory efforts and several clinical studies with encouraging and sometimes dramatic results. Biochemical studies have produced evidence that the molecule responsible for the transfer of the specific antigenic sensitivity is a small peptide with a molecular weight of approximately 5000 DA, and it has been suggested that two or three ribonucleotides are attached to the peptide. Unfortunately, attempts to sequence the peptide have failed, because of the presence of a blocked amino terminus.

The transfer of antigen-specific CMI information by this moiety is thought provoking, for it apparently contravenes essential tenets of immunology and molecular biology. However, since the experimental evidence supporting the antigen-specific transfer is uncontested, various hypotheses for understanding its mechanism have been proposed, but so far, none has been proven totally acceptable.

The specificity issue continues to be one of the essential problems, the second being the structure. We know that the dialysates contain non-specific immunoregulatory molecules that can enhance and, in certain doses, down-regulate CMI. Two such molecules were purified and named IMREG I and IMREG II by Gottlieb and his co-workers (8), but they are incapable to transfer sensitivity to a new antigen. Nevertheless, such moieties could play a role in enhancing a weak response to a ubiquitous antigen and thus provide false evidence of specific transfer. Studies undertaken in the early days with such rare antigens as coccidioidin (9) or keyhole limpet haemocyanin (KLH) (6, 7, 10) preclude non-specific enhancement of ‘lapsed’ immunological memory. Several reports have established that TF is capable of transferring DTH to rare antigens that the recipient could not have encountered by chance.

The overall picture became more complex when two types of antigen-specific activity were described within the dialysates: a) inducer or helper activity, which is the activity of the conventional transfer factor and b) anti-transfer factor or suppressor activity. Briefly, the distinctive properties of the two entities are as follows: transfer factor binds to its related antigen, suppressor factor binds to the related antibody (IgG); inducer factor is absorbed by T suppressor cells and macrophages, whereas suppressor factor is absorbed by T-helper cells and macrophages; inducer factor is derived from T-helper cells, suppressor factor from T-suppressor cells. (11)

Considering the results of our preliminary studies, we contend that antigen-specific factors may be derived from each one of the lymphocyte sub-populations. Obviously, a very important task is to purify and identify these molecules and put them into clinical use. Moreover, it is worth emphasising that the possibility of using the moiety derived from cytotoxic T lymphocytes (CTL) opens up vast new areas in clinical applications, since these cells play a fundamental role in the defence mechanisms against infectious and neoplastic diseases.

Be that as it may, TF’s characteristics (low molecular weight, undefined chemical structure, unconventional mode of action, proteinaceous nature, resistance to most proteolytic enzymes) together with its biological properties (non-species specificity, transfer of antigen-specific information) have generated more opponents than supporters. And the frustration resulting from unsuccessful attempts to solve this multi-faceted riddle, especially the failure so far to unravel the molecular structure, apparently due to a blocked amino terminus of the peptide forbidding its sequence, has led some scientists in the 90s to doubt even its existence, following the precepts of the paradigm of hard biological science: reject facts rather than endanger established theories, in other words reject anything missing a molecular explanation for it is better to deny a fact than get mixed with a fluke. Modern medical logic would rather that treatments were inefficacious than incomprehensible (12).

One has to add that the pharmaceutical industry did not pay sufficient attention to the moiety because the prohibitive costs of bringing new drugs onto the market together with the lack of patent protection (i.e. the impossibility of filing strong patents after decades of published academic work), and the difficulties involved in production made commercialisation apparently not viable. And a compound producing such astounding results as those described in the literature, which has not been on the market after so many years, gradually begins to lose its appeal and its credibility.

An effective treatment

Maybe some clinical studies of the ‘70s are subject to criticism, especially if one wishes to apply a posteriori today’s criteria for designing clinical trials, numerous reports have established unequivocally the efficacy of transfer factor in treating several pathologies. Moreover, in favour of its clinical use, one should stress the total lack of toxicity and the absence of side effects: the observation period for establishing this exceeds today’s strictest criteria. Indeed, for nearly three decades, several hundreds of patients have received large amounts of TF and none has ever reported signs of acute or chronic toxicity. It is of interest to observe that during all these years, no publication has ever refuted reported observations.

An impressive number of clinical studies have demonstrated the efficacy of transfer factor in treating or even preventing infections due to several viruses. I shall mention briefly hereafter some viral, parasitic, fungal and mycobacterial infections, as well as some immunological genetic deficiencies whose response to TF therapy is well documented. This mini-review is far from being exhaustive.

Viral Infections. In a most elegant, controlled and uncriticised trial, which was published in a prestigious journal, Steele and co-workers were able to protect leukaemic children receiving chemotherapy, from varicella zoster virus infections using a varicella-zoster-specific TF (13,14). This observation not only confirms the powerful effect of TF in fighting viral infections, but also it clearly introduces the concept of using TF for prevention.

In the early 1980’s, ourselves and other investigators described the significant improvement obtained by the use of herpes-simplex-virus-specific transfer factor in treating patients suffering from recurrent genital and/or labial herpes (15-18). These clinical observations were corroborated by experiments in a mouse model we have developed: HSV-specific TF was able to prevent mouse death following a lethal injection of the virus (19), thus confirming the preventative potential of this molecule. More recently, patients suffering from recurrent herpes keratitis showed dramatic improvement when treated with herpes-simplex-virus-specific transfer factor (20,21), whilst additional studies have confirmed the efficacy of TF in treating genital and labial herpes infections (22).

Other clinical studies have shown that specific TF may produce a spectacular improvement in acute cytomegalovirus (CMV) infections (23), another member of the herpes family, whereas African children suffering from Burkitt’s lymphoma - a tumour caused by the Epstein-Barr virus (EBV) in Africa, also belonging to the herpes family - treated over a long period with EBV-specific transfer factor showed a significant decrease in the rate of relapses (24). Similar impressive results were obtained in Malaysia in preventing relapses of nasopharyngeal carcinoma (NPC) – a tumour caused by EBV in South-East Asia – by the administration of an EBV-specific transfer factor (25).

HHV-6, also member of the herpes family and suspected to play a role in the chronic fatigue syndrome (CFS), as well as in AIDS progression, is proven to be highly responsive to HHV-6-specific transfer factor treatment (26). One may be confident that the recent member of the family, HHV-8 (27), responsible for Kaposi’s sarcoma, will be as responsive to TF treatment as the other herpes viruses.

Results from using specific TF against other than the herpes family viruses have also been very good. For instance, chronic active hepatitis B responds to specific transfer factor (8, 28), whereas new viruses, e.g. those of the retroviral family, also seem to be sensitive to HIV-specific TF treatment. In preliminary studies, HIV-specific and SIV-specific transfer factors have produced extremely encouraging results in AIDS patients (29-31) and in macaques suffering from SAIDS (32) respectively. The use of the non-antigen-specific moieties, IMREG, has also induced a significant improvement in AIDS sufferers (33).

Malignant Diseases. Although outside the scope of this review, it is worth mentioning that TF treatment has produced encouraging and sometimes dramatic results in several cancers. One should cite the pioneering work of Fudenberg in treating osteosarcoma patients (34), but also results obtained with melanoma, breast cancer, and more recently lung (35,36) and prostate cancer (37) patients.

Parasitic infections also respond to transfer factor therapy. The outstanding work of Sharma and co-workers in treating cutaneous leishmaniasis (38, 39) should be mentioned; their results were confirmed by Delgado et al. (40). Other parasitic diseases known to respond effectively to TF are schistosomiasis and cryptosporidiosis (41).

Mycobacterial Infections. Several reports cite positive results in treating patients with lepromatus leprosy (42,43), mycobacterium fortuitum pneumonia refractory to antibiotic therapy and tuberculosis (44, 45, 46). Considering the present re-emergence of the latter and the appearance of antibiotic-resistant germs, transfer factor may have a role to play for the prevention and/or the treatment of this infection in the years to come.

Fungal infections. Chronic mucocutaneous candidiasis is an immunodeficiency characterized by chronically relapsing Candida albicans infections and it responds extremely well to TF treatment (47, 48). In a recent study, a significant clinical improvement was noticed in all but one of the fifteen patients treated. In addition, it was shown that Candida-specific TF increases the patients’ immune reactivity to Candida antigens (49).

Rare syndromes. Behçet’s syndrome, probably of viral origin, and Wiskott-Aldrich syndrome, a genetic immunodeficiency, are both responsive, and sometimes spectacularly so, to TF therapy (50-54).

Allergies. It is worth mentioning that TF derived from mouse CD8 lymphocytes immunised with pollen and house dust showed an inhibition effect in vitro in the LMI test (55). The extracts were after in vitro replication administered to patients suffering from asthmatic reactions to pollen, allergic conjunctivitis, or hay fever. All patients experienced a 50-100% improvement (Viza D., Vich J., and Hebbrecht N.: unpublished data).

Perspectives

Production and Availability. In theory, the in vitro production of specific TF has solved the availability problem. Sequencing the molecule will render production by genetic engineering a less expensive alternative.

Suppressive activity. The dialysates that have been utilized up to now for the quasi-totality of clinical studies are a mixture of antigen-specific and antigen-non-specific inducer and suppressor factors. I propose that, in certain cases, the use of purified factors would produce even more dramatic results. Preliminary studies in my laboratory had indicated that extracts obtained from immune CD8 lymphocytes are effective against allergies, but also against viral diseases such as herpes, or SAIDS (32), most likely because in the latter, the CTL component within the CD8 population is crucial. Indeed, the CTL play an important role in the control of viral diseases, as has been discussed with regard to herpes (22). By contrast, extracts derived from the suppressor lymphocyte sub-population within the CD8 cells are active in allergic or autoimmune disorders. Obviously, this is an area with great clinical interest and potential.

The black box effect. Despite its huge potential, transfer factor’s extraordinary replicative property has been exploited only sparingly in producing preparations with new specificities. However, since the beginning of clinical studies, TF has been obtained from patients’ household contacts and used to treat putative infectious diseases such as multiple sclerosis, Behçet’s syndrome, alopecia totalis, lupus erythematosus, chronic systematic epidermodysplasia, malignant tumours, neurological diseases such as Alzheimer’s disease, autism, amyotrophic lateral sclerosis and retinitis pigmentosa. In most instances, results have been impressive, reminding us incidentally that, because of genetic diversity, not all humans respond in the same fashion to one pathogen. Thanks to TF, the physician can obtain help from those who naturally resist a given microorganism, in order to treat those who are more vulnerable.

However, there is more to it. The TF supply from such household contacts is limited and it will usually benefit no more than one patient. But, an active-household-contact-TF can be replicated in tissue culture (4), and theoretically produce unlimited amounts, the donor’s immune system having already identified the pathogen, even if the physician ignores it. This is what I call the black box effect: the tissue culture cells function like a photocopier, receiving and reproducing blindly CMI information from the inducing TF molecules, in the absence of knowledge concerning the antigenic specificity.

We used this procedure to prepare HIV-specific TF in 1983 in my laboratory, long before the viral aetiology of AIDS was established. Such procedures could be applied for other emerging identified (e.g. Ebola, SARS) or unidentified viruses.

Preventative Activity. The most important potential for transfer factor lies in its use for prevention i.e., as a prophylactic vaccine addressing CMI. Reports have shown that when a virus-specific TF is administered before an encounter with the virus, the recipient is protected. The most significant studies in this respect are those of Steele, who was able to protect marmosets from a lethal herpes simplex virus 1 (HSV-1) injection using TF from a human HSV-1 positive donor (56) or leukaemic children from varicella zoster virus using a VZV-specific TF (13, 14), and those of my group, who managed to protect mice against a lethal injection of HSV (19).

When the benefits of conventional vaccines may be offset by often extremely serious side effects, as those reported in France for instance from the use of the hepatitis B vaccine, or those observed in several soldiers of the Gulf Wars, the study of utilising TF for prophylaxis is of paramount interest.

Molecular observations and speculations. The current reluctance to reconcile facts with theory and imagine the transfer of information by a small peptide should not be a deterrent, but rather a stimulus for research. One should not forget that half of the central dogma of molecular biology i.e., transfer of information from RNA to DNA, was blasted more than a quarter of a century ago, resulting in a Nobel Prize, shared by Temin and Baltimore in 1975, whilst the present prion threat, based on a protein-to-protein transfer of information mechanism theory, although not sufficiently understood to be controlled, won the 1997 Nobel Prize for Medicine to Prusiner. One can wager that, for the daring and stubborn young scientist who continues the now seemingly perilous path of transfer factor, another Nobel Prize lies ahead. For all leads point out that the transfer of information by the TF is not a trivial artefact.

It is hoped that the facts and arguments presented briefly here will continue to propel further study of transfer factor molecules, which will provide leads to elucidate the immunological and biological riddle underlying their mode of action. For the unavailability of the amino terminus for sequencing cannot remain an insurmountable problem. Recent work has partially solved the amino-acid sequence riddle, identifying conserved sequences (i.e. LLYAQDLEDN), thus giving biochemical flesh to a still elusive entity (57).

References

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