Transfer factor

Transfer factor (TF) is an extract of low molecular weight containing several lymphokine molecules with immunomodulating properties. It has been described for the first time by Lawrence in the early ‘50s. It seems capable of transferring antigen-specific information to T-lymphocytes, and it is present in the lymphocytes of mammals and birds. It has been widely used over the past forty years in the treatment of viral, parasitic, fungal infections and allergic disorders, as well as immunodeficiencies, neoplasias, viz. cancer of the lung and prostate. Encouraging clinical results have also been observed in patients suffering from candidiasis and tuberculosis.

It has been thought that the potential of this compound for answering the challenge of unknown pathogenic agents is considerable as is its preventative potential. Data have shown that antigen-specific TF administered before a viral infection can prevent the onset of the disease, TF acting as a preventative vaccine based on cell mediated immunity.

Its molecular structure has only partially been unravelled. It seems that to a small peptide (ca. 5000 DA) are attached 2-3 ribonucleotides. However, this lack of knowledge did not prevent its clinical use since it is possible to produce large quantities of specific transfer factor in tissue culture or in immunised animals.

HISTORY, PROPERTIES AND THERAPEUTIC EFFECTS
The first observations postulating the existence and establishing the concept of transfer factor dates from the early 1950s when H.S. Lawrence showed that delayed type hypersensitivity (DTH) to a given antigen could be transferred from one individual to another via cell-free 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 and he surmised that its molecular weight was less than 12,000 Daltons, as it filters through a standard dialysis bag. Since that time, all transfer factor preparations for clinical and experimental studies 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 fifteen hundred reports have confirmed Lawrence’s original observations and established that the dialyzable extracts thus obtained are capable of transferring specific immune information in vitro to naïve lymphocytes or in vivo to patients or experimental animals. This information concerns only cell-mediated but not humoral immunity, 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.

Since the early 70’s, transfer factor has been used more often than not successfully for the treatment of viral, parasitic, fungal infections, and also as an adjuvant treatment in autoimmune, allergic and malignant disorders. Its apparent success is of no surprise since cell-mediated immunity (CMI) plays a crucial role in the control of infectious, parasitic, and autoimmune diseases, as well as cancer.

Because the TF extract is usually obtained from the total lymphocyte population containing helper and suppressor lymphocytes, it acts as a modulator of the immune system. It boosts the immune defences when required, e.g. in infectious, malignant or genetically impaired immune disorders or it exerts a suppressing effect on a hyperactive immune system when its down-regulation is desirable, e.g. in allergic disorders.

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. It is known that the dialyzable extract containing the TF molecules also contains other low molecular weight lymphokines e.g. IMREG 1 and 2. Thus, 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.

It seems that the total dialysate obtained from peripheral lymphocytes is a cocktail of molecules that provide immunoregulatory activity, in addition to the adoptive transfer of novel antigenic specificities to the immunological memory of the recipient. Hence the qualification of TF as an immunomodulator, i.e. a lymphokine with immunomodulatory activity mediating adoptive immunity, in contrast with so-called active (antibody induction by immunisation with the corresponding antigen) or passive (mediated by antibody injection) immunity.

Nonetheless, and notwithstanding encouraging 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.

Until 1974, the only source of transfer factor was pooled leucocytes from blood donors, which limited material supplies, 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 material used was practically unknown, but presumably large, since each batch reflected the collective immune experience of several individuals. For this reason, these preparations were improperly called “non-specific”, indicating multiple but unknown specificities.

Thus, despite several encouraging reports in the early 1970s, 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, Viza and co-workers reported that TF with known specificities could be replicated in tissue culture, using a lymphoblastoid cell line. In the late 1970s, the same group and other investigators presented evidence that specific TF obtained from mammals after immunisation with a given antigen was also active in humans.

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

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 spectacular results. Biochemical studies have already produced evidence that the molecule responsible for the transfer of the antigenic specificity is a small peptide with a molecular weight of approximately 5000 DA, and it has been suggested that two to three ribonucleotides are attached to the peptide. Unfortunately, attempts at sequencing the peptide have failed, because of the presence of a blocked amino terminus.

The transfer of antigen-specific CMI information by this extract 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 proven totally acceptable.

The specificity issue thus remains one of the essential problems. TF dialysates contain non-specific immunoregulatory molecules which can usually enhance and, in certain cases, down-regulate CMI. Two such molecules named IMREG I and IMREG II were identified by Gottlieb and his co-workers. 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 with such rare antigens as coccidioidin or keyhole limpet haemocyanin (KLH) preclude non-specific enhancement of “lapsed” immunological memory. Several human and animal studies have established that TF is capable of transferring CMI to rare antigens that the recipient is unlikely to 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. 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 derives from T-helper cells, suppressor factor from T-suppressor cells.

Be that as it may, TF’s characteristics (low molecular weight, undefined chemical structure, unconventional mode of action, protein-like nature but resistant 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 by conventional methods, has led scientists to doubt its very existence.

Despite promising results and hundreds of publications, failure to explain TF’s mechanism of action and define its molecular structure aroused doubts about its very existence. And even though recent work by Kirkpatrick has partially determined an amino-acid sequence (LLYAQDLEDN), thus giving some biochemical reality to the elusive moiety, no further publication has confirmed and complemented these data since.

Moreover, the pharmaceutical industry did not pay sufficient attention to this moiety because of the prohibitive costs of bringing a new medicine onto the market and the lack of patent protection (the impossibility of filing patents after decades of published academic work). In addition, the difficulties involved in production made commercialisation unviable. And a compound producing such astounding results as those described in scientific literature, which has not been on the market for so many years, gradually begins to lose its credibility. As for the commercial preparations obtained from colostrums and today available via the internet they scarcely increased the credibility of the product. Their acclaimed effects have never been tested or confirmed independently, neither in vitro nor in vivo, and the alleged clinical improvements cannot thus be differentiated from a placebo effect.

CLINICAL RESULTS
Even if some clinical reports of the ‘70s are subject to justified criticism, hundreds of studies have established the efficacy of transfer factor in treating several pathologies. Its lack of toxicity and the absence of side effects made the use of this extract appealing. Moreover, despite current scepticism, no publication has ever rejected reported clinical claims. An impressive number of clinical studies have demonstrated the efficacy of transfer factor in treating and even preventing viral infections. For instance, Steele and co-workers were able to protect leukaemic children receiving chemotherapy from varicella zoster virus infections using varicella-zoster-specific transfer factor. In the early 1980s, Viza and Dwyer described significant improvement obtained by the use of herpes-simplex-virus-specific transfer factor in treating patients suffering from recurrent genital and/or labial herpes. The clinical observations were later corroborated by experiments in a mouse model.

Other clinical studies have shown that specific transfer factor may produce a spectacular improvement in acute cytomegalovirus (CMV) infections. Moreover, in Africa, children suffering from Burkitt’s lymphoma (a tumour caused by EBV) treated over a long period with EBV-specific TF showed a significant decrease in the rate of relapses. Other viral infections e.g. hepatitis B respond equally well to specific TF.

Transfer factor treatment has proven to be helpful in several neoplasias. One should cite the pioneering work of Fudenberg and that of Pizza. Osteosarcoma, melanoma, breast, lung, prostate and kidney cancer patients have benefited from TF therapy.

Parasitic infections also respond to TF therapy as the data of Sharma, confirmed by Delgado, in treating cutaneous leishmaniasis suggest. Other parasitic diseases known to respond effectively to TF are schistosomiasis and cryptosporidiosis, and several reports cite positive results obtained in treating patients with mycobacterial infections such as lepromatus leprosy, mycobacterium fortuitum pneumonia refractory to antibiotic therapy and tuberculosis. Chronic mucocutaneous candidiasis, an immunodeficiency characterized by chronically relapsing Candida albicans infections also responds well to TF treatment.