TRANSFER FACTOR: AN IMMUNOMODULATOR FOR FIGHTING
*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.
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.
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
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
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.
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
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
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
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
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
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,
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)
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
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
are both responsive, and sometimes spectacularly so, to TF therapy
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).
Production and Availability. In theory, the
in vitro production of specific TF has solved the availability
problem. Sequencing the molecule will render production by
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
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).
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