, ISSN: 0684-4551
Biotecnologia Aplicada 12 (1):16-22 (1995)
ARTICULO ORIGINAL COMPLETO / ORIGINAL FULL PAPER
CLINICAL AND IMMUNOLOGICAL EVALUATION OF ASTHMATIC PATIENTS
IN A DOUBLE BLIND TREATMENT PROTOCOL WITH TRANSFER FACTOR
Maria Cristina Di Prisco^1, Juan Carlos Jimenez^1 and Pedro
^1 Biomedicine Institute, Central University of Venezuela,
P.O.Box 4043, Caracas, Venezuela. ^2 Center for Genetic
Engineering and Biotechnology. P.O.Box 6162, Havana 6, C.P.
Recibido en febrero 1994. Aprobado en marzo de 1995.
Key words: Extrinsic asthma, Transfer Factor.
We evaluated clinically and immunologically the therapeutic
effect of Transfer Factor (TF) in 17 patients with mild or
moderate-severity extrinsic bronchial asthma. TF (1 U) or
placebo was administered following a double blind protocol
during 6 months (32 doses). The immunological evaluation of
the patients and of 21 normal individuals, consisted in
immediate hypersensitivity skin tests for common
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environmental allergens, delayed hypersensitivity tests
(DH) for tuberculin (PPD), C. albicans
and T. rubrum
serum IgE (PRIST), specific serum IgE (RAST), eosinophils
count, and CD3+, CD4+ and CD8+ lymphocyte subpopulation
counts using the avidin-biotin method. The patients
presented 3.05 +/- 1.6 crises per month and used frequently
beta-adrenergic drugs and teofiline. Before treatment,
there was a higher proportion of positive allergic
reactivity skin tests (p < 0.01), higher serum IgE levels
(p < 0.001) and eosinophils counts (p < 0.01) among
patients than in controls. The CD3+ lymphocyte percentage
was less in the patients (p < 0.05) as well as the
intensity of the DH tests for C. albicans
and T. rubrum
< 0.05). These data confirm the atopic condition of the
selected patients. After treatment, there was clinical
improvement, decrease in the frequency of crisis as
compared to before treatment (p < 0.001), decrease in the
frequency and intensity of cough (p < 0.003) and in the use
of conventional drugs (p < 0.002). The DH response to PPD
and C. albicans
was more intense after treatment (p <
0.02). CD3+, CD4+, and CD8+ subpopulations were not
modified, so it will be convenient to study T-cell function
further. These results indicate that TF improved the
clinical condition but did not modify DH reactivity of the
patients. The normalization of the cell immunity tests
could be associated to clinical improvement, but the
correlation between these immunological and clinical
parameters requires a larger number of evaluations.
Evaluamos clinica e inmunologicamente el efecto terapeutico
del Factor de Transferencia (FT) en 17 pacientes con asma
bronquial extrinseca de severidad leve o moderada, bajo un
protocolo a doble ciegas aplicando 32 dosis (1 U/mL) del FT
o de placebo durante 6 meses. La evaluacion inmunologica de
los pacientes y de 21 individuos normales, consistio en
pruebas de piel para hipersensibilidad inmediata para
alergenos ambientales comunes, y retardada (HR) para
tuberculina (PPD), C. albicans
y T. rubrum
, IgE serica
total (PRIST), IgE serica especifica (RAST), eosinofilia y
cuantificacion de subpoblaciones linfocitarias CD3+, CD4+ y
CD8+, con el metodo de la avidina biotina. Los pacientes
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presentaron 3.05 +/- 1.6 crisis por mes y utilizaban
frecuentemente beta-adrenergicos y teofilina. Antes del
tratamiento, el estudio de la reactividad alergica en piel
demostro un porcentaje de positividad mas elevados en los
pacientes que en los controles (p < 0.01), niveles de IgE
serica total y eosinofilia tanbien mas elevados en
pacientes que en controles (p < 0.001 y p <0.01
respectivamente). El porcentaje de linfocitos CD3+ fue
menor en los pacientes (p < 0.05), y asi mismo la
intensidad de las pruebas de hipersensibilidad retardada
para C. albicans
y T. rubrum
(p < 0.05). Estos datos
confirman la condicion atopica de los pacientes
seleccionados. Despues del tratamiento se observo mejoria
clinica, se demostro una disminucion en el numero de crisis
de asma por mes comparado con el numero de crisis antes del
tratamiento (p < 0.001), disminucion de la frecuencia e
intensidad de la tos (p < 0.003) y disminucion del uso de
medicamentos convencionales (p < 0.002). La respuesta
hipersensibilidad retardada al PPD y a C. albicans
intensa despues del tratamiento (p < 0.02). Las
subpoblaciones CD3+, CD4+, y CD8+ no se modificaron despues
del tratamiento, por lo que seria adecuado estudiar con mas
profundidad la funcion de celulas T. Estos resultados
indican que el FT mejoro la condicion clinica y no modifico
la reactividad de HR de los pacientes. La normalizacion de
las pruebas de inmunidad celular podria estar asociada a la
mejoria clinica, sin embargo, la asociacion entre estos
parametros inmmunologicos y clinicos requiere mayor numero
Different studies have shown that patients with extrinsic
asthma have high allergic reactivity to common
environmental allergens (Rackemann, 1947), high levels of
total serum IgE (Ishizaka, 1981), and increased eosinophils
count in peripheral blood and sputum (Fukuda et al
They often show low cell-mediated immune response toward
specific antigens (Leung and Geha, 1986), and a high
susceptibility to viral and bacterial infections (Busse,
1991). Many therapeutic methods have been applied to these
patients, but the results are seldom fully satisfactory.
Some of these procedures represent a high risk to the
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patient for adverse side effects during or after the
treatment (Spitzer et al
., 1992). Therefore, the evaluation
of new, non-conventional treatment protocols in these
A dialyzable extract obtained from peripheral blood
leukocytes, called Transfer Factor (TF), has been used in
the treatment of a variety of viral (Cabezas- Quiroga et
., 1990) bacterial, fungal (Corbiel et al
., 1984) and
parasitic infections (Delgado et al
., 1981), that are often
associated to a depressed cell-mediated immunity (Carey et
., 1987). TF has also been used in patients with
malignant diseases who have similar immunological
alterations (Miller et al
TF is a non immunogenic preparation containing low
molecular weight molecules, capable of transferring
immunological information to non responder individuals,
mainly for delayed hypersensitivity reactions (Lawrence,
1955). It is well known that atopic patients frequently
show severe viral or fungal infections and asthmatic
patients may specifically suffer respiratory infections
that worsen their clinical picture (Lemanske et al
Therefore, asthmatic patients with a possible depression of
cell-mediated immunity are candidates for TF treatment.
The aims of this study were to evaluate the therapeutic
effect of TF on the clinical symptoms of extrinsic asthma
patients and its possible modulation of their immunological
MATERIALS AND METHODS
We evaluated 17 patients (mean age 29.5 +/- 14.0 years)
with extrinsic asthma, of low (5 crises per year) to
moderate (5 to 12 crises per year) severity. None of the
patients had been treated with specific hyposensitization
or systemic steroids. No respiratory infection was detected
in any of the patients. A control group consisting in 21
healthy subjects (29.2 +/-8.0 years), with no family or
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personal atopic history was used for comparison of baseline
data. The patients' written informed consent was obtained,
and the study was approved by the Ethical Committee of the
We used a dialyzable extract from normal human blood donor
leukocytes, previously induced by Sendai virus to stimulate
interferon alpha production (Fernandez and Lopez, 1986).
The TF was prepared at the Center for Biological Research,
We performed a randomized double-blind, 6 month protocol.
Nine patients were treated with TF and 8 patients received
placebo (saline solution pH 7.2). One unit of TF
(equivalent to the extract obtained from 5 x 10^8 total
leukocytes) or the placebo was administered subcutaneously,
twice weekly for 8 weeks and then once weekly up to 6
months. Each patient received 34 units. Patients were
clinically evaluated monthly and were allowed to use
conventional treatment when necessary: 2 or 3 daily doses
Symptom severity was evaluated according to the Institute
of Biomedicine, Caracas, Allergy Clinic scale. Treatment
administration, as well as all clinical and laboratory
evaluations were done blindly. The code was broken only for
Immediate hypersensitivity skin testing
Cutaneous prick tests were performed with partially
purified extracts of common environmental allergens. These
were: house dust, Dermatophagoides pteronyssinus,
Aspergillus fumigatus, niger
and flavus, Rhizopus sp,
Hormodendrum sp, Alternaria sp, Fusarium sp, Candida sp,
house mosquito, fly, butterfly, honey bees,
cockroach, dog and cat epithelia, Melinis minutiflora
pollen, Ascaris lumbricoides
antigens, negative control,
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histamine (Linch et al
., 1984). Positive reactions were
taken as immediate wheal diameters of equal to or larger
Delayed hypersensitivity skin testing
Delayed hypersensitivity tests were performed before and
after the 6 month treatment, with tuberculin (PPD; 2 IU/
0.1 mL), Candida albicans
antigens (300 mg/mL) and
antigens (1:100). Positive reactions
were recorded when a 10 mm or larger induration was
Serum IgE levels
The PRIST (Phadebas, Pharmacia, Sweden) technique for the
measurement of total serum IgE level was used. The results
were expressed in international units (IU/mL).
A paper disk RAST technique (Ceska and Lundkvist, 1972) was
used for the measurement of specific IgE against common
environmental allergens (Wide et al
., 1967).The positivity
of the tests for specific IgE was taken as 0.35 PRU/mL
(level 1), according to the Phadebas
Blood eosinophils counts
Differential eosinophils counts were performed on blood
T cell subpopulations assay
The monoclonal antibodies ior-T3, ior-T4, and ior-T8 were
prepared at the Center of Molecular Immunology, La Habana,
Cuba. These antibodies were used at the following
dilutions: 1:20, 1:5 and 1:200 respectively.
Twenty milliliters of heparinized blood was obtained by
venepuncture and lymphocytes were separated using a
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Histopaque (Sigma) density gradient. The cells were
resuspended at 2 x 10^6 cells/mL and smears were prepared.
The immunostaining was performed using the avidin-biotin
immunoperoxidase technique (Hsu et al.
, 1981), as modified
by Hoffman et al
. (1982). The slides were sequentially
incubated for 30 min. at 25 C with normal horse serum
diluted 1:20 in PBS, then primary mouse monoclonal
antibody, biotinylated horse antimouse antibody (50 mg/mL)
(Vector, Burlingame, Calif.), and the avidin- peroxidase
complex (Vectastain kit, Vector). Five-minute washes with
PBS were performed between the incubation steps.
The slides were then incubated with aminoethyl carbazole in
the presence of hydrogen peroxide for 10 min. After a 5
min. washing they were counterstained with methyl green,
washed again for 5 min. and mounted in glycerol-gelatin.
A total of 200 cells was counted under standard light
microscopy, and the percentage of positive cells for each
The results were expressed as group means and were compared
by the Student's t- test for unpaired and paired data.
The total and specific IgE levels were logarithmically
transformed and the means +1 standard deviation were
calculated and compared by the Student's "t" test.
The group of 17 asthmatic patients who participated in the
protocol showed symptoms of low or moderate severity
according to the scale used (table 1). Fourteen were
classified as mild asthmatics and 3 suffered of moderate
asthma. The non asthmatic control individuals were all free
of symptoms and family or personal history of atopy. The TF
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and placebo treated groups were equivalent for age, sex and
severity of symptoms before treatment.
Clinical results. Severity of symptoms of asthmatic
Tf group Placebo group
Before After Before After
1.77 +/- 0.9^ * 0.55 +/- 0.70 1.38 +/- 1.10 0.74 +/- 1.1
2.11 +/- 0.6 1.22 +/- 0.90 2.00 +/- 0.75 1.25 +/- 1.0
1.66 +/- 1.1 0.80 +/- 1.10 1.50 +/- 1.10 0.80 +/- 1.1
1.77 +/- 0.8 ^**0.66 +/- 0.86 1.75 +/- 1.00 0.63 +/- 0.7
3.12 +/- 1.7^ ***1.25 +/- 1.10 2.62 +/- 1.50 1.75 +/- 0.4
During TF treatment patients did not show any secondary
adverse reaction. Controls were not treated.
Before TF therapy, skin testing showed a higher percentage
of positivity towards house dust (p < 0.001),
. (p < 0.0l), insects (p < 0.01) and A.
antigen (p < 0.05) in patients, as compared to
normal controls. Patients also had higher levels of total
serum IgE (p < 0.001) and eosinophils counts (p < 0.001)
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than controls (table 2). These results confirmed the atopic
background of the asthmatic patients.
Total serum IgE levels and peripheral blood eosinophils
Before TF group (9) Placebo group (8)
All patients Control Before After Before After
(2253.5) (622.7) (1630) (4120) (846) (2128)
^*9.8+/-5.3 2.2+/-1.6 9.8+/-5.0 11.1+/-4.0 9.8+/-5.0 14.1
Total serum IgE levels are expressed as geometric mean +
Eosinophils are expressed in percentages of the whole
^ *p < 0.001 patients vs. control before treatment
^**p^ < 0.05 TF group before and after treatment
Delayed hypersensitivity reactions and T cell subpopulations
Before treatment, the skin test responses to C. albicans
and T. rubrum
antigens were smaller (p < 0.05) in patients
than in controls (table 3). Similarly, the number of CD3+
positive T cells was less in the patients than in the
controls (69 +/-10% vs
. 76 +/- 5%; p < 0.05). No difference
was detected in CD4+ and CD8+ markers.
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Delayed hypersensitivity reaction before and after treatment
BeforeTF group (9)Placebo group (8)
All patients Control Before After Before
146+/-187 124+/-147 146+/-185 *250+/-232 181+/-199 139
&150+/-244 302+/-335 61+/-72 *681+/-852 264+/-399 970
&56+/-146 148+/-267 101+/-187 109+/-220 0+/-0 1
Values are mean +/- SD of the induration size (mm^2)
^**p < 0.05 TF group after vs. before treatment
Evaluation after treatment
Evaluation of the TF and placebo groups was performed
immediately after the six months of treatment (table 1). TF
patients showed a statistically significant decrease in the
number of asthma crises per month (p < 0.001), cough
episodes (p < 0.003) and utilization of conventional
treatment (p < 0.002). No differences were detected in
wheezing. No differences were found when symptom severities
were compared between the TF and placebo groups.
The positivity percentage in immediate hypersensitivity
skin tests did not show substantial changes after
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treatment. Nevertheless, an increased allergic reactivity
towards A. lumbricoides
antigen (p < 0.05) was detected in
the TF group (figure 1). The levels of specific IgE
antibodies toward house dust, Dermatophagoides sp,
antigens, insects and molds, are shown
in table 4. The total serum IgE levels and peripheral blood
eosinophils counts increased after treatment in the TF
Specific serum IgE in asthmatic patients before and after
Allergens All patients (17) FT (9) Placebo (8)
Home dust 3.13+/-3.5 2.57+/-2.3 1.68+/-1.7
1.97+/-1.0 2.0+/-1.86 0.34+/-0.4
1.45+/-0.7 2.30+/-1.7 ND
Values greater than 0.35 PRU/mL were considered positive
Delayed hypersensitivity reactions and T cell subpopulations
TF treated patients showed an increase response towards PPD
and C. albicans
antigens (p < 0.05) when compared with
their previous responses. However, when the TF group was
compared with the placebo group no significant differences
Although a tendency toward an increase in the peripheral
blood lymphocyte subpopulations was observed, no
statistically significant differences were detected after
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The immunological response of asthmatic patients is a key
aspect of the etiopathology of bronchial asthma. The most
important immunological alterations found in this disease
are a high allergic reactivity toward common environmental
allergens (Zimmerman et al
, 1988), activation of CD4+
lymphocytes associated with previous sensitization to
environmental allergens, which induce a high IgE production
(Corrigan and Kay, 1990) and high peripheral blood and
bronchial eosinophilia (Gleich, 1990).
The etiopathology of asthma is complicated by multiple
immunological and non immunological factors like a specific
genetic pattern and abnormal biochemical responses, such as
a low sensitivity threshold to histamine and beta
We developed a treatment protocol using TF, which is
capable of modulating the immunological response.
The characterization of the asthmatic patients before
treatment revealed their atopic background, compared with
The clinical evaluation revealed a statistically
significant improvement of the symptoms in the TF group
after treatment. Similar results have been reported by Feng-
Yizhen et al.
(1990), after the application of 10 to 24
doses of TF in a 6 month period. These authors found a
decreased frequency and severity of asthmatic crises and
reduced use of conventional anti-asthmatic drugs. Our
results also agree with Khan et al.
demonstrated clinical improvement in a double blind cross-
over study of 15 asthmatic patients. In the present study
no difference was found when we compared the severity of
the symptoms between the TF and the placebo group, probably
due to the small number of patients evaluated.
No changes were found in the immediate hypersensitivity
skin tests toward common environmental allergens after
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treatment. However, we detected a significant increase in
the skin test response to A. lumbricoides
in the TF group.
There is no published information available on the
influence of TF on immediate hypersensitivity reactions,
particularly on skin tests. Therefore, the change in the
allergic response to A. lumbricoides
might be associated
with an increased prevalence of intestinal parasitism in
this group of individuals. We could not confirm this
possibility as we did not perform feces examination.
The specific IgE levels to common environmental allergens
did not show changes after treatment. Nevertheless,
increased anti-A. lumbricoides
IgE levels were detected in
It is possible that a longer evaluation of the patients is
necessary to detect clearer variations in IgE levels.
Indeed, data obtained from patients under specific
hyposensitization treatments show that changes in IgE
levels occur only slowly during treatment (Peng et al
Reports in the literature are variable in this respect.
Some authors report no changes (Khan et al.
, 1978; Lu,
1983) while others have found reductions (Feng-Yizhen et
, 1990; Zhao et al.
, 1990) on IgE levels after TF
TF treatment produced a significant increase of the delayed
hypersensitivity reactions when these were compared with
the placebo group. This confirms the previous results of
Khan et al.
, (1976; 1978) and Fan et al.
, (1990). These
authors demonstrated the capacity of TF to transfer these
reactions to non-responder individuals.
The immunological mechanism of this transferred response
could be related to the action of TF on naive T cells,
inducing their capacity for a specific response. The other
possibility is that TF could act on memory T-cells and be
integrated as a part of the T-cell receptor, producing a
stronger secondary response (Dwyer, 1990). These ideas
could support the future possibility of therapeutic trials
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based on the binding capacity of peptides, which may
compete with MHC class I and II to modulate the
immunological response in allergic diseases (O'Heir et al.
1991). Moreover, TF could link to MHC class II molecules
and thus prevent specific T cell activation toward
allergens and subsequent IgE synthesis.
The quantification of CD3+, CD4+ and CD8+ peripheral blood
T lymphocyte subpopulations did not show significant
changes after TF treatment. Other studies have shown that
patients with extrinsic asthma treated with TF increased
their number of CD3+ and CD4+ peripheral blood populations
(Zhao et al.
, 1990). Nevertheless, the possibility that
other aspects of cell mediated immunity, more related to
the function of these cells in allergy, and not only to
their number, has to be explored. For example, serum IL-4
levels, soluble CD23 receptors or T-cell activation markers
may provide relevant data on T cell regulation and function
Different results have been reported in various treatment
protocols of TF therapy in asthma, probably due to the non-
standardized potency of the TF lots. It would be very
important to develop an in vitro
analysis to standarize the
actual potency of the different fractions used and
determine the optimal dose according to its biological
activity, and not only the number of cells used.
The present work demonstrates the importance of performing
new and more detailed clinical trials on the use of TF as a
non conventional treatment in extrinsic asthma patients.
Future studies must be more precise on dose, period of
treatment and the possible mechanisms by which TF modulates
the allergic responses in extrinsic asthma.
This work was supported by the Consejo de Desarrollo
Cientifico y Humanistico, Central University of Venezuela.
We gratefully acknowledge Dr. Guillermo Isturiz for his
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fundamental assistance in Neumonology.
We are very grateful to Dr. Neil Lynch for his helpful
We also thank Ms. Emperatriz Mata for her excellent
transcription of data and secretarial assistance.
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