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Decrease of Specific and Total IgE Levels in Allergic Patients After BCG Vaccination
Preliminary Report
Giovanni P. Cavallo, MD;
Mariateresa Elia, MD;
Daniela Giordano, MD;
Cristina Baldi, MD;
Raffaella Cammarota, MD
Arch Otolaryngol Head Neck Surg. 2002;128:1058-1060.
ABSTRACT
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Background A systemic reaction to mycobacteria biases the balance of T helper cell
types 1 and 2 toward T helper cell type 1. BCG vaccination mimics some characteristics
of mycobacterial infection. Children who have undergone tuberculin conversion
after BCG vaccination seem to be more likely to lose their atopic symptoms.
Inhibition of both allergic response and airway hyperreactivity after vaccination
for mycobacteria has been observed in animal experiments.
Objective To evaluate the effects that BCG vaccination has on the serological
status of allergic people.
Participants and Methods This study included 20 volunteers with a history of allergic rhinitis
who were required to undergo BCG vaccination by Italian law. Epicutaneous
allergy testing with a panel of common seasonal and perennial inhalational
allergens and 2 blood withdrawals were performed. The serum total IgE levels
and the serum allergen-specific IgE levels of each individual were measured
just before BCG vaccination and again 4 months later. Total IgE levels were
determined using the paper radioimmunosorbent test, and allergen-specific
IgE levels were determined using the radioallergosorbent test.
Results Total IgE and allergen-specific IgE levels were significantly decreased
after BCG vaccination (P = .004 and P<.001, respectively).
Conclusion BCG, an effective stimulus for cell-mediated immunity, deserves further
study to evaluate its ability to modulate the immune response associated with
allergic rhinitis.
INTRODUCTION
T HELPER CELLS play a critical role in controlling immune responses.
According to their pattern of cytokine production, T helper cells are classified
into functionally distinct subsets, including type 1 (TH1) and
type 2 (TH2) cells.1-4
The TH1 cells mainly produce interleukin (IL)-2, interferon  ,
and tumor necrosis factor ß, whereas the TH2 cells produce
IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. T helper type 1 cells are critical
for the induction of cell-mediated immunity and pathological disorders such
as diabetes. In contrast, TH2 cells bias the response toward antibody
production and allergy.5 Late phases of allergic
response are often associated with an increased expression of TH2-type
cytokines, such as IL-4 and IL-5. Interleukin 4 is essential for isotype switching
toward IgE, while IL-5, together with IL-4, switches antibody response toward
IgA.5-8
On the other hand, TH1 cells have a down-regulatory role in the
production of TH2 cytokines by releasing interferon .5, 7, 9
Differentiation between TH1 and TH2 is biased
by antigen dose and structure, the concurrence of distinct costimulatory molecules,
the kind of cells presenting the antigenic peptides, and the presence of particular
cytokines in the microenvironment.10-12
A TH1-TH2 imbalance with an increase in TH2
cells favors IgE production and the establishment of allergic reactivity.
In the last 20 years, allergies have increased in civilized countries.13 Residency in urban or industrial areas, changes in
lifestyle, and the falling incidence of microbial infections may be responsible
for this increase, to some extent. The diminishing incidence of tuberculosis
could well be one of the many contributing factors. A marked production of
TH1 cytokines is a hallmark of the systemic reaction to mycobacteria.
The subsequent inclination of the TH1-TH2 balance toward
TH1 may be responsible for an inverse association between exposure
to Mycobacterium tuberculosis and allergic diseases.14-15
Even if it is unlikely that BCG vaccination will entirely replace the
complex and long-lasting TH1 stimulation produced by mycobacterial
infection, it does mimic some of its characteristics. Children who have undergone
tuberculin conversion after BCG vaccination seem to be more likely to lose
their atopic symptoms.16 Moreover, a decrease
in IgE production and the inhibition of allergic response and airway hyperreactivity
after vaccination for mycobacteria have been observed in animal experiments.17-20
Our goal was to evaluate the effects of BCG vaccination on the serological
status of allergic persons.
PARTICIPANTS AND METHODS
From October to November 1997, volunteers were recruited at the Antitubercolosis
Dispensary, Turin, Italy. They were physicians, nurses, and medical students
who presented with negative Mantoux test results and were required by Italian
law to undergo BCG vaccination. Informed written consent was obtained for
epicutaneous allergy testing with a panel of common seasonal and perennial
inhalational allergens and, if the subject was enrolled in the study, for
2 blood withdrawals. Subjects with anamnesis of allergic rhinitis were probed
with epicutaneous allergy testing and were recruited into the study only if
the skin test was positive for at least one of the following allergens: mites,
cats, dogs, mixed molds, grass, or trees. The inclusion criterion was the
anamnesis of allergic rhinitis associated with a positive skin test result.
Subjects with a history of previous antiallergy vaccination, immunomodulatory
treatments, and anti-influenza vaccination were excluded. A total of 17 women
and 3 men (age range, 19-37 years) with a skin test that was positive for
a series of ubiquitous inhalational allergens were enrolled in the study.
Volunteers were required not to take any allergy medicines during the entire
study.
The serum total IgE levels and the serum allergen-specific IgE levels
of each individual were determined just before BCG vaccination and again 4
months later by means of commercially available enzyme immunoassay. The blood
samples of each subject, collected before and after BCG vaccination, were
labeled with a mark, coagulated at room temperature, centrifugated, frozen,
stored at -20°C, and tested with a unique assay at the end of the
collecting time. Total IgE levels (kU/L) were determined using a paper radioimmunosorbent
test (Pharmacia, Uppsala, Sweden). Allergen-specific IgE levels (kUA/L) for
an inhalational (seasonal or perennial) allergen against which the volunteer
was reactive were determined with a radioallergosorbent test (Pharmacia).
The levels of serum allergen-specific IgE determined before and after BCG
vaccination were calculated as the mean and SD of all the allergen-specific
IgE values. Statistical analysis of IgE variations was performed using a paired t test. For each patient, the levels of specific IgE before
and after BCG vaccination were calculated as the mean value of the allergen-specific
IgE values. The variation of serum specific IgE levels against perennial-only
allergens was also evaluated.
RESULTS
All the subjects enrolled in the study reported an anamnesis of allergic
rhinitis and demonstrated skin tests that were positive for at least 2 inhalational
allergens, while the tests of 11 of the 20 volunteers were positive for perennial
allergens.
Serum specific IgE levels, calculated as the mean value of the allergen-specific
IgE values of each patient, were lower in 18 of the 20 subjects 4 months after
BCG vaccination; only 2 cases demonstrated a slight augmentation (Figure 1). Total IgE levels in serum samples
obtained 4 months after BCG vaccination were lower in 18 of the 20 volunteers
(Figure 2).
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Figure 1. Specific IgE levels, calculated
as the mean value for each patient, before (t0) and 4 months after (t1) BCG
vaccination.
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Figure 2. Values of total IgE before (t0)
and 4 months after (t1) BCG vaccination.
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The levels of serum specific IgE determined before and after BCG vaccination,
calculated as mean ± SD of all the allergen-specific IgE values, were
25 ± 31 and 19 ± 27 kUA/L, respectively. Serum total IgE levels
determined before and after BCG vaccination were 269 ± 221 and 210
± 162 kU/L, respectively. Allergen-specific IgE and total IgE levels
were significantly lower 4 months after BCG vaccination (P = .004 and P<.001, respectively). Five
volunteers displayed negative radioallergosorbent test values (<0.35 kUA/L)
for one or more allergens to which they were positive before BCG vaccination.
The values of serum specific IgE against perennial-only allergens were significantly
decreased (P = .004) 4 months after BCG vaccination.
COMMENT
The requirements imposed by Italian law on obligatory BCG vaccination
of physicians, nurses, and medical students with negative Mantoux test results
enabled us to collect data from an allergic adult population with a fully
mature immune system before and after BGC vaccination. A significant difference
between the serum allergen-specific and total IgE levels determined before
BCG vaccination and 4 months later was evident from the analysis of the data.
The skin tests of the volunteers enrolled in the study were positive
for both perennial and seasonal allergens. However, the levels of serum specific
IgE against perennial-only allergens were also significantly decreased after
BCG vaccination, thus indicating that the decrease in specific IgE levels
was not related to a seasonal variation in IgE serum levels. BCG vaccination
induced a decrease in IgE serum levels; furthermore, it is notable that BCG
vaccination decreases a preexistent TH2 response in a nonspecific
manner.
The anti-influenza vaccination was considered an exclusion criterion
because it is usually performed in the fall, when mandatory BCG vaccination
is largely performed. Therefore, it may have introduced an unrelated modulation
of the immune system that adds an additional confusion factor.
The short-term effects of BCG vaccination were evaluated in terms of
the variation in serum IgE levels in adult subjects suffering from allergic
rhinitis. Controversial results are reported in other human studies on the
effect of BCG vaccination in asthmatic subjects.21-24
No significant difference in IgE levels was found in asthmatic patients who
were intradermally injected with Mycobacterium vaccae
compared with a placebo group.21 Wheezing BCG-vaccinated
children demonstrated no significant differences in IgE levels when compared
with a nonvaccinated group.22 The discrepancies
in our findings may be accounted for by the age of the vaccinated subjects,22 the time of vaccination,22
and the period in which the effects were evaluated.21-22
By contrast, fewer symptoms and increased interferon production were
described in rhinitic and asthmatic patients who were intradermally treated
with M vaccae.23 Furthermore,
successful BCG vaccination appeared to inhibit the development of atopic disorders
(including asthma) in children, although the preventive effect of BCG vaccination
did not last long.24 Our data supported the
findings that BCG vaccine would be able to reduce a preexistent TH2
response in persons with allergic rhinitis. A study of IgE serum levels in
adult asthmatic subjects before and after BCG vaccination would be an excellent
follow-up step to take.
More convincing data may emerge after long-term evaluation of the significance
and persistence of IgE responses in a larger number of subjects; however,
our preliminary findings indicate that BCG vaccination may be valuable for
modulating the allergic profile in atopic subjects. An accurate symptom evaluation
is not currently available. It is now being studied in detail on the basis
of the present serum data. The forthcoming results will be described separately.
CONCLUSIONS
Expansion of TH1 or TH2 can be selectively induced
using appropriate antigenic stimuli. The BCG vaccine is an effective stimulus
for cell-mediated immunity and may be used to modulate immune response in
atopic subjects to reduce allergic reactivity. The data from this study encourage
us to continue the study of the effects of BCG vaccination on the magnitude
and duration of IgE responses in a larger number of individuals in order to
set a protocol for its use in atopic subjects.
AUTHOR INFORMATION
Accepted for publication February 25, 2002.
This study was supported by grant 96.03034.CTO4 from the National Research
Council.
We wish to thank Guido Forni, MD, for his valuable support, as well
as all the personnel of the Antitubercolosis Dispensary, Turin, Italy.
Corresponding author and reprints: Giovanni P. Cavallo, MD, Dipartimento
di Fisiopatologia Clinica, I Clinica Otorinolaringoiatrica, University of
Turin, Via Genova No. 3, 10126 Turin, Italy (e-mail: mt.eli{at}virgilio.it).
From the Dipartimento di Fisiopatologia Clinica, I Clinica Otorinolaringoiatrica,
University of Turin, Turin, Italy.
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