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SENSITIZATION AND EXACERBATION OF ALLERGIC DISEASES
BY DIESEL ENGINE PARTICLES
David Diaz-Sanchez
University of California School of Medicine

Most studies of the health effects of diesel exhaust have focused on
the controversial issue of its role in cancer. However, recently the
role of combustion products such as diesel exhaust particles (DEP) in
modulating the immune response has garnered much attention. In
particular the effect of DEP on allergic and asthmatic diseases has
been the focus of many studies. A link between industrialization and
allergic disease has long been presumed. Indeed, only 50 years after
the first recorded reported case of allergy in 1819, Charles Blackely


al. (1987) found that people in Japan living on busy roads lined with
cedar trees have more allergies to cedar than residents living on
similar streets with much less traffic. Since that time other
epidemiological studies have reported similar findings. Kramer, et
al., showed that hay fever is greater in residential areas with heavy
truck traffic, while Weiland, et al., reported that allergic symptoms
correlate with the distance of residences to roads with heavy traffic.
The studies cited above have sparked renewed focus on the role of
fossil fuel combustion products on allergic inflammation. Because of
their universal nature, indoor concentrations of these products often
equal or exceed those found in ambient outdoor air. Consisting of an
inert carbon core containing unburned fuel petrochemicals, DEP have
been used as model pollutants to understand the mechanisms involved.
Much of the experimental work on pollution and allergy has centered on
the ability to alter immuneoglobulin production. The formation of the
allergic antibody IgE is central to the development of both allergy
and asthma. Muranaka et al. (1986) published the first demonstration
that DEP could have an adjuvant activity. Instillation of a protein or
a common pollen (Japanese cedar pollen) mixed with DEP and injected
int****ritoneally enhanced the production of allergic antibody in
mice. Shortly after Takafuji, et al., demonstrated an identical effect
if an intranasal route of administration was used. Since then, these
studies have been repeated with variations many times by multiple
groups, and DEP is consistently shown to have similar effects on
allergic antibody production if administered intratracheally or by
aerosol. A major advantage of using DEP as a model pollutant has been
the ease by which animal models have been transferred into human
studies. These studies have categorically shown the potential of DEP
to induce and exacerbate allergic antibody responses in the human
upper respiratory tract (Diaz-Sanchez
2000, Diaz-Sanchez, et al., 1994, 1999). Human allergic volunteers
were sprayed in the nose with DEP, ragweed pollen or both
simultaneously. DEP was used at doses ranging up to 0.15 mg into each
nostril. Although this dose may seem high, in certain occupational or
everyday settings (such as waiting at a bus stop) exposure to DEP can
be much higher. Nasal washes were performed at different days after
challenge. At the peak of the response, the amount of allergic
antibody to ragweed was 16-fold higher following ragweed plus DEP
challenge compared to ragweed alone. In certain individuals it was up
to 50-fold greater. In addition, DEP increased the severity of
allergic symptoms to pollen and the levels of histamine, a key
chemical mediator that causes many of the symptoms. Unfortunately, it
has been difficult to perform similar investigations on the lower
airways in humans. In a series of studies headed by Dr. Sandström,
volunteers have been exposed to diesel exhaust (Rudell et al. 1996).
However, until now these studies have been limited to normal healthy
subjects. Non-smoking subjects were exposed for 1 hour to diluted
diesel exhaust and lung biopsies and lavages performed before and
after exposure. Increased number of inflammatory cells were found in
the airways following exposure; similarly, there was an increase in
histamine levels and increased levels of inflammatory mediators and
molecules. Additionally, decreased macrophage function was observed.
If similar findings were found in asthmatic subjects, one would expect
a worsening of the disease. Several agents have been shown to cause
exacerbation of allergic disease, but few have been demonstrated to
increase the frequency of allergy, that is induce allergic
sensitization. Sensitization is defined as the ability to cause an
allergy to a substance that was previously “harmless.” We
addressed the question of whether DEP can make subjects allergic to a
“neo-allergen,” that is a protein to which subjects have
never encountered before. Keyhole limpet haemocyanin (KLH), found in
the blood of an inedible water mollusk, is just such a protein.
Allergic subjects given repeated doses of KLH produced no allergic
antibodies and no allergic symptoms. In contrast, 60% of subjects who
received DEP 24 hours prior to each KLH exposure produced allergic
antibodies and showed allergic symptoms. It is unlikely that
pollutants can convert a non-atopic into an atopic individual;
however, these studies imply that DEP and similar combustion
pollutants may cause those with the appropriate genetic predisposition
to become sensitized to pollen and other proteins to which they may
not otherwise have become sensitized. Is the effect of DEP on the
human allergic response due to its particulate nature or the chemicals
it contains? To answer these questions, we have repeated the human
exposure experiments above using either 1) carbon black, which is
elemental carbon virtually devoid of chemicals, or 2) phenanthrene, an
important hydrocarbon found in diesel. While carbon black caused
inflammation, phenanthrene caused immunological changes (Table 1). One
of the most common treatments for severe hay-fever is the use of nasal
steroids. It should be noted that while normal doses of steroids will
block pollen-induced allergic responses, they have no effect on
DEP-enhanced responses. In addition, since DEP increases histamine
levels, it is probable that normal doses of antihistamines (the most
common allergy medication used) will also be less effective. Table 1
The effect of a model hydrocarbon and a model chemical-free carbon
particle on human immune responses. Phenanthrene Carbon Black Allergic
antibody Cellular inflammation Symptoms Chemical mediators In
conclusion, we need to ask whether diesel is unique. While DEP
obviously has properties missing from other particles such as carbon
black, it should be noted that allergic endpoints can be increased in
cellular and mouse models by secondhand smoke, fly ash, phenanthrene,
benzo(a)pyrene and TCDD. Therefore, while DEP is an excellent model to
study the role of particulate pollution on allergic disease, it is
likely that many of the results and underlying mechanisms are common
to most combustion products. Acknowledgment This work was supported by
a United States Public Health service grant, AI-34567 (UCLA Asthma,
Allergy, and Immunologic Disease Center), funded by the NIAID and the
NIEHS.


Key References
1. Diaz-Sanchez, D. 2000. “Pollution and the
Immune Response: Atopic Diseases--Are
We Too Dirty or Too Clean?” Immunology
101:11-18.
2. Diaz-Sanchez, D., Dotson, A.R.,
Takenaka, H., Saxon, A. 1994. “Diesel
Exhaust Particles Induce Local IgE
Production In Vivo and Alter the Pattern of
IgE Messenger RNA Isoforms.” The
Journal of Clinical Investigation 94:1417-
1425.
3. Diaz-Sanchez, D., Penichet-Garcia, M.,
Wang, M., Jyrala, M., Saxon, A. 1999.
“Nasal Challenge with Diesel Exhaust
Particles Can Induce Sensitization to a
Neoallergen in the Human Mucosa.” The
Journal of Allergy and Clinical Immunology
104:1183-1188.
4. Ishizaki, T., Koizumi, K., Ikemori, R.,
Ishiyama, Y., Kushibiki, E. 1987. “Studies
of Prevalence of Japanese Cedar
Pollinosis Among the Residents in a
Densely Cultivated Area.” Annals of
Allergy 58: 265-270.
5. Muranaka, M., Suzuki, S., Koizumi, K.,
Takafuji, S., Miyamoto, T., Ikemori, R.,
Tokiwa, H. 1986. “Adjuvant Activity of
Diesel-Exhaust Particulates for the
Production of IgE Antibody in Mice.” The
Journal of Allergy and Clinical Immunology
79: 639-645.
6. Rudell, B., Ledin, M.C., Hammarstrom, U.,
Stjenberg, N., Lundberg, B., Sandstrom, T.
1996. “Effects on Symptoms and Lung
Function in Humans Experimentally
Exposed to Diesel Exhaust.” Occupational
and Environmental Medicine 53: 658-662.