|Defective Immune System Response to Smallpox Vaccine Detailed
in New Study
People with Eczema May Benefit From Finding
Scientists supported by the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health (NIH), have identified a defect
in the immune response of people with the skin condition atopic dermatitis that
puts them at risk of developing serious complications following smallpox vaccination.
Led by Donald Y.M. Leung, M.D., Ph.D., of the National Jewish Medical and Research
Center in Denver, the researchers used laboratory-grown human skin cells to show
that an immune system protein called LL-37 is critical in controlling replication
of vaccinia virus, the live virus that is the key component in standard smallpox
The investigators are part of NIAID’s Atopic Dermatitis and Vaccinia Network,
which was created in 2004 to integrate clinical and animal research aimed at
reducing the risk of eczema vaccinatum, a potentially deadly complication of
smallpox vaccination. Eczema vaccinatum occurs almost exclusively in people who
have a history of atopic dermatitis, a common, non-contagious skin disorder also
known as eczema.
“This new research, the first to be published by Atopic Dermatitis and Vaccinia
Network scientists, illuminates one potential mechanism leading to eczema vaccinatum
and improves our understanding of the immune responses to smallpox vaccine of
people with atopic dermatitis,” says NIAID Director Anthony S. Fauci, M.D.
Published in this month’s issue of Immunity, the study details how
the overproduction in skin cells of inflammation-promoting molecules called interleukin-4
and interleukin-13 (IL-4 and IL-13) hampers LL-37 activity in people with atopic
dermatitis. LL-37, a small protein produced in skin cells, is part of the body’s
first line of defense against invaders. Earlier research by Dr. Leung and his
colleagues suggested that LL-37 is critical in controlling the spread of vaccinia
In the current study, the investigators used skin samples taken from people
with atopic dermatitis (as well as samples taken from healthy volunteers without
skin disease and from people with another skin condition called psoriasis) to
further investigate how dysfunctions in the immune response of people with eczema
set the stage for eczema vaccinatum. When exposed to vaccinia virus, the skin
samples from healthy volunteers and from those with psoriasis reacted by producing
more LL-37. As a result, the replication of the virus was controlled and eventually
halted. In contrast, LL-37 production was minimal in skin samples from people
with atopic dermatitis and vaccinia replication was poorly controlled. Next,
the scientists exposed skin samples from people with atopic dermatitis to vaccinia,
and then added LL-37. With the LL-37 supplement, the skin cells successfully
controlled the viral replication.
Dr. Leung and his group then looked more closely at why vaccinia infection fails
to induce LL-37 production in atopic dermatitis skin. Comparing immune responses
of skin cells grown in the lab from healthy volunteers and from people with atopic
dermatitis, the researchers found that the latter skin samples produced excessive
amounts of IL-4 and IL-13. Adding IL-4 and IL-13 to skin cells from healthy volunteers
prior to vaccinia exposure reduced levels of LL-37 production. Conversely, when
the scientists applied IL-4- and IL-13-neutralizing antibodies to skin samples
from people with atopic dermatitis, LL-37 production increased significantly.
Together, these findings suggest a rationale for new treatment approaches to
eczema vaccinatum, notes Dr. Leung. One approach involves developing drugs to
mimic the action of LL-37 or developing LL-37-containing creams that could be
applied to the skin in order to boost its ability to contain vaccinia virus infection.
Another approach could be to develop agents to neutralize IL-4 and IL-13. Although
no such drugs are currently marketed, compounds that can neutralize IL-4 and
IL-13 are under study as possible asthma and allergy treatments, Dr. Leung says,
and might also be applied to eczema vaccinatum treatment.
Smallpox vaccine, which is made with live vaccinia virus (a close relative of
the virus that causes smallpox), has not been routinely given in the United States
since the early 1970s. But recent concerns about the possibility of a bioterrorist
attack using smallpox virus prompted authorities to reinstate voluntary smallpox
vaccination for specific groups, such as military personnel. In the first five
months of 2003, the U.S. Department of Defense vaccinated more than 450,000 personnel
against smallpox. During this period, the majority of those who deferred vaccination
cited atopic dermatitis or other skin conditions as the main reason.
This research also was funded by the National Institute of Arthritis and Musculoskeletal
and Skin Diseases, another NIH component.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID supports
basic and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on transplantation and immune-related illnesses, including autoimmune
disorders, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.