New network of gastrointestinal immune
Findings could lead to new vaccines
and antibacterial strategies
BOSTON - January 13, 2005 - A previously unknown network
of immune cells has been discovered in the mammalian gastrointestinal
system by a research group based in the Center for the Study of
Inflammatory Bowel Diseases at Massachusetts General Hospital (MGH).
The finding, reported in the January 14 issue of Science,
could lead to better understanding of how the immune system recognizes
and responds to dangerous bacteria and viruses and to new approaches
to immunization and infectious disease treatment.
"We found an extensive system of immune cells throughout the
intestinal tract that take up bacteria and other antigens, giving
us a new target for understanding the immune response," says
Hans-Christian Reinecker, MD, of the MGH Gastrointestinal Unit,
the study's senior author.
The investigation focused on dendritic cells which are found in
tissues in direct contact with the external environment, such as
the skin, lungs and digestive system. Characterized by long extensions
called dendrites, dendritic cells continually sample their environment
for bacteria and viruses. When dendritic cells encounter pathogens,
they ingest them, break them down and then transport protein fragments
to the cellular membrane. On the cells' surface the fragments are
displayed to other immune system cells, which will recognize the
proteins as antigens to be destroyed.
Exactly how dendritic cells monitor intestinal contents and recognize
harmful organisms was unknown, and learning more about that process
was a goal of the current study. The researchers conducted several
experiments using genetically altered mice in which one or both
copies of a gene required for cell migration and dendrite formation
was replaced with a gene that produces a fluorescent protein. Examination
of the animals' tissues revealed populations of dendritic cells
throughout the small intestine in a layer just below the epithelial
lining. It previously had been believed that gastrointestinal dendritic
cells were few in number and restricted to specialized immune organs
called Peyer's patches.
Three-dimensional computer-assisted tissue reconstruction allowed
detailed microscopic examination of the intestinal tissues, which
showed that dendrites extend from the dendritic cells through the
epithelial layer, giving them direct access to intestinal contents.
In animals without the gene required for normal dendrite growth
- which produces a receptor protein - dendrites formed but did not
penetrate the epithelium. Dendritic cells without access to the
interior of the intestine were not able to carry out one of their
normal functions, taking up the harmless strains of E. coli that
normally populate the intestine and transporting them to lymph nodes.
Introduction of disease-causing salmonella bacteria into the gastrointestinal
system of both groups of mice revealed that the receptor-negative
animals, whose dendritic cells could not effectively sample intestinal
contents, were unable to mount an effective immune defense and developed
extensive salmonella infection.
"This is a new way for the immune system in the gastrointestinal
tract to monitor and interact with the environment," says Reinecker,
an assistant professor of Medicine at Harvard Medical School. "Insights
into these mechanisms could lead to better understanding of conditions
such as Crohn's Disease and ulcerative colitis, intestinal infections
and food allergy. Targeting these dendritic cells also could help
us develop new types of vaccines. And it's possible that some of
the gastrointestinal bacteria and viruses that cause serious illness
may co-opt the activity of these cells to enter the body and bypass
some immune defenses."
Along with Reinecker, the study's co-authors are first author Jan
Hendrik Niess, MD, Stephan Brand, MD, Xiubin Gu, Beth McCormick,
PhD, and Jatin Vyas, MD, PhD, of MGH; Limor Landsman, PhD, and Steffen
Jung, PhD, of the Weitzmann Institute in Israel; Dan Littman, MD,
PhD, of the Howard Hughes Medical Institute and New York University;
Marianne Boes, PhD, and Hidde Ploegh, PhD, Harvard Medical School;
and James Fox, DVM, Massachusetts Institute of Technology. The research
was supported by grants from the National Institutes of Health;
the Deutsche Forschungsgemeinschaft; the Crohn's and Colitis Foundation
of America and the Howard Hughes Medical Institute.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
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