Notch signalling molecule important in type 2 immunity

Findings may lead to new treatments for asthma and other inflammatory-related
diseases

(Philadelphia, PA) - Defects in immune system cells called T helper cells may
lead to diseases characterized by a faulty inflammatory response such as
autoimmunity and asthma. Understanding the molecular steps involved in how T
helper cells mature may help researchers develop treatments for these diseases.

Helper T cells differentiate into two different types of cells ?Th1 or Th2 ?
which are responsible for regulating immunity to different types of pathogens.
Now, researchers at the University of Pennsylvania School of Medicine have shed
light on a key molecular switch in this differentiation.

Notch is a protein that is a critical regulator of the process by which stem and
other multipotent cells take on a specialized function, such as a T lymphocyte
or a nerve cell in organisms ranging from fruitflies to humans. Using mice in
which Notch signaling could be induced to turn off in mature T cells, the
researchers showed that Notch signaling is an important determinant of whether
an organism can mount an effective Th2 response. The mice lacking Notch
signaling were unable to mount a protective Th2 cell response against infection
by the gastrointestinal parasitic worm Trichuris muris. However, the mice did
mount a healthy Th1 response to an infection by the intracellular parasite
Leishmania major, showing that Notch signaling is specifically required for the
Th2 arm of the immune system.

These findings indicate that regulating Notch signaling may have a therapeutic
role in treating diseases caused by abnormally increased Th2 responses, such as
asthma, autoimmunity, and some forms of inflammatory bowel disease. Drugs that
inhibit Notch signaling, called gamma secretase inhibitors, are currently in
clinical trials for T-cell leukemia and Alzheimer's disease. This study ?
published in today's issue of the Journal of Experimental Medicine ? suggests
that these drugs may be useful in treating diseases typified by increased Th2
responses.

Senior author Warren Pear, MD, PhD, Associate Professor of Pathology and
Laboratory Medicine, was one of the original discoverers of the role of Notch
signaling in T-cell development. Notch activates gene transcription in the
nucleus of cells, and depending on the biochemical context, it turns certain
pathways on and others off. "The potential importance of our study is that it
shows that Notch signaling specifically influences Th2 immunity in a live animal
when challenged with a pathogen, suggesting that drugs that inhibit Notch may be
useful for treating diseases associated with a pathological Th2 response, such
as asthma," says Pear. He is also a member of Penn's Abramson Family Cancer
Research Institute and The Institute for Medicine and Engineering.

Helper T cells fight many types of infectious diseases and are also the cells
that regulate tolerance to self and the molecules that cause the pathogenesis of
such inflammatory diseases as arthritis, inflammatory bowel disease, and asthma.
Antigen-presenting cells take up pathogens and migrate to the spleen or lymph
nodes, where they instruct immature T cells how to differentiate into Th1 or Th2
helper T cells, killer T cells, or other types of immune system cells.

Some of the factors that signal a T cell to become Th1 or Th2 cells are well
characterized, but some are not. "The role of Notch in that decision-making has
been controversial," says co-author Terry Fang, a graduate student in Penn's
Immunology Program. "And this paper weighs in on this." Some studies suggest
that Notch is important for the Th1 pathway, others suggest both Th1 and Th2.
This study suggests that there's a specific requirement for Notch in Th2
differentiation only.

The specificity of Notch in regulating T-cell function is highlighted in this
study. "Mice lacking Notch failed to control infection with a pathogen requiring
a Th2 response, demonstrating that Notch is a critical regulator of this
response," adds co-author David Artis, PhD, Assistant Professor at Penn's School
of Veterinary Medicine. "The ability of these same animals to mount strong Th1
responses demonstrates the specificity of the Notch pathway in regulating this
important cell type of the immune system."

The potential clinical benefit of these new findings is that gamma secretase
inhibitors may so on be available for testing in the clinics. One potential side
effect of these drugs is that they inhibit other pathways besides Notch. In
addition, inhibiting Notch may cause side effects because this protein is used
in a wide variety of cellular processes. The new mouse model described in this
paper may be particularly useful for identifying the consequences of turning
Notch off in different organs, an important issue for assessing potential side
effects of pharmacologic Notch inhibitors.

The current work provides the rationale for determining whether manipulating
Notch signaling will be useful in combating such diseases as parasitic
infections, asthma, and inflammatory bowel disease. "The exciting possibility is
that therapies are available," says Pear. "The challenge, however, is
determining their efficacy and safety."

###

In addition to Pear, Fang, and Artis, study co-authors are: LiLi Tu, Olga
Shestova, Seth E. Pross, and Ivan Maillard, all from Penn.

This study was funded by the National Institutes of Health, the Leukemia and
Lymphoma Society, the Crohn's and Colitis Foundation of America's William and
Shelby Modell Family Foundation Research Award, the Cancer Research Institute,
and the Damon Runyon Cancer Research Foundation. This release and related images
can also be found at: www.uphs.upenn.edu/news

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of
medical education, biomedical research, and high-quality patient care. PENN
Medicine consists of the University of Pennsylvania School of Medicine (founded
in 1765 as the nation's first medical school) and the University of Pennsylvania
Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research
funds; and ranked #4 in the nation in U.S. News & World Report's most recent
ranking of top research-oriented medical schools. Supporting 1,400 fulltime
faculty and 700 students, the School of Medicine is recognized worldwide for its
superior education and training of the next generation of physician-scientists
and leaders of academic medicine.

Penn Health System comprises: its flagship hospital, the Hospital of the
University of Pennsylvania, consistently rated one of the nation's "Honor Roll"
hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first
hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities; and home health care
and hospice.

http://uphsxnet.uphs.upenn.edu/prnews




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The Hymn of Nemesis:

Nemesis, winged balancer of life,
dark-faced Goddess, daughter of Justice,
You who restrain with adamantine bridles
the frivolous insolences of mortals,
and spurning the destructive violence of mankind
drive out black envy!

Beneath Your unceasing, traceless orbit
is spun the grey fortune of man
and unnoticed You walk in his tracks,
you bend the neck that is proud.
Beneath Your arm You ever measure out life
and ever do You lower Your eye to Your bosom
as You control the scales in Your hand.

Be gracious, blessed dealer of justice,
Nemesis, winged balancer of life.
Nemesis the deathless Goddess we sing,
Victory with slender wings, all-powerful
infallible, and the assistant to Justice,
You who in displeasure at the pride of men
carry it down into Tartarus.
.