| NIMR Immunologist Anne O’Garra Gears Up to Take On TB |
 The
immune system is, simply put, the main line of defense against
pathogens. It has evolved over the eons to recognize and respond with
virtuoso skill to a seemingly infinite array of pathogens, and to do so
quickly, efficiently, and—of some importance—without killing the
host in the process. Each incoming pathogen challenges the immune system
with a series of decisions. First, to respond or not. Then, to tailor
the response to that particular invader and no other, and to hit it with
just the right amount of force. Too weak a response, and the invader
wins the day; too strong, and the host is killed, as well.
|
"I would like to know how to turn on and switch off
proinflammatory molecules at will," says Anne O’Garra of the
National Institute for Medical Research, Mill Hill, U.K. |
The immune system consists of a network of cells that have developed
to recognize a wide variety of pathogens, including bacteria, parasites,
and viruses. Pathogen-derived products can trigger immune cells to
produce cytokines, soluble molecules that promote the immune response.
This leads to the destruction or arrest of the infectious organism.
However, the immune system is a double-edged sword, since cytokines can
also result in damage to the host tissue (for example, in inflammatory
diseases). Cytokine production is therefore subject to intricate
regulation, in order to control the immune response and prevent such
damage.
How the immune system makes its commitment to a defensive strategy,
and how it regulates the level of commitment and the choice of mediators
sent to fight off the pathogen, are among the most fundamental questions
in immunology. The answers are crucial to designing drugs that either
enhance an immune response when necessary or tone one down when it’s
out of control. In this research world, immunologist Anne O’Garra, of
the National Institute for Medical Research (NIMR) at Mill Hill, London,
England, has contributed significantly. Her work over the last decade on
interleukin-10 (IL-10) and IL-12—cytokines that play crucial roles in
defining the immune response—currently places O’Garra at #2 in the
Thomson ISI Essential Science Indicators ranking of scientists in
immunology, based on collective citations to papers published between
1993 and 2003. Her two hottest papers—on the roles of IL-12 in the
development of CD4+ T-cell responses and on IL-10 and its ability to
block activation of cytokine synthesis—have garnered over 1,700 and
1,500 citations, respectively (see table on page 4). In the last decade,
her publications have included 21 papers that have each recorded more
than 100 citations.
O’Garra, 47, received her
bachelor’s degree in microbiology and biochemistry at the University
of London in 1980. At the NIMR, she earned her Ph.D. in microbiology in
1983, staying on there for a four-year post-doc in immunology. In 1987,
O’Garra left England for Palo Alto, California, to work for the DNAX
Research Institute, where by 2000 she had become a principal staff
scientist in the department of immunobiology. At the end of 2001, O’Garra
moved back to the NIMR, where she now heads the Laboratory of
Immunoregulation. Over the next few years she will be recruiting
independent investigators to expand research in the area of regulation
of innate and adaptive immune responses to different pathogens, which
will undoubtedly open up new avenues for improved adjuvants and vaccines
for prevention or therapeutic intervention in infectious diseases. This
is based upon close collaboration with the existing Divisions of
Molecular Immunology, Immune-Cell Biology, and Parasitology, Virology
and Mycobacterial Research at NIMR, as well as some of the colleges and
medical schools of London’s Universities.
O’Garra spoke to
Science Watch correspondent Gary Taubes
from her office in Mill Hill.
How would you define the state of the understanding of
cytokines and immune-system regulation when you got to DNAX in 1987?
Initially, cytokines—interleukins and
lymphokines, for example—were all thought to have individual
properties. We had found out at the NIMR in 1985 that some of them can
have overlapping properties; for example, we first described that IL-5
is a differentiation factor for eosinophils (EDF) and also a growth
factor for B cells (BCGF II). Later at DNAX it was discovered that
cytokines share chains of cytokine receptors, and basically these
different receptors are differentially expressed on different cells. So
one cytokine can act on one cell or another, depending on the expression
of receptors. When I went to DNAX, it was to continue working, as I had
at Mill Hill, on the role of cytokines in B-cell growth and development,
but also on how cytokines and antigen-presenting cells, which initiate
immune responses, may help T-cell responses. The discovery that T-helper
(Th) cells that express CD4 cell-surface antigens consisted of different
subsets, named Th1 and Th2 cells, had been made at DNAX by Mosmann and
Coffman. These cells were shown to have distinct cytokine profiles and
effector functions important in defense against infectious agents or in
immune-mediated pathologies. Th1 cells were shown to be critical for the
eradication of intracellular pathogens, and the hallmark cytokines of
Th1 cells include IFN-gamma and lymphotoxin, which can activate
microbial activity as well as cytokine production in macrophages. If
uncontrolled, however, Th1 cells can mediate inflammatory disease. Th2
cells were shown to produce the cytokines IL-4, IL-5, and IL-13, and to
activate mast cells and eosinophils, thereby eradicating helminths and
other extracellular parasites—but they were also implicated in
allergic disease. However, in the early 1990s nobody knew how Th1 or Th2
cells differentiated from a single precursor. And you had to know this
to know what direction the cell would go and whether or not you would
get the right kind of immune response. The molecular basis of how that
came about was completely unknown when I started at DNAX. So we were
interested in looking at the initiation of immune responses and in
trying to ascertain whether antigen-presenting cells that initiate
immune responses—including B cells, dendritic cells, or macrophages—
and the molecules that they produce could determine whether you got Th1
or Th2 cells. For the next ten years that was a major part of my work,
as it was with a lot of immunologists. We were trying to figure out how
you direct the Th1 and Th2 responses. What molecules do the directing
and how are they regulated? All of this was very relevant to the
question of getting the right immune response to fight infectious
pathogens or for blocking inflammatory pathways.
How did you figure it out?
The first clue we got was from a molecule named
interleukin-10, which turned out to be a really hot molecule, and is
still a really hot molecule. IL-10 was cloned at the cDNA level by Kevin
Moore, Paulo Vieira and Tim Mosmann
at DNAX, on the basis of its ability
to inhibit cytokine production from Th1 cells. We then went on to work
out the mechanism of IL-10 action.
So IL-10 could be produced by a number of different cells, including
T cells and, to our surprise, B cells—yet B cells producing IL-10
could stimulate TH1 cells, which suggested to us that Th1 cells could
not be the target of IL-10 action. This led to our key findings that
IL-10 inhibited the activation and function of dendritic cells and
macrophages. These are antigen-presenting cells which initiate immune
responses by stimulating T cells, but they also produce cytokines. So we
found that a major effect of IL-10 was to inhibit the cytokines made by
the antigen-presenting cells, and thus prevent them from stimulating the
development of the effector function of Th1 cells. This demonstrated the
broad immunosuppressive capacity of IL-10. We did a lot of further work
on the mechanism of IL-10 to inhibit the initiation of the immune
response, a main effect being the inhibition of proinflammatory cytokine
production by macrophages and dendritic cells.
Highly
Cited Papers by Anne O'Garra
Published Since 1991
(Ranked by total
citations) |
| Rank |
Paper |
Citations |
| 1 |
C.S. Hsieh, et
al., "Development of Th1 CD4+ T-cells through IL-12 produced
by listeria-induced macrophages," Science, 260(5107):
547-9, 1993. |
1,787 |
| 2 |
K.W. Moore, et
al., "Interleukin-10," Ann Rev. Immunol.,
11:165-90, 1993. |
1,561 |
| 3 |
D.F.
Fiorentino, et al., "IL-10 inhibits cytokine production by
activated macrophages," J. Immunol., 147(11): 3815-22,
1991. |
1,291 |
| 4 |
D.F.
Fiorentino, et al., "IL-10 acts on the antigen-presenting
cell to inhibit cytokine production by Th1 cells," J. Immunol.,
146(10): 3444-51, 1991. |
1,087 |
| 5 |
S.E. Macatonia,
et al., "Dendritic cells produce IL-12 and direct the
development of Th1 cells from naïve CD4+ T cells," J. Immunol.,
154(10): 5071-9, 1995. |
679 |
| SOURCE:
Thomson ISI Web
of Science |
This work prompted us to investigate further the molecules important
for the development of Th1 and Th2 cells, and led us to interact closely
with another group, in St. Louis, led by Ken Murphy at Washington
University, who had made a mouse with transgenic T-cell receptor, such
that every T cell in the mouse responded to one antigen. It meant we
could very easily look at what cytokines this T cell produces. This
allowed us to dissect how the Th1 and Th2 cells developed. In a very
exciting and close interaction with the Murphy lab, we first described
the action of another major cytokine, IL-12, to demonstrate that it is a
key inducer of the development of Th1 cells. We showed that this
cytokine, as well as other proinflammatory cytokines, was normally
turned on by bacterial stimuli acting on the macrophage. In addition, we
were first to show that the most important antigen-presenting cell, the
dendritic cell, produced IL-12. Combining these studies and our earlier
work, we then showed that IL-10 antagonized this activation and
inhibited the production of IL-12 by dendritic cells and macrophages,
and thus the development of a Th1 response.
And this is why your IL-10 and IL-12 papers have had
such an impact in the field?
With IL-12 you promote the response against
pathogens—the Th1 response—which allows eradication of the pathogen.
Th1 cells had been shown earlier to be important for the clearance of
parasites—Leishmania, for example. But nobody knew how to get
Th1 cells at will, how to direct them at will. We could do it. We could
get a tissue culture dish, isolate CD4+ T cells, and make them become
Th1 cells by stimulating them at the beginning with IL-12. We could
activate dendritic cells and macrophages to produce IL-12 and direct Th1
development, and block this process by addition of IL-10. Thus, this
work initiated an understanding of how Th1 cells develop and are
regulated, and promised to open up new avenues for improved adjuvants
and vaccines for prevention or therapeutic intervention in infectious
diseases. On the other hand, cytokines produced by Th1 cells can also
result in damage to the host tissue—in inflammatory diseases, for
example. In order to control the immune response and prevent such
damage, cytokine production is subject to complex regulation. Our work
demonstrated that IL-10 is a very important molecule in achieving this
regulation and preventing inflammatory damage to the host, but suggested
conversely that if over-produced it may lead to immune suppression in
chronic infectious diseases. This is the focus of our more recent and
future work.
So this research opens up a pharmaceutical line of
attack for fighting infections. Which type of infections?
People had suggested that IL-12 could be helpful
in eradicating cancers or HIV. What seems clear now, however, is that
IL-12 and Th1 responses could open up avenues for therapeutic
intervention in certain bacterial infections, since others have since
shown that mutations in the IL-12 and IFN-gamma receptors, as well as in
IFN-gamma signaling pathways, can lead to extreme susceptibility to M.
tuberculosis, disseminating BCG and salmonella. An understanding of
how IL-12 is induced in dendritic cells and macrophages, and how it is
regulated by IL-10 leading to suppression of the immune response, will
thus help in the design of vaccines and therapeutic intervention in
chronic infectious diseases, to achieve long-term protection and minimum
immune pathology.
But, conversely, Th1 cells can also induce pathologies, so we could
try blocking them to stop inflammatory pathologies. We could go either
way. There’s one important thing that I have to add about directing
Th1 cells: a few years after we did our initial work on the regulation
of Th1 responses, a Japanese group cloned a molecule that induced gamma
interferon production from T and NK cells. This molecule was originally
called IGIF, or interferon gamma-inducing factor, and is now called
IL-18. We showed that IGIF/IL-18 was highly synergistic with IL-12 for
Th1, but not for Th2 responses. Th2 cells don’t respond to IL-12 or
IL-18. Thus IL-18 also turned out to be very important in promoting the
Th1 response. And now, from a clinical point of view, if you ask what
the importance of IL-18 is, the answer is that if you block IL-18,
IL-12, or other Th1-inducing cytokines, you may stop inflammatory or
autoimmune pathologies, such as in multiple sclerosis or rheumatoid
arthritis—potentially fatal responses of the immune system.
Neutralizing antibodies to IL-18 might block that extreme response, thus
inhibiting host damage. So IL-12 and IL-18 are very important molecules
in directing the right kind of immune response to invading pathogens.
IL-12 and IL-18 have the potential to be used for vaccination against
infectious pathogens, while inhibition of these cytokines with
antibodies could provide therapeutics in inflammatory pathologies.
In late 2001 you left DNAX and came back to Mill Hill.
What prompted the shift?
Well, I have always regarded myself as European,
having been born in Gibraltar and educated in the U.K. Originally I
planned to go to California for two years, but I stayed for more than a
decade and had a great time. I had reached a very senior level at DNAX,
but I was still driven by basic academic-type questions. I was
interested in combining research in areas that might enhance the
findings on cytokines so that we could help fight clinical disease. The
attraction of NIMR is that it is an excellent institute for
multidisciplinary interaction. Even when I was there as a post-doc, in
the 1980s, I interacted with biochemists, immunologists, and researchers
of infectious diseases to conduct my basic research. NIMR also has a
very good five-year review system, which maintains its high standard.
Its multidisciplinary research and excellence in gene regulation,
including in the development of biological systems, plus the strength of
its other immunology divisions, all provide a great environment. I’d
also come to the stage of my life where I wanted to continue working on
the molecular basis of cytokine gene regulation, but also to extend my
work on really important pathogens that affect humans. Tuberculosis (TB)
was a logical choice given my background in examining Th1 responses.
That meant I had to interact with mycobacteriologists, which I have now
started, and in the future with clinicians studying the pathogenesis of
TB and attempting to treat the disease. That’s my mission for the
future.
In an ideal world, what would you like to accomplish in
the next five years?
With respect to my own laboratory and with
respect to molecules, I would like to know how to turn on and switch off
proinflammatory molecules such as IL-12 at will. That’s why IL-10 is a
very important molecule, because it shuts off the immune response. IL-10
may be associated with chronic TB and, in fact, the reason I chose TB,
as opposed to HIV or malaria, is because we know that patients who don’t
get Th1 responses, or who have problems with Th1 genes, succumb to TB
and bacteria such as salmonella. That’s why TB seemed an ideal
pathogen for us to tackle with our particular skills. At a broader
level, the aim is then to expand this, to have independent young
investigators around to look at important viruses and the molecular
basis of promoting viral immune responses or maybe stopping pathologies.
NIMR was the perfect place for me to come. I can continue my basic
research, asking the basic questions, but I can also lend it to the
study of important infectious diseases, interacting with London medical
schools, and eventually with developing countries, to achieve this.
 See also: Highly
Cited Authors in Immunology, 1992-2002
Science
Watch®, November/December 2003, Vol. 14, No. 6
Citing URL:
http://www.sciencewatch.com/nov-dec2003/sw_nov-dec2003_page3.htm |
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