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NEWS&VIEWS: What's the particular physiological condition?
ROSEN: We focused on a family of receptors for a lipid that
is produced by platelets and by a variety of tissue cells
called sphingosine 1-phosphate. Sphingosine 1-phosphate acts
on a family of receptors called the S1P receptors or the "edg
receptors," originally defined as endothelial differentiation
genes. They activate these receptors and regulate a range
of physiological functions that include cardiovascular function
and blood pressure. We showed that they control the recirculation
of lymphocyteswhich was never understood before.
We found that these sphingosine 1-phosphate lipids or synthetic
chemical agonists of the S1P receptors are able to alter the
trafficking of lymphocytes in a reversible way. These are
very potent. They act on receptors in the low nanomolar and
sub-nanomolar range. They lead to the misdirection of lymphocytes.
Lymphocytes circulate around the body in order to mediate
immunity and mediate the bystander damage of tissueswhether
it's a transplanted tissue as in a rejection or damage to
normal tissue as in autoimmunity. This mechanism regulates
the egress of lymphocytes from lymph nodes and, as we show
in a paper that we've just submitted for review, the egress
from thymus into the blood.
Lymphocytes normally come from two organs, the bone marrow
and thymus, then enter the bloodstream. They circulate through
the blood to secondary lymphoid organslymph nodes, Peyer's
patch, the spleen. If they encounter antigen in the secondary
lymphoid organ, they begin to proliferate and to undergo clonal
expansion, producing various effector cells. These effector
cells leave the lymphoid organs and return to the blood, having
acquired the ability to enter the tissue spaces and remove
what they recognize as non-self. This could be a transplanted
organ, a viral or a bacterial antigen, or, in the case of
autoimmune disease, normal tissue that has broken tolerance
and has become recognized as non-self.
We've discovered a couple of key steps are regulated by
these sphingosine 1-phosphate receptors. There is a biological
toggle switchan on-off switchthat is regulated
as you activate these receptors. You essentially shut off
a switch and, as you activate these receptors, the lymphocytes
disappear in a reversible way from peripheral blood and you
can protect an animal or a person from transplant rejection
and from autoimmune-mediated tissue damage.
NEWS&VIEWS: At the same time, though, you are suppressing
the immune system.
ROSEN: In fact, you are. One of the reasons we are particularly
interested in this research topic is that it represents a
mechanism of immunosuppression that has the potential to be
significantly less dangerous than other mechanisms of immunosuppression.
Why do I say this? What are the other modalities of immunosuppression?
Corticosteroids not only suppress lymphocytes, but also lead
to significant reductions in function and number of myelomonocytic
cells, neutrophils, and monocytes. So a patient's ability
to withstand bacterial or fungal infection is compromised.
In addition, corticosteroids cause significant changes in
metabolism. They are diabetogenic and cause significant loss
of bone mass, which can lead to osteoporosis and bone fractures.
Calcineurin inhibitors, like cyclosporin, are used for serious
autoimmune disease and for treatment of transplant rejection.
They have a number of mechanism-based toxicities including
causing dose-dependent renal dysfunction and hypertension.
Rapamycin and the TOR kinase inhibitors cause significant
alternations in blood lipids, some of which can cause acute
What we have here is a mechanism that can spare the use
of these other drugs that are potentially very toxic. Secondly,
it impairs lymphocyte recirculation, but doesn't impact on
myelomonocytic cell function. So, it should not cause enhanced
bacterial and fungal infections, which would be an advantage
to patients. There are no metabolic consequences that one
knows of associated with this mechanism. It should, therefore,
not produce osteoporosis, pathologic fractures, or diabetes,
nor should it promote renal dysfunction or blood pressure
NEWS&VIEWS: What would you guess the potential side effects
ROSEN: One could guess that potential side effects would
be those associated with, for instance, the inability to clear
a localized viral infection. There is data in the literature
showing that the systemic response to a viremic delivery of
antigen, in this case of LCMV in mice, is quantitatively normal,
but distributed differently. In other words, you get T-cells,
but the effector CD8 cells are largely restricted to the lymph
nodes and don't get into the periphery. We see the same thing
for CD4 effector cells in a paper that we've got coming out
in the April 1 issue of Journal of Immunology. You
can mount responses to systemic infection, but not necessarily
in the right place.
One should always bear in mind that one would generally
only use immunosuppressive strategy in somebody who was seriously
ill. It's not something one would use for a disease that is
self-limiting and non-disabling.
NEWS&VIEWS: What happens to the lymphocytes themselves?
Are they sequestered in the lymph nodes, and, if so, what
happens to them theredo they eventually go back into
ROSEN: Let's take it in two steps. What do we know? We know
that cells will accumulate acutely in lymph nodes. Lymph nodes
in the mouse for instance might increase in size by about
20 percent over the first two to three days. By 14 days, these
nodes have returned to normal size and appear to maintain
that normal size, so it doesn't seem to directly affect cell
fate in that sort of timeframe. In the long-run, we don't
know what happens to the fate of lymphocytes.
As you sequester cells in lymph nodes, you actually stop
egress from the thymus. In fact, in a paper that we have currently
sent out for review, we can actually stop export of cells
from thymus by about 95% within two hours. We can switch this
mechanism on and off and the cells arrest in the thymus.
Over time, the thymic cortex will thin and the medulla will
become more cellular as more mature T cells are behind the
barrier blocking their egress into blood. Do we understand
the homeostatic mechanisms that come into play to regulate
thymic size and the feedback loops? I would argue to you that
That becomes one of the future approaches that we would
take. How do you use evoked responses to small molecules to
unlock or understand homeostatic pathways that are very hard
to discern in the steady state? By small molecules, I mean
chemical probes, small organic molecular probes of protein
function that allow one to measure and perturb the physiology
in measurable waysin other words, chemical biology.
That is one of the general approaches that we like to take
within the lab.
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