Kofi, this is getting really interesting. IDO puts to sleep T-cells
while it actually activates the TREGs (!!). It seems that Tryptophan
feeds/stimulate the T-cells responsible for autoimmune reactions while
its metabolites downstream of IDO stimulate the TREGs much like PGE2.
No wonder these mechanisms are "exploited" by the fetus as well as
cancer cells ... Having leaky-gut after tonsil removal - tonsils are
full of IDO, makes sense. (just wondering what does PGE2 or LTB4 do
to the T-cells in this immunotolerance context).
J Immunol. 2008 Oct 15;181(8):5396-404.
The indoleamine 2,3-dioxygenase pathway is essential for human
plasmacytoid dendritic cell-induced adaptive T regulatory cell
Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR.
Division of Hematology-Oncology, Blood and Marrow Transplantation,
Department of Pediatrics and The Cancer Center, University of
Minnesota Medical School, Minneapolis, MN 55455, USA.
Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic
CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+)Foxp3(+)
regulatory T cells (Tregs). However, the intracellular mechanism or
mechanisms underlying PDC-induced Treg generation are unknown. In this
study, we show that human PDCs express high levels of IDO, an
intracellular enzyme that catabolizes tryptophan degradation.
Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to
up-regulate surface expression of B7 ligands and HLA-DR Ag, but also
significantly increases the expression of IDO and results in the
generation of inducible Tregs from CD4(+)CD25(-) T cells with potent
suppressor cell function. Blocking IDO activity with the pharmacologic
inhibitor 1-methyl-D-tryptophan significantly abrogates PDC-driven
inducible Treg generation and suppressor cell function. Adding
kynurenine, the immediate downstream metabolite of tryptophan,
bypasses the 1-methyl-D-tryptophan effect and restores PDC-driven Treg
generation. Our results demonstrate that the IDO pathway is essential
for PDC-driven Treg generation from CD4(+)CD25(-) T cells and
implicate the generation of kynurenine pathway metabolites as the
critical mediator of this process.
Chem Immunol Allergy. 2008;94:124-37.
Immune regulation and tolerance to fungi in the lungs and skin.
Romani L, Puccetti P.
Department of Experimental Medicine and Biochemical Sciences,
University of Perugia, Perugia, Italy.
The balance of pro- and anti-inflammatory signaling is a prerequisite
for successful host/fungal interactions and requires the coordinate
actions of both innate and adaptive immune systems. Although
inflammation is an essential component of the protective response to
fungi, its dysregulation may significantly worsen fungal diseases and
limit protective antifungal immune responses. The newly described Th17
develop - mental pathway may play an inflammatory role previously
attributed to uncontrolled Th1 responses and serve to accommodate the
seemingly paradoxical association of chronic inflammatory responses
with fungal persistence in the face of an ongoing inflammation. In
this scenario, unrestricted fungal growth could result from the
activation of not only pathogenic Th17 cells, but also Th2 cells whose
activation is strictly dependent on fungal burden. The capacity of
regulatory T cells (Tregs) to inhibit aspects of innate and adaptive
antifungal immunity is required for protective tolerance to fungi.
Indoleamine 2,3-dioxygenase (IDO) and tryptophan catabolites
contribute to such a homeostatic condition by providing the host with
immune defense mechanisms adequate for protection, without necessarily
eliminating fungal pathogens - which would impair immune memory - or
causing an unacceptable level of tissue damage. IDO and tryptophan
metabolites may prove to be potent regulators capable of taming
overzealous or heightened inflammatory host responses.
a gene (GCN2) that tells mice to eat a well-balanced diet and yeast
make bread rise also selectively silences the immune system; GCN2
responds to low amino acid levels; GCN2 is a nutrition sensor in
telling it it has enough nutrients to grow; indoleamine 2,3-
(IDO) is expressed in the GI tract and tonsils where the immune
regularly meets foreign substances it might need to ignore; IDO
the fetus from rejection during pregnancy; tumors and persistent
can hijack the IDO mechanism to hide from attack; IDO degrades
tryptophan which is essential to T-cell survival; this doesnt kill
T-cell but does render it selectively non-responsive; the T-cells in
GCN2 knockout mice ignore IDO so GCN2 is necessary for immune
represses the immune system by degrading tryptophan (the precursor to
serotonin) which is important to the function of T-cells; tumors can
recruit IDO secreting dendritic cells to protect themselves from the
Protective Mechanism Exploited By Tumors May Provide New Cancer
Like a parasite exploiting its host, some tumors protect themselves by
recruiting non-tumor cells that normally help keep the immune system
in check, say researchers at the Medical College of Georgia.
When the researchers looked into the lymph nodes where tumors drain --
typically the first place tumors spread -- they found a subset of
normal host immune cells were expressing IDO, an immunosuppressive
enzyme also expressed by the fetus to help avoid rejection by the
mother's immune system.
They also found that when they gave a drug to block IDO expression,
the immune system rallied.
"Our hypothesis in this situation was that the bad guys in this case
were actually cells from the host, perfectly normal cells that had, in
a sense, been requested by the tumor," says Dr. David Munn, pediatric
hematologist-oncologist and lead author on the study published in the
July 15 issue of Journal of Clinical Investigation.
Now they have shown in an animal model that these normal cells are a
type of dendritic cell that was previously ignored by the scientists
because they believed the cells were involved in making antibodies not
in suppressing the immune system. By recognizing the actual role of
these previously discarded cells, the MCG scientists and their
collaborators have moved significantly closer to using this approach
to help cancer patients.
"We have demonstrated that the IDO inhibitor drug is useful in mice,"
says Dr. Munn. "It's useful in a tumor model that is related to the
kinds of patients we would want to treat. This brings us closer to
being able to approach the FDA suggesting that IDO inhibitor drugs
would be appropriate to use in patients."
The National Institutes of Health will do toxicity studies of the IDO
inhibitor as well as other studies needed to take the proposal for
clinical trials to the Food and Drug Administration, Dr. Munn says.
Should the FDA move toward clinical trials, it likely will be at least
a year before studies begin to look at the safety and efficacy of the
treatments that would help make tumors more vulnerable to the immune
system, Dr. Munn says. He added that the therapy likely would be an
adjunct to existing approaches such as chemotherapy and possibly a
tumor vaccine that stimulates the immune response.
"It's a general property of any tumor that survives long enough to
come to medical attention that it has figured out a way to evade the
immune system," Dr. Munn says. "What we would hope is that some group
of tumors would rely primarily on this IDO mechanism to do that. It
may not be because they are a particular type of tumor. It may be that
tumors try different mechanisms and some breast cancers, colon
cancers, melanomas or whatever hit on this particular strategy."
The idea of using this strategy against tumors began in 1998 when MCG
scientists reported in Science that the fetus used IDO -- indoleamine
2,3-dioxygenase -- to locally disable the mother's immune system and
avoid rejection. The potential of using the IDO mechanism to
manipulate immune response is being explored in other areas as well,
such as protecting transplanted organs from rejection and helping the
immune system fight HIV infection.
Fortunately, several compounds that might inhibit IDO already existed,
developed as part of studying pathways involving the natural amino
acid, tryptophan. Tryptophan is a precursor to the neurotransmitter,
serotonin, and some popular antidepressants work by making serotonin
more available to the brain. IDO suppresses the immune response by
degrading tryptophan, which also is important to T cells, major
orchestrators of the immune response.
The MCG researchers were able to identify and isolate the IDO-
expressing cells recruited by the tumor by using state-of-the-art cell-
sorting equipment purchased for MCG by the Georgia Research Alliance.
"Once we had them isolated, that allowed us to test them in vitro to
see if they really were suppressive like we thought," Dr. Munn says.
"Then, the most convincing part of this to us was that we could
transfer the cells from a mouse that had a tumor into another that
didn't and see if the immune system of the tumor-free mouse also
became suppressed. And the answer was, 'Yes it did.'"
While he is excited about the potential of using the laboratory
findings to help patients, Dr. Munn says the steps from bench to
bedside are still complex. In the last few years, scientists have
recognized that the immune system is not a passive observer. Rather,
there are ongoing natural mechanisms, including IDO expression, that
actively help keep the immune system tolerant. "We have to be tolerant
of ourselves all the time; otherwise, you get autoimmune diseases such
as arthritis and lupus," Dr. Munn says. "It's the difference between a
car that is sitting there not moving but doesn't have on the emergency
brake so it could move versus one that has on the emergency brake and
can't move until you take it off. Natural tolerance mechanisms are
like a brake that must be removed before the immune system will attack
"If you take off the brakes (for example with an IDO inhibitor drug),
you may make people sick. We need to be very careful that we do not do
something that causes harm to patients. So that is our next task: to
test it in animal models to see if it's a safe and appropriate thing
to give patients," Dr. Munn says.
His collaborators at MCG include Dr. Andrew Mellor, director of the
MCG Immunotherapy Center; Drs. Madhav D. Sharma and Deyan Hou,
assistant research scientists; Dr. Babak Baban, research associate;
Dr. Jeffrey R. Lee, gastrointestinal pathologist; Dr. Phillip
Chandler, senior research scientist; and Dr. Pandelakis Koni,
immunologist. Also, Drs. Scott J. Antonia and Jane L. Messina of the
H. Lee Moffitt Cancer Center in Tampa, Fla. The research was funded by
the NIH and the Carlos and Marguerite Mason Trust.
Nutrition gene key in regulating immune system
Story by Toni Baker
Photo by Phil Jones
May 17, 2005
A gene that signals a yeast cell to make bread rise and mice to eat a
better diet also helps selectively silence the immune system,
researchers have found.
The finding may help explain how a mother avoids rejecting a
genetically foreign fetus and provides a new target for treatments to
help the immune system ignore other desirables like a transplanted
?Think of this like a radio transmitter and a receiver,? says Dr.
David H. Munn, pediatric hematologist-oncologist at the Medical
College of Georgia and lead author of the study in the May issue of
The transmitter is indoleamine 2,3-dioxygenase, or IDO, an enzyme
particularly expressed in places such as the gastrointestinal tract
and tonsils where the immune system routinely meets up with foreign
substances it might want to ignore.
Drs. Munn, Andrew L. Mellor and Simon J. Conway published a Science
article in 1998 showing IDO?s role in protecting the fetus from
rejection by the mother?s immune system during pregnancy. Later they
learned that tumors and persistent viruses such as HIV may hijack this
mechanism to shield themselves from immune attack.
They knew IDO degraded tryptophan, an amino acid essential to the
survival of T cells. They weren?t so certain what happened at the
The researchers wondered if T cells exposed to IDO might simply starve
to death without enough trytophan, one of nine essential amino acids
attainable only through food. ?If the T cells are just starving, then
you don?t need a receiver. They just die. But the T cells didn?t seem
to be dying. They seemed to be rendered selectively non-responsive,?
says Dr. Munn. ?That sounded more like the T cell was participating in
So the researchers started looking at the few genes known to respond
to amino acid levels and found GCN2.
GCN2 is present and active in many cells, but its major sites of
action are unknown and its role in T cells was unexplored, Dr. Munn
says. ?GCN2 is a nutrition sensor in yeast,? says Dr. Munn. GCN2
helps yeast know when it has sufficient nutrition to grow; bread keeps
rising until yeast run out of nutrition. A paper published in March in
Science explores GCN2?s role in mammalian survival by enabling mice to
sense they need to eat a well-balanced diet to stay healthy.
Dr. Munn contacted Dr. David Ron, a professor of medicine and cellular
biology at New York University School of Medicine?s Skirball
Institute, studying the nutritional aspects of the gene. Dr. Ron, a co-
author on the Immunity paper, shared a GCN2 knockout mouse he
developed and helped the MCG researchers study the gene?s role in T
When these knockout mice were exposed to IDO, their T cells simply
The researchers had found a receiver and possibly more.
?No one had known any gene specifically targeted by IDO, and now we
have one,? says Dr. Munn. ?We had not known how T cells were turned
off. We didn?t know if the T cells just were never activated, or if
they were actively suppressed by IDO. They all look like resting T
cells. Now we do know that there are differences.?
MCG researchers want to know more about how GCN2 puts T cells to
sleep. ?Whatever it?s doing doesn?t appear to be killing the T cells.
It would be nice to be able to mimic the effect of IDO by using a drug
that activates this pathway.? Now that they have a knockout,
comparative studies with regular mice can determine other genes that
might be impacted downstream of GCN2.
Another big question is whether T cells deactivated by this system can
be reactivated. Knowing the role of the GCN2 gene makes it easier for
scientists to watch what happens to the T cells affected by IDO in a
?We know that IDO itself is an important pathway. Evidence is emerging
that IDO seems to contribute to several important regulatory processes
in the immune system,? Dr. Munn says of findings from labs across the
country. ?But there has been a question in the field about how the IDO
expressed in one cell can signal to neighboring T cells. Here?s our
first evidence of one way it may do so. By giving you a target in the
T cell that IDO is talking to, it helps you understand the system
better and we think it also may give us another target for drugs to
try to intervene in the system.?
Well, there's a prostaglandin receptor right on Tregs. Dosing them with
a COX-2 inhibitor shrinks some cancers by 50% by disabling the
regulatory T-cell hiding them from the body's immune system.
Unfortunately, that by itself also makes COX-2 inhibitors an extremely
bad idea for autoimmune patients (but the FDA continues to let Celebrex
be advertised for arthritis).
LTB4 is interesting for the way it attacks viruses associated with
autoimmunity. I've posted on that. LTB4 is sometimes needed for
cathelicidin to work in some cell types.
Interestingly, some pollens contain LTB4 ligands which might help
explain the immunomodulatory properties of some honey/royal jelly.
I can't begin to tell you how simple if profound it is that autoimmune
patients just watch their turkey intake solely over the tryptophan.
This is a fascinating finding that goes a long way to explaining why
I've met so many autoimmune people with fungal problems. I myself have
been on nystatin for about seven years now.
Interestingly, butyrate activates FoxP3 and also inhibits chitin
production in Candida which is what people with allergies and asthma
typically react to [PMID 16871939].
> a gene (GCN2) that tells mice to eat a well-balanced diet and yeast
> to make bread rise also selectively silences the immune system; GCN2
Hey, dude. I posted this reference myself. It's in my patented "Bill
Faulkner Stream of Consciousness School of Court Reporting" style.