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From: Taka on 5 Aug 2008 22:43
Curr Drug Metab. 2007 Apr;8(3):245-66.

Pharmacological targeting of IDO-mediated tolerance for treating
autoimmune disease.

Penberthy WT.
University of Cincinnati, Cincinnati, OH 45237, USA.

Cells at the maternal-fetal interface express indoleamine 2,3
dioxygenase (IDO) to consume all local tryptophan for the express
purpose of starving adjacent maternal T cells of this most limiting
and essential amino acid. This stops local T cell proliferation to
ultimately result in the most dramatic example of immune tolerance,
acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-
tryptophan causes a sudden catastrophic rejection of the mammalian
fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1,
and LPS use IDO induction in responsive antigen presenting cells
(APCs) also to transmit tolerogenic signals to T cells. Thus it makes
sense to consider IDO induction towards tolerance for autoimmune
diseases in general. Approaches to cell specific therapeutic IDO
induction with NAD precursor supplementation to prevent the collateral
non-T cell pathogenesis due to chronic TNFalpha-IDO activated
tryptophan depletion in autoimmune diseases are reviewed. Tryptophan
is an essential amino acid most immediately because it is the only
precursor for the endogenous biosynthesis of nicotinamide adenine
dinucleotide (NAD). Both autoimmune disease and the NAD deficiency
disease pellagra occur in women at greater than twice the frequency of
occurrence in men. The importance of IDO dysregulation manifest as
autoimmune pellagric dementia is genetically illustrated for Nasu-
Hakola Disease (or PLOSL), which is caused by a mutation in the IDO
antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to
psychotic symptoms rapidly progressing to presenile dementia likely
due to unchecked increases in microglial IDO expression, which
depletes neurons of tryptophan causing neurodegeneration.
Administration of NAD precursors rescued entire mental hospitals of
dementia patients literally overnight in the 1930's and NAD precursors
should help Nasu-Hakola patients as well. NAD depletion mediated by
peroxynitrate PARP1 activation is one of the few established
mechanisms of necrosis. Chronic elevation of TNFalpha leading to
necrotic events by NAD depletion in autoimmune disease likely occurs
via combination of persistent IDO activation and iNOS-peroxynitrate
activation of PARP1 both of which deplete NAD. Pharmacological doses
of NAD precursors repeatedly provide dramatic therapeutic benefit for
rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis,
other autoimmune diseases, and schizophrenia in either the clinic or
animal models. Collectively these observations support the idea that
autoimmune disease may in part be considered as localized pellagra
manifesting symptoms particular to the inflamed target tissues. Thus
pharmacological doses of NAD precursors (nicotinic acid/niacin,
nicotinamide/niacinamide, or nicotinamide riboside) should be
considered as potentially essential to the therapeutic success of any
IDO-inducing regimen for treating autoimmune diseases. Distinct among
the NAD precursors, nicotinic acid specifically activates the g-
protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing
tolerogenic prostaglandins PGE(2) and PGD(2). Next, PGD(2) is
converted to the anti-inflammatory prostaglandin, 15d-PGJ(2). These
prostaglandins exert potent anti-inflammatory activities through
endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1
along with PPARgamma respectively. Nicotinamide prevents type 1
diabetes and ameliorates multiple sclerosis in animal models, while
nothing is known about the therapeutic potential of nicotinamide
riboside. Alternatively the direct targeting of the non-redox NAD-
dependent proteins using resveratrol to activate SIRT1 or PJ34 in
order to inhibit PARP1 and prevent autoimmune pathogenesis are also
given consideration.
PMID: 17430113
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