Transcript Document

The suppressive effect of 1.0 mg/kg buprenorphine on IFN-g production is
attenuated by administration of the opioid receptor antagonist, naltrexone.
K.A. Carrigan et al., Int Immunopharmacol 2004, 4:419-428
0
CD4+ T lymphocytes are the primary cell target for human immunodeficiency virus-1 (HIV-1),
and these cells are known to express opioid receptors.
Due to the need for new treatment approaches to HIV-1 infection, we sought to determine
whether the non-selective opioid receptor antagonist naltrexone would affect HIV-1
expression in CD4+ lymphocyte cultures and whether naltrexone would alter the antiviral
properties of zidovudine (AZT) or indinavir.
Activated CD4+ lymphocytes were infected with a monocytotropic or T-cell tropic HIV-1 isolate,
and p24 antigen levels were measured in supernatants of drug-treated or untreated (control)
cultures.
While naltrexone alone did not affect HIV-1 expression, at a concentration of 10−12–10−10 M
naltrexone increased the antiviral activity of AZT and indinavir 2–3-fold.
Similar findings with a k-opioid receptor (KOR) selective antagonist supported the possible
involvement of KOR in naltrexone’s potentiation of the antiretroviral drugs.
The results of this in vitro study suggest that treatment of alcohol or opiate dependent
HIV-1-infected patients with naltrexone is unlikely to interfere with the activity of
antiretroviral drugs. Also, based upon naltrexone’s safety profile and its synergistic
activity in vitro, these findings suggest clinical trials should be considered of naltrexone
as an adjunctive therapy of HIV-1 infection.
1
The analgesic property of opiates has been known since ancient times.
Only recently has an appreciation of the broad effects of opioids on the
inflammatory response emerged. Acting largely through m-, k- and dopioid G protein-coupled receptors on T lymphocytes and
macrophages, cognate ligands modulate many activities of these
cells, including cytokine production. In addition to acting as chemotactic
stimuli, opioids can, through the process of heterologous crossdesensitization, act as stop signals in leukocyte trafficking. When
administered into the central nervous system, certain chemokines can
“We
propose that opioids should be considered members of
cross-desensitize to the analgesic effect of opioids. We propose that opioids
the
cytokine
familymembers
and thatoffuture
research
opioids
could
should
be considered
the cytokine
familyon
and
that future
yield
new
foryield
inflammatory
and
diseases,
research
ontherapies
opioids could
new therapies
forinfectious
inflammatory
and
including
HIV-1 infection.”
infectious diseases,
including HIV-1 infection.
2
Opioid and chemokine receptor expression by T cells, monocytes, microglial cells and neurons. Neuron–microglial cell communication
occurs through the release of various chemical mediators, including the production of CX3CL1 (fractalkine) by neurons and the production
of additional chemokines, such as CCL3, CCL4 and CCL5, by microglial cells.
The chemokines produced by microglial cells (and astrocytes) in the brain act as chemoattractants and/or activators of circulating T cells
and monocytes. The production of CCL2 is a potent chemoattractant for the passage of monocytes through the blood–brain barrier. In
addition, endogenous opioids, produced in the brain and by cells of the immune system, act to regulate circulating immune cells and
microglial-cell inflammatory activities.
3
Model describing the influence of opioids on HIV replication. MOR activation of macrophages and potentially T cells and microglia initiates
an increase in the expression of chemokines CCL2, CCL5 and CXCL10, which might act to attract susceptible T cells, monocytes and/or
macrophages or microglia to the site of HIV infection.
m-opioid receptor (MOR) ligands also signal an upregulation in the expression of the major HIV coreceptors CCR5 and CXCR4. By contrast,
k-opioid receptor (KOR) activation directly (and probably indirectly) inhibits the expression of proinflammatory cytokines and chemokines.
This results in a depressed state of cellular activation and reduced HIV replication. In addition, KOR signals an inhibition of the expression
of CCR5 and CXCR4, leading to reduced HIV binding and reduced chemotaxis of potentially susceptible target cells.
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m-Opioid modulation of HIV-1 coreceptor expression
and HIV-1 replication Steele A.D, et al., 309:99–10 (2003)
A substantial proportion of HIV-1-infected individuals are intravenous drug
users (IVDUs) who abuse opiates. Opioids induce a number of
immunomodulatory effects that may directly influence HIV-1 disease
progression. In the present report, we have investigated the effect of
opioids on the expression of the major HIV-1 coreceptors CXCR4 and
CCR5. For these studies we have focused on opiates which are ligands
for the m-opioid receptor. Our results show that DAMGO, a selective mopioid agonist, increases CXCR4 and CCR5 expression in both CD3+
lymphoblasts and CD14+ monocytes three- to fivefold. Furthermore,
DAMGO-induced elevation of HIV-1 coreceptor expression translates into
enhanced replication of both X4 and R5 viral strains of HIV-1. We have
confirmed the role of the m–opioid receptor based on the ability of a mopioid
receptor-selective
antagonistato
block them-opioid
effects ofagonist,
DAMGO. We
“Our results
show that DAMGO,
selective
have
also found
thatand
morphine
enhances CXCR4
and
CCR5
expression
+ lymphoblasts
increases
CXCR4
CCR5 expression
in both
CD3
and subsequently
increases both X4 and R5 HIV-1 infection. We suggest
+ monocytes
and
CD14
threefivefold.
Furthermore,
that the capacity of m-opioids
to to
increase
HIV-1
coreceptorDAMGOexpression and
induced
of HIV-1
expression
translates into
replicationelevation
may promote
viralcoreceptor
binding, trafficking
of HIV-1-infected
cells,
enhanced
replication
both X4 and R5 viral strains of HIV-1.”
and enhanced
disease of
progression.
Low-dose naltrexone effects on plasma chemistries and clinical
symptoms in autism: a double-blind, placebo-controlled study
Bouvard M.P., et al.
The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5
mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint
clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits
were achieved with both PLC and NTX, with marginally better overall results following
NTX, and degree of improvement appeared to be related to plasma chemical profiles.
Massively elevated levels of b-endorphin were observed in all children with assays
using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70%
of the children exhibited abnormally low levels of adrenocorticotropic hormone, and
smaller subsets exhibited elevated norepinephrine (6@%), arginine-vasopressin
(SO%), and serotonin (20%). The best clinical responders exhibited the clearest
normalization of the elevated plasma chemistries, especially in C-terminal&endorphin
and suggest
serotonin.that
There
wasonly
some
evidencea of
therapeutic
“The results
NTX
benefits
subgroup
of carry-over
autistic
effects in both clinical and biochemical measures in those children who received NTX
children,
identified
by the
certain ofplasma
before
PLC.who
The may
resultsbesuggest
that NTX
onlypresence
benefits aofsubgroup
autistic
abnormalities.
These
results
suggest
a
possible
linkage
between
children, who may be identified by the presence of certain plasma abnormalities.
abnormal
especially
related
to chemistries,
the proThese
resultsplasma
suggest chemistries,
a possible linkage
betweenthose
abnormal
plasma
opiomelanocortin
and autistic symptoms.”
especially
those relatedsystem,
to the pro-opiomelanocortin
system, and autistic symptoms.
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Smith J.P., et al.,
102:820–828, 2007
Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease
STUDY HIGHLIGHTS
What Is Current Knowledge
The current medical therapy of Crohn’s disease includes medications
that target the immune system or inflammatory modulators.
Opioid systems (peptides and receptors) play an integral role in
gastrointestinal fluid regulation, pain perception, and inflammation.
Many of the current drugs for treatment of Crohn’s disease carry a
greater risk of infection from immunosuppression or allergic reactions,
and some must be administered parenterally.
What Is New Here
 An opioid antagonist, naltrexone 4.5 mg, administered by mouth
once daily significantly improved Crohn’s disease activity index
(CDAI) scores and symptoms in subjects with active Crohn’s
disease.
Quality of life significantly improved with low-dose naltrexone
therapy and remained improved after discontinuation of the drug.
Naltrexone therapy was well tolerated in Crohn’s disease with
minimal side effects.
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Low-dose naltrexone therapy in multiple sclerosis
Agrawal Y.P.
The use of low doses of naltrexone for the treatment of multiple
sclerosis (MS) enjoys a worldwide following amongst MS patients.
There is overwhelming anecdotal evidence, that in low doses
naltrexone not only prevents relapses in MS but also reduces the
progression of the disease. It is proposed that naltrexone acts by
reducing apoptosis of oligodendrocytes. It does this by reducing
inducible nitric oxide synthase activity. This results in a decrease
in the formation of peroxynitrites, which in turn prevent the inhibition
of the glutamate transporters. Thus, the excitatory neurotoxicity of
glutamate on neuronal cells and oligodendrocytes via activation of the
a-amino-3- hydroxy-5-methyl-isoxazole-4-propionic acid class of
glutamate receptor is prevented. It is crucial that the medical
community respond to patient needs and investigate this drug in a
clinical trial.
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Antibodies to Neuron-Specific Antigens in Children
with Autism: Possible Cross-Reaction with Encephalitogenic Proteins from Milk,
Chlamydia pneumoniae and Streptococcus Group A
Journal of Neuroimmunology, 129:168-177 2002
A. Vojdani, A.W. Campbell, E. Anyanwu, A. Kashanian, K. Bock, E. Vojdani
Infections, Toxic Chemicals and Dietary Peptides Binding to Lymphocyte Receptors
and Tissue Enzymes are Major Instigators of Autoimmunity in Autism
Int J Immunopathol Pharmacol 16(3):189-199, 2003
A. Vojdani, J.B. Pangborn, E. Vojdani, E.L.Cooper
Heat Shock Protein and Gliadin Peptide Promote Development of Peptidase
Antibodies in Children with Autism and Patients with Autoimmune Disease
Clin Diag Lab Immunol 11(3):515-524, 2004
A. Vojdani, M. Bazargan, E. Vojdani, J. Samadi, A.A. Nourian, N. Eghbalieh, E.L. Cooper
Immune Response to Dietary Proteins, Gliadin and
Cerebellar Peptides in Children with Autism
Nutritional Neuroscience, 7(3):151-161, 2004
Vojdani, T. O’Bryan, J.A. Green, J. McCandless, K.N. Woeller, E. Vojdani, A.A. Nourian, E.L. Cooper
Antibodies against Central Nervous System Antigens in Autism:
Possible Cross-Reaction with Dietary Proteins and Infectious Agent Antigens.
Neuropsychiatric Disorders & Infections, pp 171-186, 2005, S.H. Fatemi (ed), Taylor & Francis Ltd
Vojdani, T. O’Bryan, J.A. Green, J. McCandless, K.N. Woeller, E. Vojdani, A.A. Nourian, E.L. Cooper
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journal of
Neuroimmunology
Journal of Neuroimmunology (In Press)
Low natural killer cell cytotoxic activity in autism: the role of
glutathione, IL-2 and IL-15
A. Vojdani, et al.
Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in
one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK
cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood
samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This
counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells.
At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different
clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p < 0.001). Low NK cell
activity in both groups did not correlate with percentage and absolute number of CD16+/CD56+ cells. When the NK
“The
induction
NK cellbased
activity
by IL-2,CD16
IL-15
and
glutathione
waswho
more
+/CD56
+ cells,
cytotoxic
activity wasofexpressed
on activity/100
several patients
had displayed NK
cell activity belowin15aLU
exhibited normal
celllow
activity.
after this We
correction
factor, 45%
of 45%
the children
pronounced
subgroup
with NK
very
NKOverall,
cell activity.
conclude
that
of
with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we
a
subgroup
of children
autism
low with
NK orcell
activity,
and IL-2
thatand
low
cultured
lymphocytes
of patientswith
with low
or highsuffers
NK cell from
activity/cell
without
glutathione,
IL-15.
intracellular
of glutathione,
IL-2
IL-15wasmay
responsible.”
The induction of levels
NK cell activity
by IL-2, IL-15
and and
glutathione
morebe
pronounced
in a subgroup with very low
NK cell activity. We conclude that 45% of a subgroup of children with autism suffers from low NK cell activity, and
that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.
100
90
81%
80
71%
70%
64%
70
56%
60
50%
50
56%
53%
46%
41%
40
30
20
8%
10
0
Controls
1
2
3
4
5
6
7
8
9
10
Figure 2 - % NK cell activity below 15 lytic units in controls and patients with autism
Percentage
of NK
activity
below 15 lytic units in controls and patients
obtained from
10 cell
different
clinics
with autism obtained from 10 different clinics.
Vojdani A. et al., Journal of Neuroimmunology 2008 (In Press)
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12
Effects of Opioids on the Immune System
Schematic representation of the hematopoietic system showing the differentiation pathways sensitive to opioids.
from Effects of Opioids on the Immune System – Roy S. and Loh H.H., Neurochemical Research, 21:1375-1386, 1996
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NALTREXONE
High Dose
Low Dose
d-Opioid Receptor
Antagonist
d-Opioid Receptor
Agonist
Inhibition of
T, B and NK function
IFN-g and IL-2
production
Stimulation of
T, B and NK function
IFN-g and IL-2
production
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MECHANISM OF ACTION OF LDN
LDN
Increase in
endogenous
enkephalin
and endorphin
Inhibition
of
proinflammatory
cytokines
Interaction of the
nuclear opioid
growth factor
receptor
Blockade of
opiate-R in GI
tract
Regulation of
TReg and
production of
IL-10 and
TGF-b
Effect on no.
of liquid bowel
movements
Promotion
Of DNA
synthesis
Enhancement
of
immune
function
Improvement
in
inflammatory
reaction
Healing
of
corneal
ulcers
Healing & repair
of mucosal
tissue
Improvement
in Crohn’s
disease
activity
Down
regulation
of
TH-17
15
The Role of Environmental Factors in Gut-Brain
Inflammation and Its Possible Inhibition by LDN
LDN
LDN
LDN
LDN
LDN
LDN
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