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Vol. 286, Issue 2, 883-889, August 1998
Neuro-Behavioural Biology Center (P.G., T.S., N.K.), Institute of Science and Technology for Research and Development, Mahidol University at Salaya, Nakornpathom 73170, Thailand and Thanyarak Hospital (T.U.), Department of Medical Services, Ministry of Public Health, Thunyaburi, Pathumthani 12130, Thailand
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Abstract |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Conflicting results, both decreased and increased, have been reported
concerning the function of T-lymphocytes in heroin addicts. We
investigated the alterations of T-lymphocyte proliferative responses
and immunophenotypic markers on lymphoid cells in heroin addicts and
during different periods of heroin withdrawal in addicted subjects.
This study has demonstrated a decrease in the response of T-lymphocytes
to 1.2, 2.5, 5 and 10 µg/ml of phytohemagglutinin stimuli in heroin
addicts and 1- to 5-day heroin withdrawal subjects compared with
controls. Similarly, in an in vitro study,
10
, 10 and
10 M concentrations of morphine were shown
to suppress 0.6 and 2.5 µg/ml of PHA-stimulated T-lymphocyte obtained
from naive subjects. This inhibitory effect of morphine on PHA
stimulation was completely abolished by 100 µM naloxone. The
immunological parameters of total T-lymphocytes (CD3), T-helper cells
(CD4), cytotoxic T-cells (CD8), B-cells and natural killer cells that
are the immunophenotypic markers studied by flow cytometric analysis
were altered in heroin addicts, 15- to 21-day and 6- to 24-month heroin
withdrawal subjects, when compared with controls. These results suggest
that heroin addicts and short period (15 to 21 days and 6 to 24 months)
of heroin withdrawal have decreases in their immune system functioning and that the heroin withdrawal subjects seem to gradually reverse their
immunological parameters to normal levels when withdrawal was sustained
2 years. This is the first report examining immune function in heroin
withdrawal subjects using the "cold turkey" method. The results are
beneficial for further study of the mechanism responsible for the
opioid-induced changes in immune function.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Because
of the AIDS epidemic, interest in studying the effects of drugs of
abuse, especially opiates, on the immune system has increased greatly.
This issue is now of paramount importance because of the association of
AIDS with intravenous drug abuse. Heroin abusers are a high-risk group
for the development of AIDS and HIV infection. Intravenous drug abusers
account for 7.3% of the total AIDS cases in Thailand (Wongkhomthong
et al., 1995
). Indeed, the HIV-seropositivity rate among
intravenous drug abusers can be even greater, ranging from 5% in
certain areas to 75% in others (Curran et al., 1984), and
this group is generally regarded as posing the most substantial risk of
furthering spread of the disease. Even in the absence of AIDS,
increasing evidence indicates that chronic use of opioid drugs can
affect the functioning of the immune system. Heroin addicts have an
increased susceptibility to a variety of infectious diseases (Louria
et al., 1967), and alterations in a wide variety of immune
parameters also have been reported among them (for reviews, see
Rouveix, 1992; Sibinga and Goldstein, 1988; Carr et al.,
1996).
A variety of changes in the immune system have been observed,
indicative of both decreased and increased functioning in heroin addicts. The absolute number and percentage of total and active T
lymphocytes in the peripheral blood of opiate addicts and T-cell rosette formation were significantly depressed (McDonough et
al., 1980). In contrast, an increase in the absolute number of
T-cells in the blood of heroin addicts who were not malnourished was
reported in another study (Heathcote et al., 1981). Similar
conflicting results have been reported concerning the functional
activity of T lymphocytes from heroin addicts. Brown et al.
(1974) found impaired in vitro responsiveness of lymphocytes
to each of the three mitogens (PHA, concavanalin A, pokeweed mitogen)
in heroin addicts relative to control values. Similarly, a suppressed
PHA response in methadone patients was reported (Quagliata et
al., 1977); but Reddy et al. (1987) found normal
T-proliferative responses to both concavanalin A and tetanus toxoid
antigen in another group of healthy addicts.
Immunophenotypic markers on lymphoid cells in human addicts have been
studied using flow cytometric analysis. There was a profound decrease
in the T-helper/cytotoxic T-cell (CD4/CD8) ratio in heroin addicts
(Donahoe et al., 1987). Shine et al. (1987) found
a normal pattern of T-cell subsets and a normal CD4/CD8 ratio in
another group of healthy intravenous drug abusers and methadone
patients. Most of the data have suggested that opiates are involved in
the cell-mediated immune responses in heroin addicts. However, data of
immune responses in heroin-withdrawal subjects during various
withdrawal periods are not available at this moment. Thus, the evidence
for the immunomodulatory, and even the immunocompromising potential of
opioids is compelling. Still, our understanding of the effects of
opioids on the immune system is incomplete. Controversial results, in
part, may be due to the specific mechanisms responsible for
morphine-induced changes in the immune system being undefined. In
addition, most of the heroin addicts are polydrug users. It is
necessary to better understand the way in which heroin modulates immune
responses, as well as the relationship between these effects, and to
investigate whether this results in increased susceptibility to
infections. We focused our attention on studies of the heroin-addicted and heroin withdrawal subjects by considering the lymphocyte
proliferative responses, the expression of total T lymphocytes (CD3),
T-helper cells (CD4), cytotoxic T-cell (CD8) antigenic markers of
T-cells, B cells and NK cells. We conducted studies in humans because
humans are significantly different from even the closest primates, and certainly profoundly different from rodents, with respect to certain specific immune indices and the pharmacokinetics of many drugs, as well
as neuroendocrine functions. This is the first study of the immune
function in heroin withdrawal subjects who used the "cold turkey"
method, with no supplement of methadone or other drugs in the
withdrawal period.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subject selection.
Subjects consisted of parenteral heroin
abusers and heroin withdrawal subjects from Thanyarak Hospital, which
is one of the biggest hospitals in Thailand, with ~100 to 200 cases
of outpatient drug abusers daily. All subjects were men, aged 20 to 40 years, and none had recent infections, active inflammatory disease or a
positive HIV or HBsAg test. They were free of drugs affecting the
immune system and had no history of neuropsychiatric disorders. Subjects participating in this study gave written informed consent. All
of the parenteral heroin abusers were selected from those who had a
history of intravenous injection of heroin for 1 year, with a daily
heroin dosage of not less than 600 mg. They absolutely did not abuse
other drugs. The heroin withdrawal subjects used the "cold turkey"
method for withdrawal from heroin, after which they experienced
"craving" with some withdrawal symptoms, such as rhinorrhea,
lacrimation, piloerection, restlessness, irritability, insomnia,
abdominal cramps, muscle "bone" aches and so on. They were free of
drugs for suppressing the withdrawal symptoms.
Serum and urine analyses. Blood and urine from volunteers in all groups of this study were obtained between 9:00 to 11:30 a.m. Blood was collected into polyethylene tubes containing 1000 U/ml heparin. Routine medical and immunological histories were obtained from all subjects. Routine urine analysis was performed, emphasizing the measurement of type and quantity of substances abused. Urine morphine was reported positive by a cutoff limit at >5.50 µg/ml. Sera from all subjects were tested for HIV antibodies using a particle-agglutination test for screening of antibodies to HIV (Serodia-HIV, Tokyo, Japan) at Thanyarak hospital and double-checked by using MICRO RED kit (BioRad, Hercules, CA) for screening of HIV-1/HIV-2 antibodies in our laboratory. Blood chemistry studies to assess hepatitic function were determined in all subjects.
Lymphocyte cultures.
Freshly drawn venous blood (10 ml) from
subjects was diluted 1:1 with Hanks' balanced salt solution. The cell
suspension (20 ml) was layered on 4 ml of Ficoll-paque solution
(Pharmacia, Uppsala, Sweden) (specific gravity, 1.083) for
separation of lymphocytes according to the method of Sacerdote et
al. (1991). After centrifugation at 600 × g for
20 min, the layer containing lymphocytes was transferred to another
centrifuge tube, washed twice in 10 ml of Hanks' balanced salt
solution and then centrifuged at 1200 × g for 10 min.
The cells were resuspended again with RPMI media containing 10%
heat-inactivated fetal calf serum, 100 IU/ml penicillin, 100 mg/ml
streptomysin, 1% L-glutamine (Sigma Chemical, St. Louis,
MO) and 1 mM HEPES (Sigma). Then, the suspension was centrifuged at
1200 × g for 10 min. The pellets were lymphocytes that
were brought to culture for studying proliferation.
Cell preparation for immunofluorescent staining in flow
cytometric studies.
Peripheral blood samples were collected into
EDTA anticoagulant tubes and processed within 2 hr of collection. All
samples were prepared using lysed whole blood and stained with the
following panel of two-color antibody conjugates: LeucoGATE
(CD45FITC/CD14PE) [CD45/CD14], isotype control
(IgG1FITC/IgG1PE)[
1/2],
CD3FITC/CD16+56PE(Leu4/11C+19), CD3FITC/CD19PE(Leu-4/12),
CD3FITC/CD8PE(CD3/CD8)[Leu-4/2] and CD3FITC/CD4PE (CD3/CD4)
[Leu-4/3]. After a 15-min room temperature incubation period, the red
blood cells were lysed with FACSLysing Solution (Becton Dickinson, San
Jose, CA). Samples were then fixed in a 1.0% paraformaldehyde solution
before flow cytometric analysis.
Flow cytometric analysis.
Flow cytometric studies were
performed on a FACScan Analyzer (Becton Dickinson, San Jose, CA). The
FACScan used an air-cooled argon ion laser with emission at 488 nm. The
FACScan was calibrated using an automatic software, AutoCOMP and
CaliBRITE beads. SimulSET software was used for data acquisition and
analysis, and LeucoGATE defined the lymphocyte gate, which included
95% of the total lymphocyte population. Isotype controls defined
autofluorescence and positioned the quadrant markers to calculate the
percent positive cells for a given antibody.
Statistical analysis. Results were expressed as mean ± S.E.M. Student's t tests were performed on continuous variables. For studies involving multiple comparisons, data were analyzed by Tukey-Kramer multiple comparison test.
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Results |
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Abstract
Introduction
Methods
Results
Discussion
References
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PHA-stimulated T lymphocyte proliferation in heroin-addicted and heroin withdrawal subjects. The base-line characteristics of all subjects; normal (N; n = 17), heroin addicts (H; n = 19) and heroin withdrawal subjects (HW; n = 17) in the T-lymphocyte proliferation study are shown in table 1. The ages of the subjects ranged from 22 to 28 years. The dosage range of heroin that was used by heroin addicts and heroin withdrawal subjects was 600 to 1200 mg/day. The durations of heroin abuse were 2.95 ± 0.53 and 1.36 ± 0.18 years in heroin addicts and heroin withdrawal groups, respectively. Urine morphine of >5.50 µg/ml was detected in the heroin-addicted group.The duration of withdrawal periods ranged from 1 to 5 days. They all were negative in HIV and HBsAg tests.
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Comparison of lymphocyte subsets among normal, heroin-addicted and heroin withdrawal subjects. To further evaluate the immunosuppressive responses in heroin abusers and heroin withdrawal subjects during various periods of time, flow cytometric analysis was performed and subjects were selected accordingly. The base-line characteristics of all subjects: normal (N; n = 17), heroin addicts (H; n = 15), 15- to 21-day heroin withdrawal (HW1; n = 15), 6- to 24-month heroin withdrawal (HW2; n = 16) and 3- to 5-year heroin withdrawal (HW3; n = 15), are shown in table 2. The average age was between 21 to 31 years, with the same daily doses of heroin use (range, 600-1200 mg/day). The average durations of heroin abuse were 2.95 ± 0.53, 1.90 ± 0.78, 6.10 ± 1.22 and 6.00 ± 1.05 years in heroin addicts and in 15- to 21-day (HW1), 6- to 24-month (HW2) and 3- to 5-year (HW3) withdrawal groups, respectively. They all were free from HIV and HBs infections. The mean ± S.E.M. values of percent and absolute numbers of lymphocyte and total T-lymphocyte (CD3) obtained from various groups of subjects are shown in figure 4, A-D. There was no significant difference in the percentages of lymphocytes and total T-lymphocytes among different groups compared with controls. However, the absolute numbers of lymphocytes (fig. 4B) and total T-lymphocytes (CD3) (fig. 4D) were both significantly increased in heroin addicts, gradually declining to normal levels as heroin withdrawal progressed. The percentages of T-helper cells (CD4) obtained from heroin addicts and short period heroin withdrawal groups were significantly decreased, reverting to normal levels when heroin withdrawal had continued for a longer period of time (6 months to 5 years) (fig. 5A). In contrast, the percentages of cytotoxic T-cell (CD8) obtained from heroin addicts and short period heroin withdrawal groups were significantly increased (P < .001), reverting to normal levels when heroin withdrawal had continued for a longer period of time (fig. 5C). The absolute numbers of CD8 in different groups of subjects were altered in the same manner as the percents of CD8 (fig. 5D), whereas the absolute numbers of CD4 in all cases did not show any significant difference among groups (fig. 5B). The ratios of T-helper/cytotoxic T-cell (CD4/CD8) were shown to be significantly decreased in heroin addicts (P < .001), in 15- to 21-day heroin withdrawal (P < .001) and in 6- to 24-month heroin withdrawal (P < .05) compared with normal subjects, whereas this ratio reversed to normal values in 3- to 5-year heroin withdrawal subjects (fig. 5E). Both the percentage (fig. 6A) and absolute numbers of B-cells (fig. 6B) obtained from heroin addicts and 15- to 21-day heroin withdrawal subjects were significantly increased (P < .01) compared with those obtained from normal subjects, whereas the numbers obtained from subjects during longer periods of heroin withdrawal were comparable to those of normal subjects. The percentage of NK cells (fig. 6C) obtained from heroin addicts and the 15- to 21-day heroin withdrawal group were significantly decreased (P < .05 and P < .01, respectively) compared with normal subjects, whereas the absolute numbers of NK cells (fig. 6D) from all groups of subjects were not significantly different. However, the percentage (fig. 6C) and absolute number of NK cells (fig. 6D) in the 6- to 24-month heroin withdrawal group were increased significantly (P < .05) compared with heroin-addicted subjects.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Alteration of immune function in heroin addicts.
Opiates have
been shown to produce effects on immune function in vivo
(Weber and Pert, 1989), and clinical observations that opiate addicts
have increased susceptibility to infections (Louria et al.,
1967) were subsequently shown to be related to deficits in immune
function (Brown et al., 1974). Our study has demonstrated a
decrease in the response of T lymphocytes to a wide range of concentrations of mitogenic (PHA) stimuli in heroin-addicted subjects. This data supports the result from Roy et al. (1995), who
demonstrated that chronic morphine treatment in vivo
inhibited PHA-IL1-activated thymocyte proliferation. It has been
proposed that the effects of opioids on lymphocyte proliferation may
operate via a direct interaction with opioid receptors
(Sibinga and Goldstein, 1988). To test the above hypothesis, the effect
of morphine in vitro has therefore been studied. Morphine
attenuated the mitogen-induced lymphocyte proliferation in a
dose-dependent manner. Roy et al. (1991) showed a
suppressive effect of chronic morphine treatment on macrophage colony
formation in bone marrow. In addition, morphine inhibited proliferation
of PHA-IL-1 activation of naive mice thymocytes in a dose-dependent
manner could be demontrated in vitro (Roy et al.,
1995). Our data also indicate that this inhibitory effect was abolished
by naloxone. However, our unpublished observation showed that neither
morphine nor naloxone could significantly alter the background (without
PHA) proliferation of lymphocyte. Roy et al. (1996) and Wick
et al. (1996) demonstrated that morphine-mediated inhibition
of Bac1.2 F5 macrophage in culture was partially reversible by
naloxone, and their previous experiment showed that activation of
thymocyte with PHA-IL1 in vitro resulted in a dramatic
increase in (3H)-morphine specific binding (Roy
et al., 1992). Collectively, we suggest that PHA might
induce proliferation of different population of lymphocytes containing
different affinities of opioid receptors that are more or less
sensitive to morphine.
found a normal pattern of T-cell subsets in a group of
healthy intravenous drug abusers and methadone patients, whereas Sei
et al. (1991) and Novick et al. (1989) found that parenteral heroin abusers had higher absolute numbers of CD4 cells in
the peripheral blood.
NK cell activity mediated predominantly by large granular lymphocytes
is also regulated by opioid compounds. In vitro,
-endorphin and met-enkephalin augmented NK activity in a
dose-dependent and naloxone-reversible fashion (Matthews et
al., 1983; Kay et al., 1984). Morphine was slightly
suppressive (Matthews et al., 1983), and DAMGO suppressed NK
activity (Weber et al., 1989). Shavit et al.
(1986) have previously shown that opiates interacting with opiate
receptors in the brain are implicated in the suppression of NK
activity. Those authors suggested novel central nervous system
mechanisms through which the immune response might be regulated. In the
present study, the percentage of NK cells was suppressed in heroin
addicts. This was supported by a previous study showing that parenteral
heroin addicts had significantly reduced NK activity while the absolute
numbers of NK cells in peripheral blood were unchanged (Novick et
al., 1989). The similar findings had previously been reported by
Reddy et al. (1987) and DePaoli et al. (1986), who observed reduced NK cell activity in HIV-seronegative parenteral drug addicts and a further reduction in HIV-seropositive patients.
The present study in heroin addicts has shown an increase in both the
number and the percentage of B cells by immunofluorescence staining.
Johnson et al. (1982) reported that 
-endorphin in
vivo significantly depressed primary antibody production to sheep
red blood cells. Both met-enkephalin and leu-enkephalin are modulate inhibitors, whereas - and -endorphin are not effective. Morphine seems to have no effect on antibody production where animals are immunized with a T-independent antigen. However, in vivo
administration of -endorphin inhibited the primary antibody response
to keyhole limpet hemocyanin but enhanced the secondary response (Munn
et al., 1989).
Immune status in heroin-withdrawal subjects.
The immune
function in heroin withdrawal subjects also was a focus of the present
study. In most previous studies of heroin addiction, the data were
obtained from patients who were not only polydrug abuses but also in
the withdrawal state; most patients were either treated with drugs to
suppress withdrawal symptoms, in methadone maintenance therapy or both.
The patients in our study not only were single-drug abusers but, in the
withdrawal state, also were free of any drug, as heroin withdrawal was
carried out "cold turkey." This would make our results extremely
beneficial for the better understanding of heroin withdrawal
mechanisms. In a previous study (Novick et al., 1989) of
long-term stabilized methadone-maintenanced patients, NK cell activity
and absolute B- and T-cell subset numbers were not significantly
different from those of normal control subjects. Kind (1988) performed
a study in unselected groups of former narcotic addicts in methadone maintenance treatment for varying periods of time, including patients both with and without continuing polydrug and alcohol abuse. He found
that 53% of subjects had normal NK cell cytotoxicity. However, methadone itself has been shown to have immunomodulatory effects, and
these effects are dose dependent. At doses below 75 mg/kg, it was
possible to reverse the immunodepressive effect of heroin (Novick
et al., 1989). In contrast, in an in vitro study,
Kind (1988) showed that neither opioid antagonist (naloxone) nor opioid agonist (methadone) altered NK cytotoxicity until drug concentrations pf >104 M above pharmacological levels
were reached, at which point both compounds reduced NK activity in
parallel responses. In the present study, the suppression of lymphocyte
proliferation responses was partially reversed in the heroin withdrawal
subjects. All parameters, assessed by flow cytometric analysis, were
altered in heroin addicts but gradually returned to normal levels, with
the exception of the short period of withdrawal (15 to 21 days), where
they seemed to get worse. However, the total recovery in almost all
immunological parameters obtained here would not occur before 3 to 5 years after drug withdrawal. Our studies supported the notion that
"the time course of the development of tolerance following initial
drug exposure and the persistence of tolerance following sudden removal of the drug was found to parallel the development and decline of immune
reactions" (Cochin and Kornetsky, 1964). Our result clearly
demonstrates that the immunological deficits evidenced during drug
consumption are reversible slowly after heroin is withdrawn, without
taking methadone and concomitantly in parallel with the decline of the
withdrawal signs and other neurobehavioral effects.
). Other recent
studies also suggest that morphine-mediated effects on the immune
system operates through central processes (Hernandez et al.,
1993; Fecho et al., 1993). However, there was an indication that the HPA axis was not necessarily involved in all opioid-mediated immunosuppressive effects because injection of opioid compounds into
specific sites of the brain that resulted in a suppressive effect on
immune function (e.g., lymphocyte proliferation on splenic NK activity) did not change the circulating levels of corticosterone (Band et al., 1992; Hernandez et al., 1993).
Collectively, these results provide convincing evidence for the local
and systemic activity of opioids on immunocompetence and immune
homeostasis. Attempts to definitively prove of the existence of opioid
receptors on cells of the immune system have been unsucessful in
various laboratories, including our own by using radioligand binding. However, recently, molecular techniques have provided data (Sedqi et al., 1995; Chuang et al., 1995; Wick et
al., 1996; Roy et al., 1996) indicating the existence
of opioid receptors on cells of the immune system.
In conclusion, the results from our study indicate a depression in
PHA-stimulated T lymphocyte proliferation, both as an in vitro effect of morphine and in heroin addicts, including the modulation of surface markers observed on T cells. The alteration of
the T lymphocyte proliferative responses and surface markers seems to
gradually reverse to normal levels when heroin is withdrawn. The
mechanisms responsible for the opioid-induced changes in immune function are still unclear. They may be mediated directly
via opioid receptors present on lymphocytes (Wick et
al., 1996; Roy et al., 1996) and/or indirectly
via opioid receptors in the central nervous system.
Molecular biological and biochemical characterizations suggest that
immune cell differentially express classic opioid receptors. In
addition, the presence of a novel class of opioid receptor in immune
cells has been suggested, and it is believed that the antiproliferative
effect is mediated via this receptor type (Roy and Loh,
1996). However, multifactorial elements might be involved in such
alteration. Efforts should be continued and expanded to facilitate an
interchange of new ideas that will accelerate research and lead to the
more rapid development of new and more effective treatments for
substance abuse.
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Acknowledgments |
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We express their appreciation to the staff of Thanyarak Hospital for their support, helpful cooperation and suggestions.
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Footnotes |
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Accepted for publication April 8, 1998.
Received for publication December 12, 1997.
1 This work was supported by a Mahidol University Research Grant (P.G.) and a Thanyarak Hospital Research Fund (T.U.).
Send reprint requests to: Piyarat Govitrapong, Ph.D., Neuro-Behavioural Biology Center, Institute of Science and Technology for Research and Development, Mahidol University at Salaya, Nakornpathom 73170, Thailand. E-mail: grpkk{at}mahidol.ac.th
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Abbreviations |
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PHA, phytohemagglutinin; NK, natural killer; HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome; HPA, hypothalamus-pituitary-adrenal; IL-1, interleukin-1; RPMI, Roswell Park Memorial Institute; DAMGO, [D-Ala2,MePhe4, Gly-ol5]enkephalin; HBsAg, hepatitis B antigens.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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