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Combination thymosin alpha 1 and lymphoblastoid
interferon treatment in chronic hepatitis C
Rasi G; DiVirgilio D; Mutchnick MG; Colella F;
Sinibaldi-Vallebona P; Pierimarchi P; Valli B; Garaci E
Istituto di Medicina Sperimentale, CNR-Roma, Italy.
Gut (England) Nov 1996, 39 (5) p679-83
BACKGROUND: Monotherapy for chronic hepatitis C using
interferon (IFN) results in a very small proportion of
patients exhibiting a sustained response. Clinical trials
assessing the benefit of combination drug therapy may provide
evidence of improved treatment response over that seen with
single drug treatment. AIM: To assess the response in patients
with chronic hepatitis C to one year of combination treatment:
thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and
lymphoblastoid (L)-IFN, 3 MU thrice weekly.
PATIENTS AND METHODS: Fifteen patients with serum HCV RNA
positive chronic hepatitis C were studied. Eleven patients
were treatment naive and four had failed previous standard IFN
therapy. Thirteen patients were HCV RNA serotype 1b. All
patients were given combination T alpha 1 and L-IFN therapy
for one year with a six month follow up period.
RESULTS: Six months after initiation of treatment seven
patients (47%) were sera HCV RNA negative and at completion of
the one year treatment 11 (73%), including two who had failed
previous standard IFN treatment, had negative serum HCV RNA.
Six months after treatment, six patients (40%), including five
with HCV type 1b, showed a sustained response characterized by
a negative serum HCV RNA.
CONCLUSIONS: The results of this open label trial suggest
that there may be a potential benefit to combining an immune
modulator (T alpha 1) with an antiviral (IFN) in the treatment
of chronic hepatitis C. Verification of the observations in
this study require completion of a randomised controlled
study.
Effective immunization against neuroblastoma using
double-transduced tumor cells secreting GM-CSF and
interferon-gamma.
Bausero MA; Panoskaltsis-Mortari A; Blazar BR; Katsanis
E
Department of Pediatrics, University of Minnesota,
Minneapolis 55455, USA.
J Immunother Emphasis Tumor Immunol (United States) Mar 1996,
19 (2) p113-24
Murine neuroblastoma, neuro-2a, was transduced with the
retroviral vector MFG-granulocyte-macrophage
colony-stimulating factor (GM-CSF), to examine immune
stimulation conferred by localized GM-CSF production.
Expression of murine GM-CSF by neuro-2a (N-2a/GM)
significantly reduced its tumorigenicity. Moreover,
immunization of mice with irradiated N-2a/GM cells resulted in
a significant protective effect against live tumor challenge
14 days later. Approximately 41% of mice immunized with
irradiated N-2a/GM versus 0% of those vaccinated with
irradiated parental tumor survived. Surviving mice were
rechallenged after 50 days with wild-type neuro-2a or with the
Sa1 syngeneic sarcoma to discern whether the generated
immunity was durable and tumor specific. All mice survived
wild-type neuro-2a challenge, whereas none survived
inoculation with Sa1. Because both CD4+ and CD8+ T cells were
necessary during priming to this MHC class Ilo, II-tumor,
these data indicate that major histocompatibility complex
(MHC) class I+, II+ antigen-presenting cells (APCs) were
required for the T-cell antitumor response. Co-expression of
GM-CSF and IFN-gamma, both of which have immunostimulatory
activities on antigen-presenting cells, abrogated the
tumorigenic potential of this tumor and increased
immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of
mice with preexisting retroperitoneal tumors with irradiated
N-2a/GM and irradiated N-2a/IFN/GM improved survival. There
was a trend for nonirradiated transduced cells to be more
immunogenic than their irradiated counterparts.
Immunohistochemistry of tissues from the vaccination site
revealed a pronounced macrophage infiltration associated with
nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that
vaccination involving nonirradiated neuroblastoma cells
transduced with genes that stimulate APCs may be a useful
approach in stimulating antitumor T-cell responses.
Improved sustained response following treatment of
chronic hepatitis C by gradual reduction in the interferon
dose.
Shiffman ML; Hofmann CM; Luketic VA; Sanyal AJ; Contos MJ;
Mills AS
Hepatology Section, Medical College of Virginia, Richmond, Va
23298, USA.
Hepatology (United States) Jul 1996, 24 (1)
p21-6
Interferon (IFN) treatment of chronic hepatitis C virus
(HCV) is associated with a high rate of relapse. IFN is
thought to exert its effect against HCV via direct viral
inhibition and immune stimulation. We have hypothesized that
relapse following termination of therapy results from the
sudden withdrawal of this immune modulatory effect and that
gradual reduction in the IFN dose may decrease the incidence
of relapse. One hundred six patients with chronic HCV were
enrolled into this 24-month controlled, randomized prospective
trial. All were treated with 5 mU of interferon-alpha-2b three
times a week for 6 months. Patients who achieved biochemical
response were randomized to either stop or taper IFN gradually
at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU
(all three times a week). 0.5 mU twice weekly and then once
weekly. Liver histology was assessed by Knodell index and HCV
RNA was measured by a quantitative polymerase chain reaction
(PCR) assay. Of the 92 patients who completed the initial 6
months of IFN treatment, 47 (51%) achieved biochemical
response. Twenty-one of these patients were randomized to stop
IFN treatment and 25 to taper (1 drop-out). At randomization
patients were well matched with respect to age, sex, race,
serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients
who stopped IFN treatment compared with only 60% who tapered
IFN (P= .04). Virological relapse occurred in 90% of patients
who stopped and only 48% of persons who tapered IFN therapy.
At completion of the 24-month study patients who achieved
long-term sustained biochemical response had a significantly
lower mean Knodell score (3.5 vs. 6.5) and a significantly
greater number were HCV RNA negative in serum (85% vs. 18%)
compared with relapsers. We conclude that gradual reduction in
IFN dose is associated with a significant higher rate of
sustained response and clearance of HCV RNA from serum
compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology
supporting the premise that response to IFN therapy can
prevent progression to cirrhosis.
Improved immunotherapy of a recombinant
carcinoembryonic antigen vaccinia vaccine when given in
combination with interleukin-2.
McLaughlin JP; Schlom J; Kantor JA; Greiner JW
Laboratory of Tumor Immunology and Biology, National Cancer
Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Res (United States) May 15 1996, 56 (10)
p2361-7
Interleukin-2 (IL-2) has been an effective immune modulator
in several active-specific immunotherapy experimental
protocols using either viral or oncolysate-based vaccines. In
this report, data indicate that IL-2 administration can
appreciably augment the therapeutic effect of a single
immunization of a recombinant vaccinia virus-carcinoembryonic
antigen (rV-CEA) vaccine using a CEA-expressing syngeneic
experimental murine model system. A single rV-CEA immunization
of C57BL/6 mice bearing palpable CEA-positive colon
adenocarcinoma tumors results in complete tumor regression in
approximately 20% of the mice. The addition of a course of
low-dose IL-2 results in complete tumor regression in 60-70%
of the mice. Moreover, the combination of rV-CEA and IL-2
induces systemic immunity, which protects those tumor-free
mice from subsequent rechallenge with the CEA-expressing tumor
cells. No such tumor regression or protection was observed in
those mice immunized with the wild-type vaccinia vaccine
(V-Wyeth) alone or with IL-2 administration alone. Cellular
immune assays revealed that the addition of IL-2 to rV-CEA
immunization significantly increased the CEA-specific T-cell
proliferative responses as well as the cytolytic T-cell
responses when compared with rV-CEA immunization alone. The
enhanced CEA-specific immune response, coupled with the
improved experimental therapeutic outcome following IL-2
administration, suggests that treatment with that cytokine may
effectively substitute for multiple rV-CEA immunizations in
active-specific immunotherapy clinical protocols directed at
CEA-expressing tumors.
Vitamins and immunity: II. Influenceof L-carnitine
on the immune system.
De Simone C; Ferrari M; Lozzi A; Meli D; Ricca D; Sorice
F
Acta Vitaminol Enzymol (Italy) 1982, 4 (1-2)
Vitamin A affects the antibody responses and may affect
phagocytic function and properdin levels. Pyridoxine
deficiency impairs nucleic acid synthesis and depresses
antibody formation, delayed hypersensitivity reactions and the
ability of phagocytes to kill bacteria. Pantothenic acid
deficiency impairs antibody formation. Vitamin-C deficiency
increases the incidence of infection, primary by a negative
influence on reparative processes. Deficiencies of other
vitamins either have not been sufficiently studied or have a
variable effect. Moreover, even substances which for their
biosynthesis require an adequate vitamin supplementation may
exert immunomodulatory influences. With this respect the
authors report their results on the influence of L-carnitine
on the immune system. L-carnitine increases the proliferative
responses of both murine and human lymphocyte following
mitogenic stimulation and increase polymorphonuclear
chemotaxis. Furthermore, L-carnitine, even at minimal
concentrations, neutralizes the lipid induced
immunosuppression.
Suppression of tumor growth and enhancement of
immune status with high levels of dietary vitamin B6 in BALB/c
mice.
Gridley DS; Stickney DR; Nutter RL; Slater JM; Shultz
TD
J Natl Cancer Inst 1987 May;78(5):951-9
Effects of dietary vitamin B6 at levels ranging from
deficiency to megadoses on the development of herpes simplex
virus type 2-transformed (H238) cell-induced tumors and on in
vitro responses relating to cell-mediated immunity were
examined. Male BALB/cByJ mice (n = 260), 5 weeks of age, were
fed 20% casein diets containing pyridoxine (PN) at 0.2, 1.2
for the control diet, 7.7, or 74.3 mg/kg diet for 4-11 weeks.
After 4 weeks of dietary treatment, 120 of the mice received
an injection of H238 cells; mice without H238 injection served
as controls. At 4, 8, and 11 weeks, animals from each group
were euthanized and blood and spleen samples obtained. Mice
fed 0.2 mg PN developed mild deficiency symptoms and gained
significantly less weight than those fed 1.2-, 7.7-, and
74.3-mg PN diets. Thirteen to 16 days after tumor cell
injection, primary tumor incidence was lowest in mice fed 74.3
mg PN; later, incidence among groups was similar. Mice fed 1.2
mg PN had the largest primary tumor volume, the highest
incidence of lung metastases, and the greatest number of
metastatic nodules per animal at 7 weeks post injection.
Overall, lower tumor volumes were found in animals fed 7.7 and
74.3 mg PN (14 and 32% less than the tumor volume for those
fed 1.2 mg PN, respectively); mice fed 0.2 mg PN had the
lowest tumor volume. Blood and spleen lymphoproliferative
response to stimulation by phytohemagglutinin or concanavalin
A generally tended to be higher in mice fed 7.7 and 74.3 mg PN
as compared to that in animals fed either 0.2 or 1.2 mg PN.
However, decreased mitogen-stimulated responsiveness was
observed in all animals with progressive tumor growth. Tumor
growth also resulted in splenomegaly and increased thymic
atrophy. Significant negative relationships between tumor
volume and tumor pyridoxal 5-phosphate (PLP) concentrations
were observed for 1.2-, 7.7-, and 74.3-mg PN diet groups.
These data suggest that high dietary intake of vitamin B6 may
have suppressed tumor development by either immune enhancement
or PLP growth regulation of this tumor.
The activities of coenzyme Q10 and vitamin B6 for
immune responses.
Folkers K, Morita M, McRee J Jr
Institute for Biomedical Research, University of Texas,
Austin 78712.
Biochem Biophys Res Commun 1993 May
28;193(1):88-92
Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been
administered together and separately to three groups of human
subjects. The blood levels of CoQ10 increased (p < 0.001)
when CoQ10 and pyridoxine were administered together and when
CoQ10 was given alone. The blood levels of IgG increased when
CoQ10 and pyridoxine were administered together (p < 0.01)
and when CoQ10 was administered alone (p < 0.05). The blood
levels of T4-lymphocytes increased when CoQ10 and pyridoxine
were administered together (p < 0.01) and separately (p
< 0.001). The ratio of T4/T8 lymphocytes increased when
CoQ10 and pyridoxine were administered together (p < 0.001)
and separately (p < 0.05). These increases in IgG and
T4-lymphocytes with CoQ10 and vitamin B6 are clinically
important for trials on AIDS, other infectious diseases, and
on cancer.
Research on coenzyme Q10 in clinical medicine and
in immunomodulation.
Folkers K; Wolaniuk A
Drugs Exp Clin Res (Switzerland) 1985, 11 (8)
p539-45
Coenzyme Q10 (CoQ10) is a redox component in the
respiratory chain. CoQ10 is necessary for human life to exist;
and a deficiency can be contributory to ill health and
disease. A deficiency of CoQ10 in myocardial disease has been
found and controlled therapeutic trials have established CoQ10
as a major advance in the therapy of resistant myocardial
failure. The cardiotoxicity of adriamycin, used in treatment
modalities of cancer, is significantly reduced by CoQ10,
apparently because the side-effects of adriamycin include
inhibition of mitochondrial CoQ10 enzymes. Models of the
immune system including phagocytic rate, circulating antibody
level, neoplasia, viral and parasitic infections were used to
demonstrate that CoQ10 is an immunomodulating agent. It was
concluded that CoQ10, at the mitochondrial level, is essential
for the optimal function of the immune system.
Immunoenhancing effect of flavonoid compounds on
lymphocyte proliferation and immunoglobulin synthesis.
Brattig NW; Diao GJ; Berg PA
Int J Immunopharmacol (England) 1984, 6 (3)
p205-15
Flavonoid compounds are lipophilic agents which can
interact with membrane lipids and may affect responsiveness of
immune cells. We therefore studied whether cianidanol
((+)-catechin), the O-methyl-derivative
(+)-3-methoxy-5,7,3',4'-tetrahydroxyflavan and
palmitoyl-derivative
(+)-3-palmitoyl-5,7,3',4'-tetrahydroxyflavan influence T and B
cell functions. In addition, immunomodulatory property of
ubiquinone 50 was also investigated. As controls were used
cyclosporin A and inosine which are known to inhibit or
enhance immune responses, respectively. The in vitro
spontaneous, antigen and mitogen induced proliferation as well
as immunoglobulin synthesis of peripheral blood mononuclear
cells from healthy individuals was determined in the presence
of different concentrations of the agents. All flavonoid
compounds and ubiquinone 50 significantly increased (p less
than 0.05 - less than 0.01) the spontaneous lymphocyte
transformation but hardly affected antigen, alloantigen and
mitogen induced proliferative response. Only cianidanol and
O-methyl-derivative enhanced significantly (p less than 0.05 -
less than 0.01) spontaneous, pokeweedmitogen and
Staphylococcus aureus Cowan I induced immunoglobulin synthesis
while the palmitoyl-derivative and ubiquinone 50 had only
minor influence on B cell function. In contrast,
Staphylococcus aureus induced immunoglobulin production was
neither increased by inosine nor suppressed by cyclosporin A.
These studies show that especially cianidanol and the
O-methyl-derivative can exert an immunoenhancing effect on T
and B cell functions.
Immunological senescence in mice and its reversal
by coenzyme Q10.
Bliznakov EG
Mech Ageing Dev 1978 Mar;7(3):189-97
A pronounced suppression of the humoral, hemolytic, primary
immune response in old (22 months) mice was demonstrated as
compared with this response in young (10 weeks) mice. The
suppression is associated with a lower thymus weight:body
weight ratio. In contrast, the ratios spleen weight:body
weight and liver weight:body weight in 10 weeks and 22 months
old mice remain almost constant. A single administration of
coenzyme Q10--a non-toxic, non-specific stimulant of the host
defense system--partly compensates the age-determined
suppression of the humoral, immune response. This suppression
probably results from an age-dependent imbalance of T cells: B
cells ratio and a decline of their immunological
responsiveness which is compensated by the administration of
coenzyme Q10.
Immune effects of preoperative immunotherapy with
high-dose subcutaneous interleukin-2 versus neuroimmunotherapy
with low-dose interleukin-2 plus the neurohormone melatonin in
gastrointestinal tract tumor patients.
Lissoni P; Brivio F; Brivio O; Fumagalli L; Gramazio F; Rossi
M
J Biol Regul Homeost Agents (Italy) Jan-Mar 1995, 9 (1)
p31-3
Surgery-induced immunosuppression could influence
tumor/host interactions in surgically treated cancer patients.
Previous studies have shown that high-dose IL-2 preoperative
therapy may neutralize surgery-induced lymphocytopenia.
Moreover, experimental studies have demonstrated that the
immunomodulating neurohormone melatonin (MLT) may amplify IL-2
activity and reduce its dose required to activate the immune
system. On this basis, we have compared the immune effects of
presurgical therapy with high-dose IL-2 with respect to those
obtained with preoperative neuroimmunotherapy consisting of
low-dose IL-2 plus MLT. The study included 30 patients with
gastrointestinal tract tumors, who were randomized to undergo
surgery alone, or surgery plus a preoperative biotherapy with
high-dose IL-2 (18 million IU/day subcutaneously for 3 days)
or low-dose IL-2 (6 million IU/day subcutaneously for 5 days)
plus MLT (40 mg/day orally). Patients underwent surgery within
36 hours from IL-2 interruption. Both IL-2 plus MLT were able
to prevent surgery-induced lymphocytopenia. However, mean
number of lymphocytes, T lymphocytes and T helper lymphocytes
observed on day 1 of postoperative period was significantly
higher in patients treated with IL-2 plus MLT than in those
receiving IL-2 alone. Moreover, toxicity was less in patients
treated with IL-2 and MLT. This biological study shows that
both immunotherapy with high-dose IL-2 or neuroimmunotherapy
with low-dose IL-2 plus MLT preoperatively are tolerated
biotherapies, capable of neutralizing surgery-induced
lymphocytopenia in cancer patients. Moreover, the study would
suggest that the neuroimmunotherapy may induce a more rapid
effect on postoperative immune changes with respect to IL-2
alone.
Pineal-opioid system interactions in the control of
immunoinflammatory responses.
Lissoni P, Barni S, Tancini G, Fossati V, Frigerio F
Division of Radiation Oncology, San Gerardo Hospital, Monza,
Milan, Italy.
Ann N Y Acad Sci 1994 Nov 25;741:191-6
Several studies have demonstrated involvement of the pineal
gland in the regulation of neuropeptide secretion and
activity. In particular, the existence of links between the
pineal gland and the brain opioid system has been documented.
Both opioid peptides and melatonin (MLT), the most
investigated pineal hormone, play an important role in
neuromodulation of the immunity. Moreover, the immune effects
of MLT are mediated by endogenous opioid peptides, which may
be produced by both the endocrine system and the immune cells.
In addition, the immune dysfunctions that characterize some
human diseases, such as cancer, depend not only on the immune
system per se, but also at least in part, on altered secretion
of immunomodulating neurohormones, including MLT and opioid
peptides. Therefore, the exogenous administration of
neurohormones could potentially improve the immune status in
humans. The present study evaluates the effects of MLT on
changes in the number of T lymphocytes, natural killer cells,
and eosinophils induced by exogenous administration of
interleukin-2 (IL-2). Macrophage activity was also evaluated
by determining serum levels of its specific marker, neopterin.
The study was performed in 90 patients with advanced solid
neoplasms, who received IL-2 at a dose of 3 million IU/day
subcutaneously for 6 days a week for 4 weeks plus MLT at a
daily dose of 40 mg. Both drugs were given in the evening. The
results were compared to those in 40 cancer patients treated
with IL-2 alone. The mean increase in T lymphocytes, natural
killer cells, and eosinophils was significantly higher in
patients treated with IL-2 plus MLT than in those who received
IL-2 alone.
Evidence for a direct action of melatoninon the
immune system.
Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF
Department of Physiology, University of Hong Kong.
Biol Signals 1994 Mar-Apr;3(2):107-17
Pineal melatonin modulates the mammalian immune system. In
vivo studies showed that melatonin enhanced the natural and
acquired immunity while in vitro studies demonstrated its
inhibitory influence. The mechanism of melatonin action on the
immune system remains unknown. Actions through lymphokines or
opioid release or via other endocrine changes have been
proposed. In this paper, a direct action of melatonin on the
lymphoid tissue is hypothesized. 2-[125I]Iodomelatonin binding
sites have been identified in the membrane homogenates of
thymus, bursa of Fabricius and spleens of a number of birds
and mammals. The bindings were stable, saturable, reversible,
specific and of high affinity. The Bmax ranged from 0.6 to 3.9
fmol/mg protein. The Kd was in the physiological range of
circulating melatonin levels, about 30-70 pmol/l. The binding
sites in the primary lymphoid organs demonstrated diurnal
variation in density, with higher levels found at the middle
of the light period. However, those in the spleen did not vary
with the time of the day.An age-dependent decrease in the
density was also found in the chicken bursa of Fabricius. In
addition, when the nocturnal melatonin secretion was
suppressed by constant light exposure, the density of the
binding sites increased in the guinea pig spleen.
Immunosuppression with cortisol injection in young ducks
decreased the density of the melatonin binding sites in the
thymus. The regulation of the binding characteristics by
physiological variation in melatonin levels and/or
immunological status of the animals provide evidence that
these 2-[125I]iodomelatonin binding sites in the lymphoid
tissues may be physiologically significant and represent true
melatonin receptors. The melatonin receptors in the lymphoid
organs may be coupled to a G protein as Guanosine
5'-0-(3-thiotriphosphate inhibited 2-[125I]iodomelatonin
binding in the spleen by increasing the Kd and decreasing the
Bmax.
The immuno-reconstituting effect of melatonin or
pineal grafting and its relation to zinc pool in aging
mice.
Mocchegiani E, Bulian D, Santarelli L, Tibaldi A, Muzzioli M,
Pierpaoli W, Fabris N
Gerontology Research Department, Italian National Institute
for Research on Aging (INRCA), Ancona.
J Neuroimmunol 1994 Sep;53(2):189-201
It has been demonstrated that melatonin, the main
neuro-hormone of the pineal gland, affects thymic functions
and the regulation of the immune system. In addition,
experimental evidences indicate that melatonin can modulate
zinc turnover. The knowledge that with advancing age both
melatonin and zinc plasma levels decline, and that zinc
supplementation in old mice is able to restore the reduced
immunological functions, has prompted investigations on the
effect of chronic melatonin treatment or pineal graft in old
mice on the age-related decline of thymic endocrine activity,
peripheral immune functions and zinc turnover. Both melatonin
treatment in old mice and pineal graft into the thymus of old
mice correct the reduced thymic endocrine activity and
increase the weight of the thymus and its cellularity. A
restoration of cortical thymic volume, as detected by the
percentage of tissue in active proliferation, is also observed
in old mice after both treatments. Thymocyte CD phenotype
expression is also restored to young values. At peripheral
level, recovery of peripheral blood lymphocyte number and of
spleen cell subsets, with increased mitogen responsiveness
also occurs. Melatonin treatment or pineal graft induce also a
restoration of the altered zinc turnover in aged mice with an
increment of the crude zinc balance from negative (-1.6
microgram/day/mouse) to positive value (+1.2
microgram/day/mouse), similar to that one of young mice (+1.4
microgram/day/mouse). The reduced zinc plasma level is
restored to normal values. These findings support the idea
that the effect of melatonin on thymic endocrine activity and
peripheral immune functions may be mediated by the zinc
pool.
The immunoneuroendocrine role of melatonin.
Maestroni GJ
J Pineal Res (Denmark) Jan 1993, 14 (1) p1-10
A tight, physiological link between the pineal gland and
the immune system is emerging from a series of experimental
studies. This link might reflect the evolutionary connection
between self-recognition and reproduction. Pinealectomy or
other experimental methods which inhibit melatonin synthesis
and secretion induce a state of immunodepression which is
counteracted by melatonin. In general, melatonin seems to have
an immunoenhancing effect that is particularly apparent in
immunodepressive states. The negative effect of acute stress
or immunosuppressive pharmacological treatments on various
immune parameters are counteracted by melatonin. It seems
important to note that one of the main targets of melatonin is
the thymus, i.e., the central organ of the immune system. The
clinical use of melatonin as an immunotherapeutic agent seems
promising in primary and secondary immunodeficiencies as well
as in cancer immunotherapy. The immunoenhancing action of
melatonin seems to be mediated by T-helper cell-derived opioid
peptides as well as by lymphokines and, perhaps, by pituitary
hormones. Melatonin-induced-immuno-opioids (MIIO) and
lymphokines imply the presence of specific binding sites or
melatonin receptors on cells of the immune system. On the
other hand, lymphokines such as gamma-interferon and
interleukin-2 as well as thymic hormones can modulate the
synthesis of melatonin in the pineal gland. The pineal gland
might thus be viewed as the crux of a sophisticated
immunoneuroendocrine network which functions as an
unconscious, diffuse sensory organ.
The pineal neurohormone melatonin stimulates
activated CD4+, Thy-1+ cells to release opioid agonist(s) with
immunoenhancing and anti-stress properties.
Maestroni GJ, Conti A
Laboratory for Experimental Pathology, Istituto Cantonale di
Patologia, Locarno, Switzerland.
J Neuroimmunol 1990 Jul;28(2):167-76
In previous studies we showed that in mice the pineal gland
modulates the immune response via the circadian synthesis and
release of melatonin. Exogenous melatonin proved also to exert
immunoenhancing effects and to counteract completely the
immunologic effect of acute stress. Melatonin was active only
in vivo, in mice primed with T-dependent antigens and its
effects on the primary antibody response and thymus weight
were abolished by the specific opioid antagonist naltrexone.
Here we demonstrate that physiologic concentrations of
melatonin stimulate, in vitro, activated L3T4+ (CD4+) cells to
release opioid agonist(s) that can reproduce in vivo the
immunoenhancing and anti-stress effects on thymus cellularity
and antibody production of melatonin and compete with specific
binding of [3H]naloxone to mouse brain membranes. Similar
results were obtained when mitogen-activated human
immunocompetent cells were incubated with melatonin. In the
human model the results were, however, less consistent than
those obtained with murine cells, in that only four out of ten
blood donors provided cells that were responsive to melatonin.
This finding elucidates the mechanism of a novel
immuno-neuroendocrine connection with relevant implications
for our understanding of the neuroendocrine factors that may
influence the immune response in vivo in normal and stressful
situations. In addition, it opens new perspectives in a wide
range of research fields.
Endocrine and immune effects of melatonin therapy
in metastatic cancer patients.
Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F
Divisione di Radioterapia Oncologica, Ospedale San Gerardo,
Milano, Italy.
Eur J Cancer Clin Oncol 1989 May;25(5):789-95
Melatonin, the most important indole hormone produced by
the pineal gland, appears to inhibit tumor growth; moreover,
altered melatonin secretion has been reported in cancer
patients. Despite these data, the possible use of melatonin in
human neoplasms remains to be established. The aim of this
clinical trial was to evaluate the therapeutic, immunological
and endocrine effects of melatonin in patients with metastatic
solid tumor, who did not respond to standard therapies. The
study was carried out on 14 cancer patients (colon, six; lung,
three; pancreas, two; liver, two; stomach, one). Melatonin was
given intramuscularly at a daily dose of 20 mg at 3.00 p.m.,
followed by a maintenance period in an oral dose of 10 mg
daily in patients who had a remission, stable disease or an
improvement in PS. Before and after the first 2 months of
therapy, GH, somatomedin-C, beta-endorphin, melatonin blood
levels and lymphocyte subpopulations were evaluated. A partial
response was achieved in one case with cancer of the pancreas,
with a duration of 18+ months; moreover, six patients had
stable disease, while the other eight progressed. An evident
improvement in PS was obtained in 8/14 patients. In patients
who did not progress, T4/T8 mean ratio was significantly
higher after than before melatonin therapy, while it decreased
in patients who progressed. On the contrary, hormonal levels
were not affected by melatonin administration. This study
would suggest that melatonin may be of value in untreatable
metastatic cancer patients, particularly in improving their PS
and quality of life; moreover, based on its effects on the
immune system, melatonin could be tested in association with
other antitumor treatments.
Dehydroepiandrosterone (DHEA) treatment reverses
the impaired immune response of old mice to influenza
vaccination and protects from influenza infection.
Danenberg HD; Ben-Yehuda A; Zakay-Rones Z; Friedman G
Vaccine (England) 1995, 13 (15) p1445-8
Dehydroepiandrosterone (DHEA) is a native steroid with an
immunomodulating activity. Recently it was suggested that its
age-associated decline is related with immunosenescence. To
examine whether DHEA administration could effectively reverse
the age-associated decline of immunity against influenza
vaccine, aged mice were simultaneously vaccinated and treated
with DHEA. Reversal of the age-associated decline and a
significant constant increase of humoral response was observed
in treated mice. Increased resistance to post-vaccination
intranasal challenge with live influenza virus was observed in
DHEA-treated aged mice. Thus, DHEA treatment overcame the
age-related defect in the immunity of old mice against
influenza.
Dehydroepiandrosterone modulationof
lipopolysaccharide-stimulated monocyte cytotoxicity.
McLachlan JA, Serkin CD, Bakouche O
Department of Molecular Pharmacology and Biologic Chemistry,
Northwestern University Medical School, Chicago, IL 60611,
USA.
J Immunol 1996 Jan 1;156(1):328-35
Dehydroepiandrosterone (DHEA), the predominant androgen
secreted by the adrenal cortex, can be converted to both
potent androgens and estrogens. In addition to its role as a
precursor for other steroid hormones, DHEA has been proposed
to play an important role in immunity. This study has
investigated DHEA modulation of LPS-induced monocyte
cytotoxicity. Cytotoxicity markers assessed include tumor cell
killing, IL-1 secretion, reactive oxygen intermediate release,
nitric oxide synthetase activity as measured by the release of
reactive nitrogen intermediates, complement receptor-1 cell
surface protein, and TNF-alpha protein presence. Monocytes
stimulated with LPS concentrations of 1.0 micrograms/ml
displayed the above cytotoxic markers, whereas monocytes
stimulated with DHEA alone or with LPS at a lower
concentration of 0.2 ng/ml did not. However, when used
simultaneously, DHEA and LPS 0.2 ng/ml displayed a synergistic
effect on monocyte cytotoxicity protein, and TNF-alpha
cancerous cell lines, IL-1 secretion, reactive nitrogen
intermediate release, complement receptor-1 cell-surface
protein, and TNF-alpha protein to levels comparable with
levels obtained using LPS 1.0 microgram/ml. Finally, Scatchard
plot analysis demonstrated the presence of a DHEA receptor in
monocytes, suggesting that DHEA effects on LPS-stimulated
monocytes are mediated through a receptor-dependent
process.
Administration of dehydroepiandrosterone reverses
the immune suppression induced by high dose antigen in
mice.
Kim HR, Ryu SY, Kim HS, Choi BM, Lee EJ, Kim HM, Chung
HT
Department of Microbiology/Immunology, School of Medicine,
College of Oriental Medicine, Wonkwang University, Iri,
Chonbuk, Korea.
Immunol Invest 1995 May;24(4):583-93
Several factors including antigen concentration, the route
of antigen administration, hormones and cytokines have shown
to affect T cells to produce the distinct patterns of
lymphokines which exert regulatory and effector functions of
immune response. In this study, we asked whether
administration of dehydroepiandrosterone (DHEA) to mice which
were tolerized by high dose of antigen could modulate T cell
functions to restore the suppressed cellular immune response
and to produce the distinct lymphokines. An intravenous
injection of high dose of sheep red blood cells induced
suppression of delayed type hypersensitivity (DTH) and a
single subcutaneous injection of the tolerant mice with DHEA
restored the suppressed DTH response. Furthermore, in vitro
treatment of spleen cells from tolerant mice with DHEA
abolished the transfer of tolerance to naive recipients.
Lymphocytes from the DHEA-treated tolerant mice produced more
IFN-gamma and less IL-4 and IL-6 than the cells from tolerant
animals without DHEA treatment. These findings indicate that
DHEA could recover antigen-specific immune suppression by
differentially affecting T cells to produce the distinct
lymphokines.
Pregnenolone and dehydroepiandrosterone as
precursors of native 7-hydroxylated metabolites which increase
the immune response in mice.
Morfin R, Courchay G
Bio-industries, Laboratoire de Biologie, Conservatoire
National des Arts et Metiers, Paris, France.
J Steroid Biochem Mol Biol 1994
Jul;50(1-2):91-100
Dehydroepiandrosterone (DHEA) and pregnenolone (PREG) were
both metabolized by homogenates of brain, spleen, thymus,
perianal skin, ventral skin, intestine, colon, coecum and
muscle tissues from mice. The use of 2H-labeled substrates and
of the twin ion technique of gas chromatography-mass
spectrometry permitted identification of 7 alpha-hydroxy-DHEA
and of 5-androstene-3 beta, 17 beta-diol as DHEA metabolites
in digests of all tissues. The extent of PREG metabolism was
much lower than for DHEA with all tissues but amounts of the
main transformation product were sufficient in brain, spleen
and ventral skin digests for identification with 7
alpha-hydroxy-PREG. Dimethylsulfoxide (DMSO) solutions of
DHEA, PREG and of their 7-hydroxylated metabolites were
injected at different doses and time intervals prior to
proximal subcutaneous administration of a lysozyme antigen.
Quantities of anti-lysozyme IgG were measured in the serum of
treated mice and compared with that from sham-treated animals.
Increase of anti-lysozyme IgG was obtained with DHEA and PREG
(1 g/kg) when injected 2 h prior to lysozyme. Much lower doses
(160 times less) of 7 alpha-hydroxy-DHEA and -PREG were also
found to be significantly active when administered at the
moment of lysozyme injection. A larger dose of 7
beta-hydroxy-DHEA (50 mg/kg) was necessary for a similar
effect. These results suggest that in tissues where immune
response takes place, the locally-produced 7-hydroxy
metabolites of PREG and DHEA are involved in a process which
may participate in the physiological regulation of the body's
immune response.
The relationship of serum DHEA-S and cortisol
levels to measures of immune function in human
immunodeficiency virus-related illness.
Wisniewski TL, Hilton CW, Morse EV, Svec F
Department of Medicine, Louisiana State University Medical
Center, New Orleans.
Am J Med Sci 1993 Feb;305(2):79-83
Human immunodeficiency virus (HIV) is a major cause of
immunoincompetence. Whether the virus, itself, accounts for
all the deficiency remains in question. Steroids can also
influence immune function; glucocorticoids cause
immunoincompetence while dehydroepiandrosterone (DHEA)
enhances immune function. Changes in the levels of such
hormones during the course of HIV illness might result in
significant changes in immune competence. The purpose of this
study is to investigate whether
dehydroepiandrosterone-sulphate (DHEA-S) or cortisol levels
correlate with absolute CD4 lymphocyte levels. Plasma for
cortisol and DHEA-S was drawn from 98 adults with HIV. Of
these, 67 had simultaneous CD4 levels. Cortisol levels were
12.4 +/- 4.6 micrograms/dl, DHEA-S 262 +/- 142 micrograms/dl,
and CD4 levels were 308 +/- 217/mm3 (mean +/- SD).
Correlational analysis revealed a significant relationship
between DHEA-S and CD4 levels (r = 0.30; p = 0.01) but not
between CD4 levels and cortisol (r = 0.11; p = 0.36) or
cortisol/DHEA-S ratios (r = 0.17; p = 0.16). When analyzed by
clinical subgroups, significant differences were also found
with a decrease in DHEA-S levels seen in persons with more
advanced illness. The data exhibit a positive relationship
between the immune status of patients with HIV-related illness
and DHEA, leading to the hypothesis that DHEA deficiency may
worsen immune status.
Dehydroepiandrosterone enhances IL2 production and
cytotoxic effector function of human T cells.
Suzuki T, Suzuki N, Daynes RA, Engleman EG
Department of Pathology, Stanford University School of
Medicine, California 94305.
Clin Immunol Immunopathol 1991 Nov;61(2 Pt
1):202-11
Dehydroepiandrosterone (DHEA) is the most abundant adrenal
steroid hormone in humans. Although it is well established
that DHEA serves as an intermediate in sex steroid synthesis,
recent studies in mice suggest that DHEA may also be a
physiologic regulator of IL2 secretion. To explore the effect
of DHEA on the human immune system, T lymphocytes from healthy
adults were exposed to DHEA followed by stimulation with
mitogens or antigen. Upon activation with a variety of
stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA
produced significantly greater amounts of IL2 and mediated
more potent cytotoxicity than T cells activated in the absence
of this steroid hormone. The peak effect of DHEA was observed
at 10(-9) M, the concentration of hormone present in the blood
of normal adults. In contrast to its effect on murine T cells,
the IL2 enhancing effect of DHEA on human lymphocytes was
limited to fresh CD4+ T cells and CD4+ clones; neither fresh
CD8+ cells nor CD8+ clones were directly affected by DHEA
treatment, although CD8+ cells stimulated in the presence of
CD4+ cells and DHEA demonstrated enhanced cytotoxicity. The
enhancing effect of DHEA was also detected at the level of IL2
mRNA, suggesting that DHEA may act as a transcriptional
enhancer of the IL2 gene in CD4+ T cells. These results
corroborate and extend earlier studies in mice and suggest a
physiologic role for DHEA in regulating the human immune
response.
Protection from glucocorticoid induced thymic
involution by dehydroepiandrosterone.
May M, Holmes E, Rogers W, Poth M
Walter Reed Army Medical Center, Washington, D.C.
20307-5001.
Life Sci 1990;46(22):1627-31
Dehydroepiandrosterone (DHEA), the most abundantly secreted
human adrenal steroid, has no known specific function. In
spite of this fact there is an abundance of data associating
DHEA with "health" in both man and experimental animals.
Research in our laboratory has demonstrated evidence for an
antagonistic interaction between DHEA and glucocorticoids (GC)
in liver and brown adipose tissue. We hypothesized that DHEA
also antagonized effects of GC on the immune system and that
this "immune protective effect" might explain the diffuse
positive effects of DHEA reported in the literature. Effects
of GC on the immune system include involution of the thymus
when given in animals in vivo and death of thymic lymphocytes
in vivo with exposure to these steroids. We hypothesized that
DHEA would block this GC mediated thymocyte destruction in
vivo and in vitro. Pretreatment with DHEA for three days
blocked approximately 50% of the thymic involution seen with
dexamethasone. Results of in vitro experiments confirmed
protective effects of DHEA in pretreated animals. (less than
50% of cell death in lymphocytes from pretreated mice compared
with lymphocytes from control mice.) We conclude from these
studies that DHEA protects against at least one GC anti-immune
effect, thymic lymphocyte lysis.
Immune development in young-adult C.RF-hyt mice is
affected by congenital and maternal hypothyroidism.
Erf GF
Department of Biological Sciences, Smith College,
Northampton, Massachusetts 01063.
Proc Soc Exp Biol Med 1993 Oct;204(1):40-8
C.RF-hyt mice carry a mutation (hyt) that results in the
phenotypic expression of congenital hypothyroidism in hyt/hyt
mice due to a nonresponsiveness of the thyroid gland to
thyroid-stimulating hormone. Heterozygotes of this strain are
euthyroid. To further define thyroid-immune interactions, the
effect of congenital hypothyroidism and maternal
hypothyroidism on immune development were examined in 3- to
4-month-old hyt/+ and hyt/hyt progeny from hyt/+ and hyt/hyt
dams. The state of immune development in these mice was
compared on the basis of immune organ weights and the
proliferation response of splenocytes stimulated with the T
cell mitogens concanavalin A (Con A) and phytohemagglutinin
and the B cell mitogen lipopolysaccharide. In addition,
analysis of T cell subpopulations in thymus and spleen was
conducted using direct and indirect immunofluorescence and
flow cytometry. Data analyses for the main effects of
congenital hypothyroidism on immune development revealed a
significantly lower absolute thymus weight (P < 0.001), a
lower (P = 0.022) percentage of thymocytes expressing CD8
(CD8+), a higher (P = 0.010) ratio between CD4+ and CD8+
thymocytes, a lower (P < 0.001) absolute and adjusted
spleen weight, a lower (P = 0.001) Con A to phytohemagglutinin
response ratio, a higher (P = 0.003) percentage of CD4+
splenocytes, and a marginally significant (P = 0.055) increase
in the ratio between CD4+ and CD8+ splenocytes in hypothyroid
compared with euthyroid mice. Data analyses for the main
effects of maternal hypothyroidism revealed a significantly
higher absolute (P = 0.025) and adjusted (P = 0.001) thymus
weight, a higher (P = 0.006) ratio between CD4+ and CD8+
thymocytes, a lower Con A (P = 0.018) and lipopolysaccharides
(P < 0.001) response, a marginally (P = 0.069) lower Con A
to phytohemagglutinin response ratio, a lower (P = 0.001)
percentage of CD4+ splenocytes, and a lower (P = 0.003) ratio
between CD4+ and CD8+ splenocytes in progeny of hypothyroid
compared with progeny of euthyroid mothers. These data provide
further evidence for the importance of normal thyroid function
in the development, maintenance, and function of the immune
system. It was concluded that not only congenital
hypothyroidism results in altered immune development in
young-adult mice, but also long-term effects on immune
development occur in progeny of hypothyroid mothers.
Binding and functional effects of thyroid
stimulating hormone on human immune cells.
Coutelier JP, Kehrl JH, Bellur SS, Kohn LD, Notkins AL,
Prabhakar BS
Laboratory of Oral Medicine, National Institute of Dental
Research, National Institutes of Health, Bethesda, Maryland
20892.
J Clin Immunol 1990 Jul;10(4):204-10
The expression and functional relevance of thyroid
stimulating hormone (TSH) receptors on human immune cells were
studied. Flow cytometric analysis was used to study the
binding of biotinylated TSH to human peripheral blood
mononuclear cells (PBMC) and various purified lymphoid
populations. Our results indicate that the hormone binds well
to monocytes and natural killer (NK) cells and marginally to
purified tonsillar T and B lymphocytes. There was a
significant increase in the binding of TSH to purified B cells
that were activated in vitro with Staphylococcus aureaus
Cowan. In contrast, the binding of TSH to T cells was
unaltered when they were stimulated with phytohemagglutinin
(PHA). While TSH increases DNA synthesis and intracellular
cAMP levels of FRTL-5 rat thyroid cells, it did not have such
stimulatory effects on lymphocytes. However, there was a
moderate increase in Ig production by activated B lymphocytes
when they were cultured in the presence of the hormone. A
possible function for TSH as a link between the immune system
and the thyroid is discussed.
Immunorestoration in children with recurrent
respiratory infections treated with isoprinosine.
Wiedermann D, Wiedermannova D, Lokaj J
Department of Pathological Physiology, Medical Faculty, J.E.
Purkyne University, Brno, Czechoslovakia.
Int J Immunopharmacol 1987;9(8):947-9
In 27 children, 4-8 years old, with recurrent respiratory
infections of the upper and lower respiratory tracts
Isoprinosine (ISO) tablets were administered for 7-10 days at
daily doses of 50-100 mg/kg. Clinical signs of acute
respiratory disease, including temperature abnormalities and
subjective complaints, subsided in a short time and the
children showed no symptoms for periods ranging from several
weeks to several months following the therapy. The children
were selected for immunotherapy with ISO on the basis of their
low levels of E-rosette forming cells in peripheral blood.
Several immune function parameters assessed immediately after
treatment with ISO and compared with those obtained before
illness and ISO administration. Low levels of T-lymphocytes
returned to normal after ISO therapy, B-lymphocyte relative
and absolute numbers, however, were not affected by the
treatment. Nor were any changes due to ISO found in
immunoglobulins, complement components, beta 2-microglobulin
and C-reactive protein. Moreover, ISO had no stimulative
effect on spontaneous tetrazolium reductase activity of
granulocytes but it showed a slight inhibition of their
phagocytosis-associated metabolic activity.
Isoprinosine abolishes the blocking factor-mediated
inhibition of lymphocyte responses to Epstein-Barr virus
antigens and phytohemagglutinin.
Sundar SK; Menezes J
Int J Immunopharmacol 1986;8(1):101-6
Acute infectious mononucleosis (IM) is accompanied by
measurable abnormalities of immune function, including a
transient immunosuppression. The sera of patients with acute
IM contain an IgG blocking factor which binds to T-lymphocytes
and decreases their responses to antigens and mitogens. The
experiments reported herein indicate that isoprinosine, an
immunopotentiating agent, can reverse this inhibition of T
cells by IM-associated IgG blocking factor. Isoprinosine may
be a useful tool in understanding the interactions between
blocking factors and lymphocytes; moreover, isoprinosine may
be of value in patients with abnormal clinical responses to
Epstein-Barr virus (EBV) such as chronic IM or persistent
active EBV infections.
Isoprinosine as an immunopotentiator in an animal
model of human osteosarcoma.
Tsang KY; Fudenberg HH
Int J Immunopharmacol 1981;3(4):383-9
The effects of isoprinosine (ISO) on the immune responses
(Con A-induced lymphocyte proliferation, monocyte chemotactic
responsiveness, and "natural killer" cytotoxicity) of normal
hamsters and hamsters with human osteosarcoma (OS) were
investigated. Human osteosarcoma was induced in newborn inbred
hamsters (LHX/SsLAK) after induction of tolerance in utero. In
vitro, ISO increased Con A-induced proliferation of peripheral
blood lymphocytes (PBL) from normal hamsters by 23.4-48.9% and
from OS-bearing hamsters by 58.1-107.4% over controls (Con A
alone). When ISO was administered in vivo by intraperitoneal
injection. Con A-induced proliferation of PBL from both normal
and OS-bearing recipients in vitro was increased by 50-55% at
1, 3 and 5 days after injection. The chemotactic
responsiveness of monocytes from OS-bearing hamsters was also
significantly increased (59.1-97.4%) at 1, 3 and 5 days after
injection of ISO. Natural killer cytotoxicity was augmented at
1, 3 and 5 days after injection of ISO by 31.7-83.6% in normal
hamsters and 54.6-184% in OS-bearing hamsters. These results
indicate that ISO can produce a generalized enhancement of
immune function in hamsters with OS.
The effect of Biostim (RU-41740) onthe expression
of cytokine mRNAs in murine peritoneal macrophages in
vitro.
Meredith C, Scott MP, Pekelharing H, Miller K
Immunotoxicology Department, British Industrial Biological
Research Association, Carshalton, Surrey, U.K.
Toxicol Lett 1990 Oct;53(3):327-37
The immunomodulatory agent Biostim (RU-41740) was
investigated for its ability to induce the expression of
cytokine mRNAs in murine peritoneal macrophages in vitro.
Northern blot analysis showed that in quiescent macrophage
populations, both IL-1 alpha and IL-1 beta mRNA levels were
dramatically increased in response to 1 microgram/ml Biostim.
Dot-blot analysis showed that in quiescent macrophage
populations the expression of mRNAs for IL-1 alpha, IL-1 beta,
IL-6 and TNF-alpha could be elevated by concentrations of
Biostim as low as 1-10 pg/ml, detectable after 3 h exposure.
In parallel experiments LPS was effective only at the higher
concentration of 10 ng/ml. Time-course analysis showed that
the expression of these cytokine mRNAs was transient, peaking
after 1-3 h; only transcripts of IL-1 beta were detectable
after 23 h exposure. No effects were seen on the expression of
actin, a high-turnover housekeeping gene. We propose that this
type of analysis represents a sensitive, specific and
reproducible method for assessing the ability of drugs and
chemicals to modulate the expression of cytokines that play a
pivotal role in the induction of the immune response.
Isoprinosine (inosine pranobex BAN, INPX) in the
treatment of AIDS and other acquired immunodeficiencies of
clinical importance.
Glasky AJ; Gordon JF
Cancer Detect Prev Suppl 1987;1:597-609
The immunopharmacologic effects of Isoprinosine (INPX) have
been associated with clinical benefit to the patient in a
number of conditions characterized by immunodeficiency of
diverse etiology. Immunodepressed homosexuals at risk of
developing acquired immunodeficiency syndrome (AIDS) treated
with placebo or INPX experienced an increase in the function
and number of immunocompetent cells associated with clinical
improvement. A multicenter trial designed to confirm these
results has demonstrated that INPX produced an increase in
natural killer (NK)-cell activity, total T cells, and T-helper
cells, with certain effects persisting for months after
completion of the 28-day treatment period. INPX-treated
patients also experienced clinical improvement and decreased
incidence of progression to AIDS. The administration of INPX
for longer periods to patients with frank AIDS under a
compassionate-use protocol has also proved useful. Clinical
benefit associated with INPX treatment has been demonstrated
in other patients with a depressed immune response, such as
aged patients, cancer patients, severely burned patients, ill
patients, and surgery patients. This program of clinical
trials supports the therapeutic use of INPX in the treatment
of AIDS and other acquired immunodeficiencies of clinical
importance.
Immunological effests of Isoprinosine as a pulse
immunotherapy in melanoma and ARC patients in melanoma and ARC
patients
Pompidou A; Soubrane C; Cour V; Telvi L; Meunier C;
Jacquillat C
Cancer Detect Prev Suppl; 1:457-62 1987
Immunomodulatory effect of Isoprinosine are presented in
melanoma and HTLV-III/LAV infected patients. Isoprinosine (50
mg/kg) was used as a pulse immunotherapy according to two
different schedules: A) 5 days every 15 days and B) 5 days
every 15 days for 2 months, then 5 days every 2 months. The
patients' immunological profiles were tested before and during
the treatment in terms of T-cell subsets, cell number
requirement for PHA-induced proliferation, and delayed
hypersensitivity reaction to recall antigens. Primary
malignant melanoma patients are randomized between surgery
alone or associated to isotherapy (schedule A or B). Schedule
A,after an initial improvement of surgery-induced immune
deficiency, is responsible for an immunodepression, whereas
schedule B determines a prolonged restoration in immune
responses in melanoma and AIDS related complex or Kaposi
sarcoma patients as well. In vitro effects of Isoprinosine on
HTLV-III/LAV infection are presented. These data exhibit 1)
the need of an immunological follow-up during isotherapy and
2) the immunological benefit of a pulse immunotherapy during
acquired immunodeficiencies related to cancer surgery or to
HTLV-III/LAV infection in man.
A modified determination of coenzyme Q10 in human
blood and CoQ10 blood levels in diverse patients with
allergies.
Ye CQ, Folkers K, Tamagawa H, Pfeiffer C
Institute for Biomedical Research, University of Texas,
Austin.
Biofactors 1988 Dec;1(4):303-6
Two situations required a modified determination of
coenzyme Q10 (CoQ10) in human blood and organ tissue. Blood
from patients with AIDS and cancer raised apprehensions about
safety to an analyst, and the number of specimens for analysis
is increasing enormously. A modified determination replaces
silica gel-TLC with disposable Florisil columns, and steps
were simplified to allow more analyses per unit time. Data
from the modified determination are quantitatively compatible
with data from older and tedious procedures. This
determination was used for blood from 36 diverse patients with
allergies. The mean CoQ10 blood level of these patients is not
different from the mean level of so-called normal individuals,
but approximately 40% (14/36) of these allergic patients had
levels up to 0.65 micrograms/ml, which is the level of dying
class IV cardiac patients. The biosynthesis of CoQ10 in human
tissues is a complex process that requires several vitamins
and micronutrients, so that countless vitamin-unsupplemented
Americans may be deficient in CoQ10. The relationship of
allergies to autoimmune mechanisms and immunity, and the
established relationship of CoQ10 to immune states, may be a
rationale for therapeutic trials of administering CoQ10 to
patients with allergies who have low CoQ10 blood levels and
are very likely deficient.
Carnitine in human immunodeficiency virus type 1
infection/acquired immune deficiency syndrome.
Mintz M
University of Medicine and Dentistry of New Jersey-Robert
Wood Johnson Medical School at Camden 08103, USA.
J Child Neurol 1995 Nov;10 Suppl 2:S40-4
There is an increasing body of evidence that subgroups of
patients infected with human immunodeficiency virus type 1
possess carnitine deficiency. Secondary carnitine deficiencies
in these individuals may result from nutritional deficiencies,
gastrointestinal disturbances, renal losses, or shifts in
metabolic pathways. However, tissue depletion precipitated by
drug toxicities, particularly zidovudine, is a major etiology
and concern. Carnitine deficiency may impact on energy and
lipid metabolism, causing mitochondrial and immune
dysfunction. There are convincing laboratory data showing the
in vitro ameliorative effects of L-carnitine supplementation
of zidovudine-induced myopathies and lymphocyte function.
Studies measuring the impact of L-carnitine supplementation on
clinical characteristics are ongoing.
Oxidative damage and mitochondrial decay in
aging.
Shigenaga MK, Hagen TM, Ames BN
Division of Biochemistry and Molecular Biology, University of
California, Berkeley 94720
Proc Natl Acad Sci U S A 1994 Nov
8;91(23):10771-8
We argue for the critical role of oxidative damage in
causing the mitochondrial dysfunction of aging. Oxidants
generated by mitochondria appear to be the major source of the
oxidative lesions that accumulate with age. Several
mitochondrial functions decline with age. The contributing
factors include the intrinsic rate of proton leakage across
the inner mitochondrial membrane (a correlate of oxidant
formation), decreased membrane fluidity, and decreased levels
and function of cardiolipin, which supports the function of
many of the proteins of the inner mitochondrial membrane.
Acetyl-L-carnitine, a high-energy mitochondrial substrate,
appears to reverse many age-associated deficits in cellular
function, in part by increasing cellular ATP production. Such
evidence supports the suggestion that age-associated
accumulation of mitochondrial deficits due to oxidative damage
is likely to be a major contributor to cellular, tissue, and
organismal aging.
Carnitine depletion in peripheral blood mononuclear
cells from patients with AIDS: effect of oral
L-carnitine.
De Simone C; Famularo G; Tzantzoglou S; Trinchieri V; Moretti
S; Sorice F
AIDS (United States) May 1994, 8 (5) p655-60
OBJECTIVE: Reduced levels of serum carnitines
(3-hydroxy-4-N-trimethyl-am monio-butanoate) are found in most
patients treated with zidovudine. However, since serum
carnitines do not strictly reflect cellular concentrations we
examined whether a carnitine depletion could be found in
peripheral blood mononuclear cells (PBMC) from AIDS patients
with normal serum carnitine levels. In addition, we explored
whether it was possible to relate the host's immunoreactivity
to the content of carnitine in PBMC and whether carnitine
levels can be corrected by oral supplementation of
L-carnitine.
DESIGN: Immunopharmacologic study.
METHODS: Twenty male patients with advanced AIDS (Centers
for Disease Control and Prevention stage IVCI) and normal
serum levels of carnitines were enrolled. Patients were
randomly assigned to receive either L-carnitine (6 g/day) or
placebo for 2 weeks. At baseline and at the end of the trial,
we measured carnitines in both sera and PBMC, serum
triglycerides, CD4 cell counts, and the frequency of cells
entering the S and G2-M phases of cell cycle following mitogen
stimulation.
RESULTS: Concentrations of total carnitine in PBMC from
AIDS patients was lower than in healthy controls. A
significant trend towards the restoration of appropriate
intracellular carnitine levels was found in patients treated
with high-dose L-carnitine and was associated with an
increased frequency of S and G2-M cells following mitogen
stimulation. Furthermore, at the end of the trial we found a
strong reduction in serum triglycerides in the L-carnitine
group compared with baseline levels.
CONCLUSIONS: Our data indicate that carnitine deficiency
occurs in PBMC from patients with advanced AIDS, despite
normal serum concentrations. The increase in cellular
carnitine content strongly improved lymphocyte proliferative
responsiveness to mitogens. Because carnitine status is an
important contributing factor to immune function in patients
with advanced AIDS, we therefore believe that L-carnitine
supplementation could have a role as a complementary therapy
for HIV-infected individuals.
Immunological parameters in aging: studies on
natural immunomodulatory and immunoprotective
substances.
Franceschi C, Cossarizza A, Troiano L, Salati R, Monti
D
Institute of General Pathology, University of Modena,
Italy.
Int J Clin Pharmacol Res 1990;10(1-2):53-7
Several immune parameters--particularly T-cell dependent
immune responses--are altered in aged subjects. To test the
hypothesis that they may be the consequence of more general
age-related lymphocyte biochemical alterations, and
particularly of the energy producing system, the effect of
L-carnitine and acetyl-L-carnitine on cell proliferation was
studied in peripheral blood lymphocytes from donors of
different ages. The results showed that
phytohaemagglutinin-induced peripheral blood lymphocyte
proliferation was markedly increased in L-carnitine- or
acetyl-L-carnitine-preloaded lymphocytes from young and
especially from old subjects. Cells from aged subjects
considerably improved their defective proliferative
capability. Preliminary observations suggest that
L-carnitine-preloading also protected peripheral blood
lymphocytes from old donors when such cells were exposed to an
oxidative stress.
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