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Biomedical subjects

G J Maestroni

Publications and source records attributed to G J Maestroni.

17 recordsLinked to original sources
PubMed1992

Effect of adrenergic agents on hematopoiesis after syngeneic bone marrow transplantation in mice.

We show that adrenergic agents modulate hematopoietic reconstitution after syngeneic bone marrow transplantation (BMT) in mice. Chemical sympathectomy by 6-hydroxydopamine (6-OHDA) significantly increased the number of peripheral blood leukocytes after syngeneic BMT. The alpha 1-adrenergic antagonist prazosin mimicked and extended the effect of 6-OHDA, with an additional rapid and significant increase of platelets, marrow granulocyte-macrophage colony-forming units, and nucleated spleen cells. Differential leukocyte counts and spleen histology from prazosin-treated mice confirmed that myelopoiesis was greatly enhanced and accelerated. In contrast, the beta-adrenergic blocker propranolol abolished the prazosin-induced increase of platelets. The detailed mechanisms by which prazosin exerts these interesting effects remain to be elucidated.

Animals↗
PubMed1992

Role of pineal melatonin and melatonin-induced-immuno-opioids in murine leukemogenesis.

The relationship between the pineal gland, melatonin and melatonin-induced-immuno-opioids with the response of C57Bl/6 mice to A-RadLV induced T cell lymphomas was investigated. Mice were injected at day 0 with A-RadLV and from day 10 they were treated chronically with melatonin 4 mg/kg body weight, naltrexone 1 mg/kg or phosphate buffered saline, throughout the experiment. In another protocol, groups of mice were a) surgical pinealectomized at day-14, b) functional pinealectomized (24:24 hours light) from day -20 and c) sham pinealectomized. At day 0 each group was inoculated intrathymically with A-RadLV. The results show that melatonin accelerated (p < 0.005) leukemogenesis whereas the surgical pinealectomy and the functional pinealectomy delayed it (p < 0.005 and p < 0.01). Moreover, the action of melatonin was blocked by naltrexone (p < 0.005), indicating the involvement of melatonin-induced-immuno-opioids in the development of the lymphomas.

Animals↗
PubMed1991

Anti-stress role of the melatonin-immuno-opioid network: evidence for a physiological mechanism involving T cell-derived, immunoreactive beta-endorphin and MET-enkephalin binding to thymic opioid receptors.

Our previous work showed that the pineal neurohormone melatonin induces activated T lymphocytes to release opioid peptides with immunoenhancing and anti-stress properties. Here we present evidence that these peptides crossreact with anti-beta-endorphin and anti-met-enkephalin antisera, and bind specifically to thymic opioid receptors. Furthermore, the same antisera injected in prednisolone treated mice prevented the normal recovery of thymus cellularity and of the capacity to mount a primary antibody response against T-dependent antigens. Surgical pinealectomy, i.e. inhibition of endogenous melatonin and absence of antigen activation negated the effect of such antisera demonstrating the physiological relevance of this melatonin-immuno-opioids network. It is proposed that function of this network may be that of driving a correct immune recovery after the depression caused by the elevated corticosteroids level associated with immune responses and/or stressful situations.

Animals↗
PubMed1991

Immuno-derived opioids as mediators of the immuno-enhancing and anti-stress action of melatonin.

The pineal neurohormone melatonin was shown to stimulate the release of opioid peptides from activated CD4+, T lymphocytes. These immuno-derived opioids or "lymphomorphins" crossreact with anti-beta-endorphin and anti-metenkephalin antisera, bind to opioid receptors in the thymus and are the mediators of the immunoenhancing and anti-stress action of endogenous and/or exogenous melatonin. These findings proved the existence of a novel immunoneuroendocrine physiological mechanism which may be related for the long range maintenance of the immune homeostasis in spite of the unavoidable stress and/or infectious events occurring during the span of life in a normal unprotected environment.

Animals↗
PubMed1990

The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties.

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.

Animals↗
PubMed1990

The biological significance of soluble interleukin-2 receptors in solid tumors.

In an attempt to further understand the biological significance of soluble IL-2 receptors (sIL-2R) in solid tumors, we have evaluated 160 cancer patients (breast: 40; lung: 66; colon: 18; stomach: 22; uterine cervix: 14) and 58 healthy subjects, as controls. Serum mean levels of sIL-2R, measured with an enzyme immunoassay, were significantly higher in cancer patients than in controls. Metastatic cancer patients showed significantly higher values than the non-metastatic ones; this difference was significant in all tumor histotypes, except small cell lung carcinoma. Moreover, in 15 patients in whom sIL-2R were evaluated either before or after radical surgery, a significant surgery-induced increase in sIL-R mean values was seen. Finally, the chemotherapy-induced rise in sIL-2R appeared to be associated with a lack of clinical response. These results seem to suggest that sIL-2R may be a marker of host biological response in patients with solid tumors, the significance of which needs further investigation.

Adult↗
PubMed1989

Beta-endorphin and dynorphin mimic the circadian immunoenhancing and anti-stress effects of melatonin.

We have recently demonstrated that the pineal neurohormone melatonin can enhance immune reactivity in normal mice and counteract the effects of acute stress or corticosterone treatment on antibody production, thymus weight and anti-viral resistance. These remarkable immunopharmacologic effects of melatonin were abolished by naltrexone, suggesting an involvement of the endogenous opioid system. Here we compared the immunopharmacologic action of beta-endorphin, dynorphin 1-13, leu-enkephalin and metenkephalin with that of melatonin in restraint-stressed or prednisolone-treated mice and in normal nonstressed animals. We found that beta-endorphin and dynorphin 1-13 can mimic the immunoenhancing and antistress effect of melatonin. However, at variance with the pineal neurohormone, these opioids were effective in umprimed mcie, too. We found also that restraint stress or prednisolone treatment decreases the immunopharmacologic potency of beta-endorphin and augments that of dynorphin 1-13. In fact, at the doses used, beta-endorphin enhanced the antibody response in normal but not in stressed or prednisolone-treated mice, while dynorphin 1-13 was effective only in counteracting the effect of stress or prednisolone treatment. Most interestingly, all these effects proved to be dependent on the time of administration, i.e. showed a circadian rhythm in analogy with the effects of melatonin. Again, naltrexone abolished all the opioid effects, indicating that their action was exerted via opioid receptors. These findings have important scientific and practical implications.

Adjuvants, Immunologic↗
PubMed1979

A new pre-irradiation conditioning regimen which protects against radiation injury and facilitates engraftment of xenogeneic bone marrow.

Administration of a large number of xenogeneic (rat) bone marrow cells before lethal, total body irradiation in mice (preconditioning regimen) results in powerful protection from radiation damage, remarkable prolongation of their survival, facilitation of marrow engraftment and induction of rat chimerism. This protective effect is not exerted by thymus or spleen cells and does not depend on specific immune mechanisms. The preconditioning regimen is more efficient when the bone marrow cells are viable and when the cells are inoculated intravenously a few hours before irradiation.

Animals↗
PubMed1978

Pharmacological control of the hormonally modulated immune response. II. Blockade of antibody production by a combination of drugs acting on neuroendocrine functions. Its prevention by gonadotropins and corticotrophin.

Injection of a combination of three drugs, 5-hydroxytryptophan, the alpha-blocker phentolamine and the neuroleptic drug haloperidol into mice before or together with sheep red blood cells (SRBC) induces a complete and long-lasting inhibition of antibody production to SRBC and leads to specific unresponsiveness. The mice unresponsive to SRBC respond normally to another antigen. Treatment with a combination of luteotropic (LH), follicle stimulating (FSH) and corticotropic hormone (ACTH) before administration of drugs and antigen prevents the immune blockade. Injection of SRBC induces an early elevation of LH in blood. This effect is prevented by previous administration of the three drugs in combination. The hormonal response to a second injection of the same antigen of mice previously made 'unresponsive' is different from that of immunized animals. The suppression of these hormonal changes which follow antigen injection by drugs acting on neuroendocrine regulation and cell membrane adrenergic receptors represents a step forward in efforts aimed at a pharmacological control of acquired immunity.

5-Hydroxytryptophan↗
PubMed1978

Pharmacologic control of the hormonally modulated immune response. III. Prolongation of allogeneic skin graft rejection and prevention of runt disease by a combination of drugs acting on neuroendocrine functions.

A recently developed pharmacologic means for suppressing acquired immunity by drugs acting on neuroendocrine regulation has been applied to transplantation immune reactions. A number of drugs have been tested singly and in combination for their capacity to suppress the immune response of mice grafted with allogeneic skin. Another model involved newborn F1 hybrid recipients inoculated with spleen cells from donors of parental strains that had been made specifically "unresponsive" by drug and alloantigen treatment. These procedures led to the identification of a combination of four drugs that induced a remarkable delay in allograft rejection and a prolonged unresponsiveness to alloantigens. This combination of drugs also abrogated the graft-vs-host-runting syndrome in newborn hybrid recipients.

Animals↗
PubMedDate not supplied

Immunological effects of a single evening subcutaneous injection of low-dose interleukin-2 in association with the pineal hormone melatonin in advanced cancer patients.

Recent experiments have shown that a great variety of neurohormones can interact with IL-2 in the modulation of host antitumor immune response. On the basis of these data, a study was started to evaluate the effect of the pineal hormone melatonin (MLT) on IL-2-induced immune changes in cancer. The study included 30 advanced cancer patients. They were randomized to be treated with IL-2 at a dose of 3 million IU subcutaneously twice/daily (8.00 a.m. and 8.00 p.m.) for 6 days/week for 4 weeks, with IL-2 once/daily in the evening, with IL-2 once/daily plus MLT at 10 or at 50 mg/day. MLT was given orally at 8.00 p.m. Both IL-2 given twice daily and IL-2 given once daily and IL-2 given once daily in association with MTL induced a significant increase in mean number of lymphocytes, T lymphocytes, NK cells, CD25-positive cells and eosinophils, whereas the single administration of IL-2 alone was unable to determine a significant rise in the mean number of immune cells. Soluble IL-2 receptor and neopterin increase was significantly higher during IL-2 given twice/daily than during IL-2 plus MLT, while no difference was seen in TNF rise. This study would suggest that a single daily injection of low-dose IL-2 is able to efficiently activate the lymphocyte proliferation in cancer patients when it is given in association with the pineal hormone MLT.

Adult↗
PubMedDate not supplied

Modulation of interleukin-2-induced macrophage activation in cancer patients by the pineal hormone melatonin.

The concomitant induction of immunosuppressive events, at least in part mediated by macrophages, would represent one of the mechanisms responsible for the lower activity of IL-2 in vivo than in vitro. Since macrophages have recently appeared to be under neuroendocrine control, the present study was carried out to evaluate the effect of the pineal neurohormone MLT on IL-2-induced macrophage activation during cancer immunotherapy, by determining serum levels of neopterin, which is a specific marker of macrophage activity. The study included 21 advanced cancer patients (lung cancer: 12; renal cancer: 9), 10 of whom received IL-2 subcutaneous therapy alone (1.8 x 10(6) IU/m2 twice daily), or IL-2 plus MLT (10 mg/day orally at 8.00 P.M.). Neopterin levels increased in all patients during IL-2 immunotherapy, but neopterin mean peak was significantly higher in patients treated with IL-2 alone than in those who received IL-2 plus MLT. This preliminary study would suggest the possible use of neurohormones to modulate host antitumor immune response during cancer immunotherapy with IL-2.

Adult↗
PubMedDate not supplied

Endocrine effects of a 24-hour intravenous infusion of interleukin-2 in the immunotherapy of cancer.

Several experiments have demonstrated that there is a relationship between neuroendocrine and immune systems. Despite these interesting findings, only few studies have been performed up to now to evaluate the possible importance of neuroimmune interactions in influencing the biological efficacy and toxicity of cancer immunotherapy with IL-2. To analyze the effects of IL-2 on endocrine secretions, we have measured by RIA serum levels of cortisol, beta-endorphin, GH, PRL and of the pineal hormone melatonin in metastatic renal cancer patients, treated with 5-day courses of IL-2 at a daily dose of 3 x 10(6) U/m2, given through a 24-hour intravenous infusion. Six IL-2 courses were evaluated, by collecting blood samples at 4-hour intervals for 24 hours and by comparing the hormonal values with those observed in baseline conditions. Both cortisol and beta-endorphin mean values significantly increased during IL-2 infusion. GH and PRL also increased, but not in a significant manner. Finally, melatonin mean levels significantly decreased during the infusion. The IL-2-induced effects on cortisol, beta-endorphin and melatonin resulted in a complete abolition of their physiological circadian rhythm. These results show that IL-2 infusion induces important changes in endocrine secretions. Because of the immunosuppressive effect of cortisol and the stimulatory one of melatonin, their changes during IL-2 infusion might influence the biological activity of immunotherapy itself. Further studies will be required to define better the clinical importance of IL-2 induced hormonal changes.

Carcinoma, Renal Cell↗
PubMedDate not supplied

Neuroimmunotherapy of human cancer with interleukin-2 and the neurohormone melatonin: its efficacy in preventing hypotension.

The pineal hormone melatonin (MLT) has been shown to influence many biological functions, including immune response, cancer growth and brain neurotransmitter contents. On the basis of its biological properties, a study was started to evaluate the influence of MLT on IL-2 immunotherapy toxicity. The study was carried out in metastatic renal cancer patients. Thirty-three 5-day courses of IL-2 at a daily dose of 3 x 10(6) Cetus U/m2 were randomized to consist of IL-2 alone or IL-2 plus MLT (10 mg/day orally at 8.00 p.m.). The frequency of episodes of severe hypotension was significantly greater during IL-2 alone than during IL-2 + MLT. Moreover, the depressive symptomatology occurred more frequently during IL-2 alone. No other toxicity, including capillary leak syndrome, vomiting and fever, were significantly influenced by the concomitant treatment with MLT. These preliminary results would suggest that the pineal hormone MLT may be successfully associated with IL-2 in the immunotherapy of human tumors.

Circadian Rhythm↗