RESUMEN
In aging humans, night levels of melatonin (MEL) decline progressively. Also thyroid and gonadal functions decline during aging while gonadotropins (luteotropic hormone (LH) and follicle stimulating hormone (FSH)) steadily increase. A desynchronization of pineal circadian cyclicity as expressed by the progressive decrease of the MEL night peak may be permissively linked to the onset and progression of menopause. We studied the effects of exogenous, evening administration of MEL on the level of hormones which are known to be involved in the genesis and progression of menopause. Perimenopausal and menopausal women from 42 to 62years of age with no pathology or medication were selected. MEL was measured in saliva to divide them into low, medium and high-MEL patients. Half of them took 3mg MEL and half of them Placebo at bedtime (10-12p.m.) in a fully randomized and double-blind fashion. Three and six months later blood was taken for determination of pituitary (LH, FSH), ovarian, and thyroid hormones I(T3 and T4). All women taking MEL with low basal level of MEL and/or Placebo for three and six months showed a significant increase in levels of thyroid hormones. Before initiation of the study, a negative correlation was found in all women between LH, FSH and basal MEL levels. Within six months of treatment, MEL produced a significant diminution of LH in the younger women (43 to 49year-old), while no effect was seen in the older women (50-62years old). A decrement of FSH was observed in MEL-treated women with low basal MEL levels. In addition, most MEL-treated women reported a general improvement of mood and a significant mitigation of depression. MEL decline during aging may thus signal the derangement of pineal and pituitary-controlled ovarian cyclicity and the progressive quenching of fertility in women. These findings seem to show a recovery of pituitary and thyroid functions in MEL-treated women, towards a more juvenile pattern of regulation.
Asunto(s)
Melatonina/farmacología , Menopausia/efectos de los fármacos , Premenopausia/efectos de los fármacos , Adulto , Afecto/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Depresión/tratamiento farmacológico , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Hormonas Esteroides Gonadales/sangre , Humanos , Hormona Luteinizante/sangre , Melatonina/administración & dosificación , Melatonina/fisiología , Menopausia/fisiología , Menopausia/psicología , Ciclo Menstrual/efectos de los fármacos , Persona de Mediana Edad , Premenopausia/fisiología , Premenopausia/psicología , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Previous studies have shown that critically timed administration of transferrin (Tf) facilitates induction of immunologic unresponsiveness. Here, we determined in mixed leukocyte culture (MLC) and in concanavalin A (ConA)-driven cultures the effect of exogenous Tf and Tf-derived glycans (Tf-Gly) on lymphocyte proliferation. In cultures of human blood lymphocytes, Tf inhibited selectively alloantigen-driven proliferation in MLC, but not ConA-stimulated lymphocyte proliferation. Deglycosylation of Tf abrogated the inhibitory effect of Tf on alloantigen-induced lymphocyte proliferation, and, consistent with a role for glycans, an effect qualitatively and quantitatively similar to Tf was exerted by purified Tf-Gly. Glycans isolated from other proteins, for example, immunoglobulin G (IgG) or fibrinogen, failed to inhibit alloantigen-induced proliferation selectively. Rather, they suppressed lymphocyte proliferation in a non-specific manner. Determination of cytokines in MLC supernatant showed a downregulation of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-2, and IL-12 (p40), along with an upregulation of IL-10, a pattern entirely consistent with the observed effects of Tf and Tf-Gly on alloantigen-induced lymphocyte proliferation. The effect of Tf on MLC was directly IL-10-dependent. IL-10 levels were inversely correlated with lymphocyte proliferation and CD86 expression. Neutralization of IL-10 by anti-IL-10 monoclonal antibody (mAb) blocked the effect of Tf. The MLC-modulating effect of Tf (or Tf-Gly) was not dependent upon the Tf receptor CD71 but appeared to be mediated by a Gly-responsive receptor. These data suggest a role of Tf, and, in particular, Tf-Gly, in allo-interactions that is independent from the role of Tf in iron metabolism, and appears to involve co-stimulatory signals.
Asunto(s)
Interleucina-10/fisiología , Isoantígenos/efectos de los fármacos , Polisacáridos/farmacología , Transferrina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Antígenos CD/inmunología , Antígenos CD/farmacología , Antígenos de Diferenciación de Linfocitos B/inmunología , Antígenos de Diferenciación de Linfocitos B/farmacología , Concanavalina A/farmacología , Citocinas/biosíntesis , Citocinas/efectos de los fármacos , Humanos , Inmunoglobulina G/farmacología , Interleucina-10/genética , Interleucina-10/inmunología , Isoantígenos/inmunología , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Receptores de Transferrina , Transferrina/análogos & derivadosRESUMEN
Hormonal derangements almost invariably anticipate and signal the onset of tumors. Chronic, nocturnal melatonin administration delays aging in normal strains of mice. On the contrary it promotes and accelerates the onset of tumors in the cancer-prone strain of C3H/He mice. Grafting of a young pineal gland into aging mice prolongs their longevity and maintains juvenile circadian hormonal functions while pinealectomy (Px) does the opposite. We investigated if Px in C3H/He mice would modify their congenitally deranged pituitary function and affect their longevity. It was found that contrarily to Px in normal mice, Px in C3H/He mice remarkably maintains juvenile night levels of thyroid hormones and lipids, preserves a cell-mediated immune response and significantly prolongs their life. The pineal gland and its pathology may be the key for understanding, not only the causes of metabolic aging, but also the origin of those congenital or progressive aging-related hormonal alterations preceding onset of all tumors and thus allow preventive corrective interventions with pineal-derived agents.
Asunto(s)
Enfermedades del Sistema Endocrino/congénito , Enfermedades del Sistema Endocrino/fisiopatología , Longevidad , Neoplasias/fisiopatología , Glándula Pineal/fisiología , Glándula Pineal/cirugía , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Colesterol/sangre , Enfermedades del Sistema Endocrino/sangre , Enfermedades del Sistema Endocrino/cirugía , Femenino , Hipersensibilidad Tardía/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Neoplasias/cirugía , Glándula Pineal/trasplante , Enfermedades de la Hipófisis/sangre , Enfermedades de la Hipófisis/congénito , Enfermedades de la Hipófisis/fisiopatología , Enfermedades de la Hipófisis/cirugía , Hipófisis/metabolismo , Hipófisis/fisiopatología , Timo/inmunología , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Tiroxina/sangre , Triglicéridos/sangre , Triyodotironina/sangreRESUMEN
Experiments were conducted to study the effect of heterologous plasma transferrins separated and purified from human plasma pools on endocrine and immune functions of old, aging mice. Two similar experiments have shown that parenteral treatment with iron and zinc-free human transferrins produces a significant improvement of immunological and endocrine functions in the aging mice toward more juvenile values. Those changes occur in the thymus and its cell subsets, in peripheral blood lymphocytes, in the restoration of juvenile levels of thyroxine, in the increase of testis weight, and in the normalization of plasma zinc levels. These totally unsuspected effects of transferrin in aging mice suggest a most important role of endogenous transferrins in the maintenance of neuroendocrine and immune functions. The mechanism remains unexplained although the basic immunoenhancing and anti-apoptotic effect of transferrin-vehiculated zinc may be relevant.
Asunto(s)
Envejecimiento/efectos de los fármacos , Transferrina/farmacología , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Envejecimiento/inmunología , Envejecimiento/fisiología , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/patología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Testículo/efectos de los fármacos , Testículo/patología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/fisiología , Transferrina/aislamiento & purificaciónRESUMEN
Proteic molecules were found in the bone marrow that were later identified as transferrins. When applied to transplantation of genetically incompatible bone marrow in supralethally irradiated recipient mice, the transferrins obtained from plasma of bone marrow donors promoted engraftment, permanent hemopoietic chimerism, and donor-type immune character. A combination of donor-matched transferrins and antigens was needed for induction of xenogeneic (interspecies) "tolerance" or unresponsiveness to donor antigens in chemically immunosuppressed mice treated with human transferrins and donor leucocytes. This novel and unique property of transferrins may explain the genesis and maintenance of immunogenic identity and allow a reshaping of the immune system.
Asunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Órganos , Transferrina/inmunología , Inmunología del Trasplante , Trasplante Heterólogo/inmunología , Animales , Humanos , Tolerancia Inmunológica , RatonesRESUMEN
We have investigated for 35 years the relationship between the neuroendocrine and the thymo-lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal-programmed event similar to growth and puberty. The continuation of our interventions with melatonin against the typical degenerative diseases of aging must be based on an accurate evaluation of its mechanisms of action. Melatonin being a ubiquitous molecule in nature, we suggest that it has acquired during evolution of the species numerous levels of activities. In fact, melatonin can be found in a large variety of cells and tissues, and bindings sites and "receptors" have been identified in many tissues and cells of the neuroendocrine and immune system. Therefore, the progressive understanding of the aging-programming role of the pineal gland also depends on studies of melatonin and its basic regulatory function. Our present studies will be described.
Asunto(s)
Envejecimiento/fisiología , Sistema Inmunológico/fisiología , Fenómenos Fisiológicos del Sistema Nervioso , Neuroinmunomodulación , Glándula Pineal/fisiología , Relojes Biológicos/fisiología , Evolución Biológica , HumanosRESUMEN
Chronic, night administration of melatonin to aging mice and transplantation of a young pineal gland into the thymic rudiment of older mice and rats have been studied with the aim of evaluating their effects on aging of gonadal, sexual, and reproductive functions. Both melatonin administration and young-to-old pineal grafting positively affect size and function of testes and maintenance of juvenile hippocampal and testicular LHRH-receptors and beta-adrenergic receptors in the tests of old rats and mice. These results demonstrate that a pineal-directed circadian function and cyclicity is fundamental for the regulation of sexual, reproductive physiology, and that proper intervention with melatonin may potentially postpone aging of both neural and gonadal sexual function.
Asunto(s)
Envejecimiento/fisiología , Ritmo Circadiano , Melatonina/administración & dosificación , Glándula Pineal/trasplante , Reproducción/fisiología , Timo/fisiología , Animales , Hipocampo/metabolismo , Masculino , Melatonina/farmacología , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Receptores LHRH/metabolismo , Testículo/anatomía & histología , Testículo/metabolismoRESUMEN
The models developed in our laboratory demonstrate that ageing initiates and progresses in the pineal gland. However, the ageing postponing effects of pineal grafting into older recipients cannot be explained by a simple maintenance and/or normalization of the night melatonin synthesis and release. We propose here that the pineal gland monitors and regulates, via its control of neuroendocrine function, the maintenance of 'self-identity' and the capacity of the immune system to recognize and react against any noxious, endogenous or exogenous agent. Senescence is characterized by the extinction of this central pineal function. The progressive decline of the self-recognition capacity distinguishes the typical diseases of ageing expressed as emergence of peripheral desynchronization and autoimmune, anaplastic, neoplastic and degenerative processes. Our approaches aim at a prevention and/or restoration of central pineal functions.
Asunto(s)
Envejecimiento/fisiología , Relojes Biológicos/fisiología , Glándula Pineal/fisiología , AnimalesRESUMEN
Previous work on the facilitation of xenogeneic and allogeneic bone marrow engraftment in irradiated mice and dogs with transferrins allowed the development of a model for induction of an apparently durable state of immunological unresponsiveness or 'tolerance' in chemically immunosuppressed mice. The system is based on the simultaneous and combined administration of donor-derived cell antigens, namely human leukocytes, and specific donor-derived or plasma pool human transferrin into BALB/c or C57BL/6 mice previously treated with prednisolone and cyclophosphamide on day 0 and day 1 of the experiment. A properly timed presentation of both donor-specific or plasma pool transferrin and leukocyte antigens into the mice on day 3 and day 16 of the experiment, in the course of initial restoration of their lymphohaemopoietic tissues and cells after severe immunosuppression, results 1-3 months later, in their inability to 'recognize' human donor lymphocytes and to mount an immediate or a delayed-type immune response against human antigens. This durable state of unresponsiveness was evaluated by a complement-mediated cytotoxicity assay, with a mixed lymphocyte culture method and confirmed by the abrogation of the humoral (antibody response to human erythrocytes) and of the cell-mediated (popliteal lymph node test) immune responses in vivo. Our findings demonstrate the capacity of human plasma-derived transferrins to induce a state of durable unresponsiveness (xenogeneic tolerance?) in mice when administered with human antigens in the course of regeneration of stem cells in the bone marrow and lymphatic organs.
Asunto(s)
Refuerzo Inmunológico de Injertos/métodos , Rechazo de Injerto/prevención & control , Antígenos HLA/inmunología , Terapia de Inmunosupresión/métodos , Transfusión de Leucocitos , Leucocitos/inmunología , Transferrina/uso terapéutico , Trasplante Heterólogo/inmunología , Animales , Ciclofosfamida/farmacología , Femenino , Antígenos HLA/administración & dosificación , Humanos , Inmunidad Celular , Inmunosupresores/farmacología , Prueba de Cultivo Mixto de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Prednisolona/farmacología , Transferrina/inmunología , Transferrina/farmacologíaRESUMEN
Endogenous factors originally found in the bone marrow (BM) and facilitating the engraftment of xenogeneic (rat) BM in lethally irradiated mice have been recently identified as transferrins (Tf). Tf have been separated and purified from plasma pools of inbred Rii/2 rats and injected in lethally irradiated BALB/c and C57BL/6 mice 1 h before the infusion of BM and for several days after BM transplantation. Other groups of irradiated mice have been similarly treated with human Tf, Tf from other strains of rats different from the BM donors and with human or rat serum albumin. A remarkable facilitation of BM engraftment and a durable graft-versus-host disease (GVHD)-free hemopoietic chimerism have been achieved in the irradiated mice when a combination of BM and Tf from the same donor rat (Rii/2) strain was used for transplantation. Durable survival and persistent chimerism were not observed in the control groups. It seems that donor Tf profoundly affects the outcome of BM transplantation when combined with donor BM. These results indicate that the mechanism by which Tf promotes engraftment of xenogeneic BM deserves investigation in order to improve this novel procedure and to extend it to other species and possibly to man.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Refuerzo Inmunológico de Injertos , Ratones/inmunología , Ratas/sangre , Transferrina/uso terapéutico , Trasplante Heterólogo/inmunología , Animales , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Quimera por Radiación , Ratas/inmunología , Albúmina Sérica/farmacología , Trasplante de Piel/inmunología , Donantes de Tejidos , Transferrina/farmacologíaRESUMEN
Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.
Asunto(s)
Melatonina/farmacología , Glándula Pineal/metabolismo , Zinc/metabolismo , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Glándula Pineal/cirugía , Factor Tímico Circulante/farmacología , Timo/efectos de los fármacosRESUMEN
Studies in mice have shown that donor-specific plasma transferrin (TF) given to the recipient in the peritransplant period facilitates engraftment of marrow from histoincompatible donors. Dogs given 920 cGy of total body irradiation (TBI) and infused with marrow from an unrelated major histocompatibility complex (DLA) different donor generally fail to engraft; only approximately 20% of dogs achieve sustained engraftment. We have now investigated in this model whether the infusion of donor-specific plasma TF would facilitate engraftment. Ten dogs were given TBI, followed at 23 h by an intravenous dose of TF, at 24 h by marrow from the same donor, and another dose of TF at 48 h; six dogs also received postgrafting methotrexate (MTX). Seven dogs (three of four without MTX, four of six with MTX) had sustained engraftment, and three dogs failed to engraft. A single dog given third-party TF failed to engraft. Among five dogs not given TF two achieved sustained engraftment. This pilot study suggests that donor-specific TF facilitates engraftment of DLA-incompatible marrow. Further studies are warranted.
Asunto(s)
Proteínas Sanguíneas/uso terapéutico , Trasplante de Médula Ósea/inmunología , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Transferrina/inmunología , Transferrina/uso terapéutico , Trasplante Homólogo/inmunología , Animales , Proteínas Sanguíneas/inmunología , Perros , Irradiación Corporal TotalAsunto(s)
Antígenos Heterófilos/inmunología , Transfusión de Leucocitos , Transferrina/inmunología , Trasplante Heterólogo/inmunología , Animales , Ciclofosfamida/farmacología , Humanos , Terapia de Inmunosupresión , Inmunosupresores/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Prednisolona/farmacología , Transferrina/aislamiento & purificaciónAsunto(s)
Carcinoma de Células Renales/sangre , Factores Inmunológicos/administración & dosificación , Inmunoterapia , Interleucina-2/administración & dosificación , Neoplasias Renales/sangre , Zinc/sangre , Adulto , Anciano , Biomarcadores , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/terapia , Ritmo Circadiano/efectos de los fármacos , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Inyecciones Subcutáneas , Interleucina-2/efectos adversos , Interleucina-2/farmacología , Neoplasias Renales/terapia , Masculino , Melatonina/metabolismo , Persona de Mediana Edad , Glándula Pineal/efectos de los fármacos , Glándula Pineal/metabolismo , Zinc/deficienciaAsunto(s)
Envejecimiento/metabolismo , Corteza Cerebral/metabolismo , Melatonina/farmacología , Glándula Pineal/fisiología , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos BALB C , Glándula Pineal/trasplanteRESUMEN
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.
Asunto(s)
Envejecimiento/inmunología , Inmunidad/efectos de los fármacos , Melatonina/farmacología , Glándula Pineal/inmunología , Timo/inmunología , Zinc/metabolismo , Envejecimiento/metabolismo , Animales , Antígenos CD/análisis , División Celular , Inmunofenotipificación , Masculino , Ratones , Glándula Pineal/efectos de los fármacos , Glándula Pineal/metabolismo , Glándula Pineal/trasplante , Linfocitos T/inmunología , Timo/citología , Timo/efectos de los fármacos , Timo/metabolismoRESUMEN
Circadian (night), chronic administration of melatonin and young-to-old pineal grafting into the thymus have provided evidence for the existence of an endogenous, primary and central "aging clock" in the pineal gland. The new model described here serves to definitely demonstrate that the replacement of the pineal gland of an old mouse with the pineal from a young, syngeneic donor mouse remarkably prolongs its life and, conversely, the "old" pineal transplanted into a younger mouse will considerably shorten its life span. Pineal cross-transplantation thus provides clear-cut evidence for the central role of the pineal gland in the initiation and progression of senescence. It offers a novel basis for interventions in the aging process.