The role of zinc in neuroendocrine-immune interactions during aging.
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Aging↗
Biomedical subjects
M Provinciali
Publications and source records attributed to M Provinciali.
Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine.
The cytotoxic activity of Natural Killer (NK) and Lymphokine Activated Killer (LAK) cells in neoplastic patients with or without antalgic treatment was studied. NK cell activity was found reduced in untreated neoplastic patients when compared to healthy subjects. The atalgic treatment with morphine (orally or intrathecally administered) was able to significantly reduce the mean values of NK cell activity found in cancer patients. In three patients the cytotoxicity of NK cells significantly decreased during transfer from oral to intrathecal administration of morphine. In contrast to the NK cell function, the development of LAK cell activity significantly increased in neoplastic patients when compared to healthy controls. Further increments were obtained during treatment with morphine. The oral treatment with morphine was able to determine a higher induction of LAK cells than the intrathecal administration of the drug. Besides providing new knowledge on the effect of morphine on immune system our findings suggest that, in order to include neoplastic patients in clinical trials of adoptive immunotherapy with LAK cells and interleukin-2 (IL-2), the antalgic therapy with oral administration of morphine may represent a better solution than the intrathecal administration of the drug.
Administration, Oral↗
Recovery of spleen cell natural killer activity by thyroid hormone treatment in old mice.
The age-dependent changes in thyroid-hormone blood levels and the effects of in vivo and in vitro thyroid-hormone administration on both basal and lymphokine-induced spleen cell natural killer (NK) activities have been investigated in young and old Balb/c mice. Both thyroxine (T4) and triiodothyronine (T3) plasma levels decline progressively with increasing age of the mice, displaying in 25-month-old mice only 50 and 60% of the T4 and T3 blood levels, respectively, found in young mice. In vivo T4 administration to old mice causes a significant increment in endogenous NK activity (2.2-fold increase), which approaches the values observed in young animals, while it does not modify NK activity in young mice. The T4 injection in old mice does not induce changes in the lymphocyte sub-populations. When T4 is administered in vitro alone or in combination with interferon (IFN) and/or interleukin 2 (IL-2), no effect is observed either on basal activity or IL-2-induced cytotoxicity, whereas the IFN sensitivity of spleen cells from old mice is significantly recovered (4-fold increase). T4 is able to increase IFN-induced cytotoxicity even when administered in vitro simultaneously with IFN to the cytotoxic assay (1.5- and 2.7-fold increases in young and old mice, respectively). Under these conditions, IFN alone is not able to exert any boosting effect even at a young age. In vivo propylthiouracil (PTU) administration completely abrogates the IFN responsiveness of spleen cells in young mice. The interruption of the PTU treatment results in a recovery of IFN-inducible NK cytotoxicity. Taken together, our findings point out the important role of thyroid hormones in the modulation of NK cell activity and provide a new insight into the mechanisms by which the endocrine system is able to influence the expression of natural immunity.
Aging↗
Reversibility of age associated NK defect by endocrinological and/or nutritional intervention.
Several abnormalities arise at the level of NK cell function in both rodents and humans with increasing age. The age-related changes are not irreversible alterations since they can be reversed either by endocrinological or nutritional approaches, suggesting that age-related microenvironmental changes may play a relevant role in the age-related immune deterioration. Whether endocrine and nutritional factors have an additive effect or act through the same intracellular mechanisms remains to be established, though the first possibility seems more likely since the action of TSH and thyroid hormones is specifically directed towards lymphokine-boosted NK activity, while AL are able to prevent age-associated defect of basal NK cytotoxicity.
Aging↗
Improvement of natural killer cell activity by in vitro active lipids (AL 721) administration in old mice.
Results of several experiments have given rise to the hypothesis that the decline of the immunocompetence with aging is at least in part related to alterations of the lipid membrane composition and, consequently, to a decrease in membrane fluidity. The age-dependent decline of mitogen responsiveness can, in fact, be reversed by a special lipid mixture designated as active lipids (AL 721), which acts by means of its fluidizing action on the plasma membrane. The purpose of this study was to examine the possibility of raising the low endogenous levels of Natural Killer (NK) activity by in vitro AL administration in old mice. When spleen cells from old mice were incubated in vitro with AL, a significant increase in cytotoxic activity was obtained over control cultures, without reaching, however, the levels observed in young mice. In spleen cells from young mice, the AL administration causes a slight augment of NK basal activity. These results suggest that cell membrane fluidity plays an important role in the efficiency of NK cells, giving support to the hypothesis that a rectification of rigidified cell membranes may represent a valuable approach to restore proper physiological functions in old age.
Aging↗
Modulation of lymphoid cell sensitivity to interferon by thyroid hormones.
The possibility of increasing the responsiveness of lymphoid cells to Interferon (IFN) was investigated by studying the effect of the in vitro preincubation of spleen cells from young mice with thyroid hormone prior to the administration of IFN on their Natural Killer (NK) activity. Both physiological concentrations of T4 or T3 are able to significantly increase the boosting action of IFN on NK cells. The increase in IFN-responsiveness is observable at various IFN concentrations and the peak level of IFN-induced NK activity is reached with less than a half-optimal IFN concentration after T4 pretreatment. The effect of T4 on the IFN-sensitivity of NK cells requires a very short time, being already fully expressed after only 30 min, with minor increments at more prolonged incubation times. These results indicate for the first time the possibility of modulating the in vitro sensitivity to IFN by a hormonal approach.
Animals↗
Role of pituitary-thyroid axis on basal and lymphokine-induced NK cell activity in aging.
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Adult↗
Improvement of decreased natural killer cell activity in cervical cancer patients by active lipids (AL 721).
In the present study we observed the absolute number of NK cells and the NK activity in 10 patients with cervical cancer. NK activity was determined before and after stimulation with Active Lipids. We reported a significant decrease of basal NK activity, but after AL stimulation NK activity was increased with statistical significance. Therefore our findings show that the reduction of NK activity in neoplastic patients is not an irreversible phenomenon since it can be restored by "in vitro" AL administration. This is important for the adoptive immunotherapy by which we could give LAK cells to the patients.
Drug Combinations↗
Timing of appearance and disappearance of IFN and IL-2 induced natural immunity during ontogenetic development and aging.
The age-dependent modifications of both basal and lymphokine-induced natural killer (NK) activity were analyzed in Balb/c inbred mice by measuring either the percentage of specific lytic activity in a 51 Cr release assay or the percentage of cells capable of binding the YAC-1 target cells. The basal lytic activity of spleen cells is low at birth, then it increases progressively and reaches a peak between 5 and 8 weeks of age and decreases thereafter, displaying in 25-month-old mice only 10% of the NK activity found in young mice. The number of spleen cells capable of binding target cells is higher at birth and then it declines progressively-old mice show about 40% of the binding capacity found in young mice. Significant in vitro NK activation is obtained in spleen cells from 25-, 50- and 750-day-old mice by incubation with interleukin-2 (IL-2) (1.8-fold increase in 25- and 50-day-old mice and 2.6-fold increase in 750-day-old mice) while no effect is obtained in 15-day-old mice. The responsiveness to in vitro stimulation with interferon (IFN) is not present in 15-day-old mice, however it appears in a defective way at the age of 25 days, and reaches its highest level in 50- and 180-day-old mice, (3.5- and 4.5-fold increase), still remaining present in 630-day-old mice, (two-fold increase) but not in 750-day-old mice. The in vivo injection with IFN increases the spleen cell NK activity of 25- and 50-day-old mice (3.6- and 2.3-fold increase respectively) but not of 15- and 750-day-old mice. The present data here confirm the existence of age-dependent variations of spleen cell NK activity and suggest a similar sequential timing of appearance/disappearance of IL-2 and IFN responsive spleen cells during ontogenetic development and aging respectively.
Aging↗
[Immuno-neuroendocrine interactions during growth and aging].
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Adrenocorticotropic Hormone↗
Neuroendocrine-thymus interactions: perspectives for intervention in aging.
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Aging↗
Thyroxine-dependent modulation of natural killer activity.
The influence of "in vitro" treatment with thyroia hormones on basal or lymphokine-induced NK cytotoxicity was analyzed in Balb/c mice using YAC-1 as target cells in a 51 Cr release assay. "In vitro" treatment with IFN or IL-2 causes a considerable increase of the natural cytotoxic activity of spleen cells from young-middle aged mice. An additive effect is observed when the two lymphokines are administered simultaneously. "In vitro" spleen cells preincubation with thyroxine increases NK citotoxic activity induced by IFN but it does not modify the basal activity or that induced by IL-2. Furthermore, thyroxine was able to significantly amplify even the maximal boosting effect induced by the simultaneous addition of both IFN and IL-2. These findings suggest a role for thyroid hormones in the modulation of natural cell-mediated citotoxicity and particularly in the espression of NK cell sensitivity to IFN.
Animals↗
Immunotherapy of bladder cancer with intralesional injection with BCG.
Immunotherapy of bladder cancer with non specific immunostimulants, such as bacillus Calmette Guerin (BCG), has been shown to significantly reduce tumor recurrences, and, when applied through intravesical BCG instillation to induce the regression of some established tumors, including carcinomas "in situ" and even some invasive tumors. Since in other tumors, namely melanomas, BCG has been proved to be most successful when infected directly into the tumor, intralesional therapy with BCG (1.5 x 10 BCG weekly for four weeks) has been applied in 20 patients affected by bladder cancer (T1 - T2). The local reaction has induced substantial reduction of the tumor mass and, in some cases, (four) total disappearance of the tumor. On the sixteen patients without total disappearance of the tumor, TUR was applied. The successive follow-up of these patients offer at present the following figures: 3 out of the four patients with remission after BCG alone are disease-free after 26-30 months, whereas one has developed after 18 months a papilloma surgically removed; 15 out of the sixteen patients treated with BCG followed by TUR are disease-free after 26-30 months. These data, compared with literature findings, support the idea that intratumoral BCG instillation of bladder cancer permits a longer disease-free period than other therapeutical approaches.
Adult↗
Plasticity of neuroendocrine-thymus interactions during aging.
Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations such as, (a) intrathymic transplantation of pineal gland or treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumor cell line or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LH-RH), (d) treatment with exogenous thyroxine or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic, involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of such interactions in old age that is responsible for age-associated dysfunction. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is at present, difficult to draw any definitive conclusions. The effect of GH, thyroid hormones, and LH-RH may be due to the presence on thymic epithelial cells supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or other pineal factors may also act through specific receptors, but experimental evidence is still lacking. The role of zinc, whose turnover is usually reduced in old age, is diverse. The effects range from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may even be more crucial. According to recent preliminary data obtained both in animal and human studies, it appears that the above reported endocrinological manipulations capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.
Aging↗
Expression of p53 and apoptosis of tumor cells in locally advanced cervical carcinoma after cisplatin based neoadjuvant chemotherapy.
Various chemoantiblastic agents cause DNA damage followed by apoptotic cell death through the activation of the p53 suppressor gene. The aim of our study was to evaluate the relationship between p53 protein expression, apoptosis of autologous tumor cells, and clinical response to neoadjuvant chemotherapy in patients with cervical carcinoma. Our study included 14 women with stage II squamous cervical carcinoma who had been admitted to the Institute of Gynecology and Obstetrics, Ancona University, between January 1990 and December 1995. The patients received neoadjuvant combination chemotherapy, consisting of three cycles of cisplatin (80 mg/m2) and bleomycin (30 mg/m2). After chemotherapy, radical surgery was performed. Bioptic specimens were obtained from cervical tumors before and after chemotherapy, and processed for DNA staining and apoptosis, and immunohistochemical staining with a monoclonal antibody against p53. Ten patients (71.4%) showed a clinical response (2 complete, and 8 partial), while of the remaining 4 cases (28.6%) 3 had no change and 1 showed progression after neoadjuvant combination chemotherapy. A significant relationship was observed between the overexpression of p53 and sensitivity to chemotherapy; responder patients showed a higher frequency of p53 positive cells than non-responders (p = .05). A significant direct relationship was observed between p53 protein immunostaining and apoptosis of tumor cells both before (p = .02) and after (p = .01) chemotherapy. Our study seems to define the relationship between p53 expression and sensitivity to cisplatin based chemotherapy in locally advanced cervical carcinoma, supporting the notion that the cytotoxic action of cisplatin can activate p53 mediated apoptosis. However, the limited number of patients in our series does not permit judgement on the clinical implications of the expression of p53 in patients undergoing neoadjuvant combination chemotherapy for locally advanced cervical carcinoma.
Adult↗