Large granular lymphocytes (LGL) were observed in the peripheral blood, spleen, lung and, to a le... more Large granular lymphocytes (LGL) were observed in the peripheral blood, spleen, lung and, to a lesser extent, bone marrow and lymph nodes, but not in the thymus of C3H/HeN mice 8 weeks old. The organ distribution of natural-killer (NK) cytotoxicity closely followed that of LGL. Nude mice had higher LGL percentages and NK activity than normal mice. In addition, the age distribution of LGL from the peripheral blood followed that of NK activity. Employing discontinuous Percoll density gradients the percentage of LGL and the NK cytotoxicity of the low density fractions could be enriched in comparison with the original populations of lymphocytes from peripheral blood and spleen, but not from thymus. These results suggest that, as recently shown for humans and rats, in mice too LGL are associated with NK activity.
We have previously reported that the synthetic nonapeptide VQGEESNDK, position 163-171 of human i... more We have previously reported that the synthetic nonapeptide VQGEESNDK, position 163-171 of human interleukin 1 (IL-1 beta), when injected in immunodepressed mice, shows immunorestorative activity similar to that of the whole protein, but with no IL-1-like inflammatory effects [Frasca et al., J. Immunol. 141, 2651-2655 (1988)]. In the present study we have compared the protective and restorative activities of the nonapeptide and human recombinant (hur) IL-1 beta on the survival of lethally irradiated mice. When mice were given a single injection of different doses of the nonapeptide or hurIL-1 beta 20 h before total-body irradiation, both molecules increased the percentage survival of mice exposed to 750 or 850 cGy, but not to 950 cGy. The nonapeptide, however, is less effective than hurIL-1 beta and displays a different dose-response relationship, suggesting that the two molecules act through different radioprotective pathways. When mice were injected with the nonapeptide or hurIL-1 beta immediately after exposure to 850 cGy, the percentage survival was also increased but restoration was lower than protection in both cases. The nonapeptide was also less effective than hurIL-1 beta in restoration, but the two molecules displayed a comparable dose-response relationship as if they shared similar mechanisms. These findings indicate that the 163-171 nonapeptide is able to protect from lethal radiation injury and to restore viability. The nonapeptide appears less effective than hurIL-1 beta but does not exhibit the IL-1-like side effects of the whole molecule.
The pharmacokinetic parameters and distribution of the adjuvant synthetic nonapeptide VQGEESNDK, ... more The pharmacokinetic parameters and distribution of the adjuvant synthetic nonapeptide VQGEESNDK, corresponding to the fragment in position 163-171 in human IL-1, were analyzed after administration to rabbit through different routes. The radiolabeled peptide did not bind to plasma proteins and, when inoculated i.v., it disappeared very rapidly from the circulation, with a t1/2 alpha of 1 min and a t 1/2 beta of 166 min. Upon administration through i.m., s.c. and oral route, the Cmax was reached between 30 and 90 min after inoculum and ranged between 7 and 4% of the administered dose. Organ distribution showed that most of the radioactivity was concentrated in kidneys and excreted in urine. From Sephadex G-10 chromatography, about 60% of the peptide recovered in the urine 4h after i.v. inoculum was intact, whereas it was more than 85% degraded when administered by other routes. The amount of intact peptide recovered in the urine correlated with the biological effectiveness through different routes, suggesting that the adjuvant effect in vivo is exerted by the intact peptide, rather than by its metabolites.
Nanoparticles and the Immune System provides a reference text for toxicologists, materials scient... more Nanoparticles and the Immune System provides a reference text for toxicologists, materials scientists and regulators and covers the key issues of interaction of nanomaterials with the immune system. The book discusses several issues that toxicologists and regulators need to know: identification of endpoints that are relevant for assessing hazard, evaluating impact on immunologically frail populations, and how to evaluate chronic/cumulative effects. In addition, the book addresses the possibility of turning the immunomodulating properties of certain nanomaterials to our advantage for amplifying immune responses in certain diseases or preventive strategies (e.g. vaccination). It raises the awareness of the importance of knowing the effects of the new nanomaterials on our immune system.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function re... more The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. The most extensively studied in this respect has been human IL-1 beta. It has been shown that enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. The understanding of the structure-function relationship of IL-1 obtained so far is expected to give rise within a short time to a new generation of synthetic and/or recombinant derivatives to be experimented for clinical purposes.
Mouse resident peritoneal M phi release AAA and metabolize it into cyclooxygenase- and lipoxygena... more Mouse resident peritoneal M phi release AAA and metabolize it into cyclooxygenase- and lipoxygenase-derived eicosanoids, when triggered in vitro with different stimuli. Pretreatment of M phi with nonimmune IFN-alpha and IFN-beta dramatically decreased AA liberation from M phi phospholipids and eicosanoid formation after stimulation of M phi with Zy, A23187, or PMA. M phi exposed to immune IFN-gamma also showed a substantial impairment of both AA liberation and eicosanoid production upon exposure to Zy. However, AA and eicosanoid release was increased by IFN-gamma, rather than depressed, in PMA-triggered M phi. In addition, IFN-gamma showed differential effects on M phi stimulated with A23187. In fact, it inhibited AA release as well as formation of lipoxygenase-derived LTC4, but it highly increased the release of the cyclooxygenase products PGE2 and 6-keto PGF1 alpha. The ability of IFN-gamma to differentially modulate AA metabolism of M phi, depending on the nature of the triggering agent, sets forth the high specificity of the regulatory capacity of this molecule. This is at variance with the down regulation of AA metabolism that is generally observed with nonimmune IFN.
Large granular lymphocytes (LGL) were observed in the peripheral blood, spleen, lung and, to a le... more Large granular lymphocytes (LGL) were observed in the peripheral blood, spleen, lung and, to a lesser extent, bone marrow and lymph nodes, but not in the thymus of C3H/HeN mice 8 weeks old. The organ distribution of natural-killer (NK) cytotoxicity closely followed that of LGL. Nude mice had higher LGL percentages and NK activity than normal mice. In addition, the age distribution of LGL from the peripheral blood followed that of NK activity. Employing discontinuous Percoll density gradients the percentage of LGL and the NK cytotoxicity of the low density fractions could be enriched in comparison with the original populations of lymphocytes from peripheral blood and spleen, but not from thymus. These results suggest that, as recently shown for humans and rats, in mice too LGL are associated with NK activity.
We have previously reported that the synthetic nonapeptide VQGEESNDK, position 163-171 of human i... more We have previously reported that the synthetic nonapeptide VQGEESNDK, position 163-171 of human interleukin 1 (IL-1 beta), when injected in immunodepressed mice, shows immunorestorative activity similar to that of the whole protein, but with no IL-1-like inflammatory effects [Frasca et al., J. Immunol. 141, 2651-2655 (1988)]. In the present study we have compared the protective and restorative activities of the nonapeptide and human recombinant (hur) IL-1 beta on the survival of lethally irradiated mice. When mice were given a single injection of different doses of the nonapeptide or hurIL-1 beta 20 h before total-body irradiation, both molecules increased the percentage survival of mice exposed to 750 or 850 cGy, but not to 950 cGy. The nonapeptide, however, is less effective than hurIL-1 beta and displays a different dose-response relationship, suggesting that the two molecules act through different radioprotective pathways. When mice were injected with the nonapeptide or hurIL-1 beta immediately after exposure to 850 cGy, the percentage survival was also increased but restoration was lower than protection in both cases. The nonapeptide was also less effective than hurIL-1 beta in restoration, but the two molecules displayed a comparable dose-response relationship as if they shared similar mechanisms. These findings indicate that the 163-171 nonapeptide is able to protect from lethal radiation injury and to restore viability. The nonapeptide appears less effective than hurIL-1 beta but does not exhibit the IL-1-like side effects of the whole molecule.
The pharmacokinetic parameters and distribution of the adjuvant synthetic nonapeptide VQGEESNDK, ... more The pharmacokinetic parameters and distribution of the adjuvant synthetic nonapeptide VQGEESNDK, corresponding to the fragment in position 163-171 in human IL-1, were analyzed after administration to rabbit through different routes. The radiolabeled peptide did not bind to plasma proteins and, when inoculated i.v., it disappeared very rapidly from the circulation, with a t1/2 alpha of 1 min and a t 1/2 beta of 166 min. Upon administration through i.m., s.c. and oral route, the Cmax was reached between 30 and 90 min after inoculum and ranged between 7 and 4% of the administered dose. Organ distribution showed that most of the radioactivity was concentrated in kidneys and excreted in urine. From Sephadex G-10 chromatography, about 60% of the peptide recovered in the urine 4h after i.v. inoculum was intact, whereas it was more than 85% degraded when administered by other routes. The amount of intact peptide recovered in the urine correlated with the biological effectiveness through different routes, suggesting that the adjuvant effect in vivo is exerted by the intact peptide, rather than by its metabolites.
Nanoparticles and the Immune System provides a reference text for toxicologists, materials scient... more Nanoparticles and the Immune System provides a reference text for toxicologists, materials scientists and regulators and covers the key issues of interaction of nanomaterials with the immune system. The book discusses several issues that toxicologists and regulators need to know: identification of endpoints that are relevant for assessing hazard, evaluating impact on immunologically frail populations, and how to evaluate chronic/cumulative effects. In addition, the book addresses the possibility of turning the immunomodulating properties of certain nanomaterials to our advantage for amplifying immune responses in certain diseases or preventive strategies (e.g. vaccination). It raises the awareness of the importance of knowing the effects of the new nanomaterials on our immune system.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function re... more The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. The most extensively studied in this respect has been human IL-1 beta. It has been shown that enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. The understanding of the structure-function relationship of IL-1 obtained so far is expected to give rise within a short time to a new generation of synthetic and/or recombinant derivatives to be experimented for clinical purposes.
Mouse resident peritoneal M phi release AAA and metabolize it into cyclooxygenase- and lipoxygena... more Mouse resident peritoneal M phi release AAA and metabolize it into cyclooxygenase- and lipoxygenase-derived eicosanoids, when triggered in vitro with different stimuli. Pretreatment of M phi with nonimmune IFN-alpha and IFN-beta dramatically decreased AA liberation from M phi phospholipids and eicosanoid formation after stimulation of M phi with Zy, A23187, or PMA. M phi exposed to immune IFN-gamma also showed a substantial impairment of both AA liberation and eicosanoid production upon exposure to Zy. However, AA and eicosanoid release was increased by IFN-gamma, rather than depressed, in PMA-triggered M phi. In addition, IFN-gamma showed differential effects on M phi stimulated with A23187. In fact, it inhibited AA release as well as formation of lipoxygenase-derived LTC4, but it highly increased the release of the cyclooxygenase products PGE2 and 6-keto PGF1 alpha. The ability of IFN-gamma to differentially modulate AA metabolism of M phi, depending on the nature of the triggering agent, sets forth the high specificity of the regulatory capacity of this molecule. This is at variance with the down regulation of AA metabolism that is generally observed with nonimmune IFN.
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