PMA-mediated inhibition of IL-2-driven differentiation of NK cell.
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Cells, Cultured↗
Biomedical subjects
C Riccardi
Publications and source records attributed to C Riccardi.
Pidotimod stimulates natural killer cell activity and inhibits thymocyte cell death.
Experiments were performed to analyze the possible effect of the immunomodulating agent Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid) on mouse Natural Killer (NK) cell activity and glucocorticoid hormone(GCH)-induced thymocyte apoptosis. The results indicate that in vivo treatment with Pidotimod (200 mg/Kg ip for 5 days) causes a significant increase in NK activity and in vitro treatment produces a significant reduction of dexamethasone-induced thymocyte apoptosis. This inhibition appears to be dose-dependent and is also evident against TPA or Ca(++)ionophore-induced apoptosis.
Adjuvants, Immunologic↗
Clinical and radiographic evaluation of the Codivilla method of surgical correction of congenital club foot. Medium-term follow-up of 235 cases.
The authors review 30 patients with congenital club foot (CCF) who were treated surgically by a slightly modified Codivilla technique. Clinical morphologic, and functional follow-up was performed an average of 10 years later, and the findings were compared to the radiographic features. The final outcome was rated good in 41% of the cases, fair in 29%, and unsatisfactory in 30%. The authors found a close correlation between the grade of the initial deformity and the final outcome. Some sign of the deformity always remained, even when the functional outcome was excellent.
Child, Preschool↗
Enhancement of murine NK cell activity generation by ST 789.
We have evaluated the effect of in vivo administration of hypoxanthine derivative ST 789 on the reconstitution of natural killer (NK) cell activity of mice undergoing syngeneic bone marrow (BM) transplantation. Lethally irradiated BD2F1 mice were injected i.v. with 10(7) syngeneic BM cells and treated with ST 789 (50 mg/Kg ip) from day 1 through day 3 after BM graft. The splenic NK activity was evaluated at 7, 10, 14 and 17 days after irradiation and BM graft by the in vitro cytotoxicity assay against NK-sensitive YAC-1 target cells. Results indicate that treatment with ST 789 significantly enhances the NK activity reconstitution as compared to medium treated controls. These results suggest that ST 789 treatment is capable to induce the in vivo expansion of BM NK-progenitor cells resulting in a shorter time of regeneration of NK cell activity.
Adjuvants, Immunologic↗
Immunorestorative properties of ST 789 on experimentally immunosuppressed and infected mice.
ST 789, a newly synthesized chemical characterized by an aminoacidic group joined to the N9 position of the hypoxanthine ring, has recently been shown to be endowed with immunomodulatory properties. In this study we tested ST 789 in vivo for protective effects in Cyclophosphamide-immunosuppressed CD1 mice experimentally infected with several bacterial and fungal pathogens. We found that immunosuppressed mice infected with either fungi or bacteria were significantly protected, as evaluated both by percent mortality and survival time, when treated with doses of ST 789 even as low as 0.2 mg/kg/day. We also observed a marked synergism when the mice were first treated with ST 789 and then additionally treated with subeffective doses of antibiotics such as Amphotericin B, Ceftazidime, and Gentamicin. Even though further studies are required to elucidate the mechanisms underlying the ST 789 effects, these results show that ST 789 is a very promising new immunomodulator whose therapeutic potential has yet to be fully exploited.
Adjuvants, Immunologic↗
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.
Corticosteroids, calcium ionophores and anti-CD3 monoclonal antibodies kill mouse thymocytes incubated in vitro. Cell death is preceded by extensive DNA fragmentation into oligonucleosomal subunits. This type of cell death (apoptosis), which physiologically occurs in the intrathymic process of immune cell selection, is usually evaluated by either electrophoretic or colorimetric methods which measure DNA fragmentation in the nuclear extracts. These techniques are unable to determine the percentage of apoptotic nuclei or recognize the apoptotic cells in a heterogeneous cell population. We have developed a flow cytometric method for measuring the percentage of apoptotic nuclei after propidium iodide staining in hypotonic buffer and have compared it with the classical colorimetric and electrophoretic techniques using dexamethasone (DEX)-treated mouse thymocytes. Apoptotic nuclei appeared as a broad hypodiploid DNA peak which was easily discriminable from the narrow peak of thymocytes with normal (diploid) DNA content in the red fluorescence channels. When the DEX-induced apoptosis was inhibited by either low-temperature (4 degrees C) incubation or cycloheximide treatment, no hypodiploid DNA peak appeared. Similarly, thymocyte death induced by sodium azide, a substance with cell-killing activity through non-apoptotic mechanisms, did not result in any variation in the normal DNA peak. The flow cytometric data showed an excellent correlation with the results obtained with both electrophoretic and colorimetric methods. This new rapid, simple and reproducible method should prove useful for assessing apoptosis of specific cell populations in heterogeneous tissues such as bone marrow, thymus and lymph nodes.
Animals↗
Effect of interleukin-4 on interleukin-2-dependent generation of natural killer cells.
We have previously shown that interleukin-2 (IL-2) is able to induce the generation of natural killer (NK) activity in bone marrow (BM) cells from mice pretreated with 5-fluorouracil. IL-2 alone could dose-dependently induce NK activity in marrow cells and interleukin-4 (IL-4) has dual effect on the NK activity in that, depending on the concentration of IL-2, IL-4 inhibits or stimulates development of NK cells. The inhibitory effect was in part antagonized by interleukin-1 alpha. These effects were not obtained when NK-reactive spleen cells were cultured with the same concentrations of IL-2 or IL-2 plus IL-4 with or without irradiated BM cells as feeders. The effects of IL-4 were also obtained by preincubation for 6-24 hr before culturing with IL-2 alone and correlated with the expression of interleukin-2 receptor (IL-2/r), suggesting that IL-4 might play a regulatory role in the IL-2-dependent generation of NK cells in BM.
Animals↗
Growth of murine natural killer cells from bone marrow in vitro: role of TNF alpha and IFN gamma.
It has been previously shown that natural killer (NK) cell growth can be induced by interleukin-2 (IL-2) in bone marrow (BM) cultures and that other cytokines (CKs), including IL-1 alpha, act synergistically with IL-2. However, as the effect of IL-2 and IL-1 alpha could be due to direct stimulation of NK progenitor cell growth, as well as to the induction of other factors, we analysed the role of the endogenous production of CKs in BM cultures. Results show that mRNAs specific for tumour necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) are detectable within hours in BM cultures supplemented with IL-2 and IL-1 alpha, and that the amount is higher when both IL-2 and IL-1 alpha are present. Antibodies directed against TNF alpha and IFN gamma abrogate the NK cell development, indicating that these CKs play an essential role. The antibodies, however, had no effect on mature NK cells. Furthermore, pretreatment of BM cells with TNF alpha or IFN gamma before culturing with IL-2, enhances IL-2 responsiveness and NK cell growth. These results suggest that induction of cytokines production may be important for growth of NK cells from BM precursors and that the synergistic effect of IL-1 alpha could be due, at least in part, to increased TNF alpha and IFN gamma production.
Animals↗
Natural killer (NK) cell generation in bone marrow cultures: role of IL-1 alpha.
Previous studies have demonstrated that IL-2 is able to induce the development of NK cells from bone marrow (BM) cultures, and that other cytokines acted synergistically with IL-2 in determining an increase of NK cells development. The addition of TNF alpha greatly enhanced the IL-2-mediated induction of NK effector. However, the effect of IL-2 and TNF alpha could be due to direct stimulation of NK progenitors, or to the endogenous production of other factors, which are then responsible of the development of NK cells. As results show that the mRNA specific for IL-1 alpha could be detected in BM cells cultured with IL-2, but not in that supplemented with IL-2 + TNF alpha, it would seem that this lymphokine plays a role only in IL-2-dependent development of NK cells. Studies with Ab anti-IL-1 alpha, showed that the antibody abrograted the IL-2-driven generation of NK cells, but did not affect the NK differentiation induced by IL-2 + TNF alpha. The cytotoxic cells generated by IL-2 or by IL-2 + TNF alpha had the phenotype of mature NK cells including expression of NK 1.1, asialo GM1, Lyt-5, LFA-1, and Thy-1. These data suggest that in spite of phenotypical and morphological similarity of the cells generated with IL-2 or IL-2 + TNF alpha, the endogenous production of IL-1 alpha, appears functionally important only for the differentiation of NK cells induced by IL-2 alone.
Animals↗
Growth and dissemination of human malignant lymphoblasts in immunosuppressed nu/nu mice.
Athymic nu/nu mice are commonly employed for the heterotransplantation of solid human tumors. Leukemias, however, have consistently proved difficult to transplant and, to enhance their take, recipient nu/nu mice have been variously immunosuppressed. In this study, the natural reactivity against human malignant T lymphoblast (PF382) of splenectomized nu/nu mice (S-nu/nu), nu/nu mice splenectomized and treated with polyinosinic-polycytidylic acid (SIC-nu/nu), and nu/nu mice splenectomized, irradiated and repeatedly injected with antiasialo GM1 antiserum (SIA-nu/nu) has been correlated with the in vivo growth of subcutaneous and intravenous PF382 cell challenges. SIC-nu/nu mice display a marked natural killer (NK) activity, quickly clear 125I-Urd-labelled PF382 cells injected intravenously and do not allow the growth of subcutaneous nor intravenous PF382 cell challenges. S-nu/nu mice display a slightly lower NK activity and slower clearance of 125I-Urd-labelled PF382 cells. Moreover, an intravenous PF382 cell challenge kills 56% of S-nu/nu mice. SIA-nu/nu mice have no NK activity, slowly clear 125I-Urd-labelled PF382 cells and always allow the growth of PF382 cells injected either subcutaneously or intravenously with a consistent pattern. Following the intravenous challenge, PF382 cells first metastasize to liver and kideny, then focal or diffuse infiltrations of the bone marrow and menings become evident. SIA-nu/nu mice thus offer an interesting experimental model for study of the pathogenesis of leukemic infiltration of the meninges, and the exploration of possible therapeutic approaches.
Animals↗
Interactions between glucocorticoid hormones and interleukins in T cell development: another possible link between neuroendocrine and immune systems.
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Effect of a new peptidyl-hypoxanthine derivative on natural killer cells and antitumor activity.
A new immunomodifier, [omega-(hypoxanthin-9-yl) pentoxy-carbonyl-leucyl-methionine] (RM06), was synthesized and its effect was evaluated on the activity of Natural Killer (NK) cells. Results indicate that RM06 is able to boost the NK activity of normal mice as well as to augment the regeneration of NK activity of lethally irradiated mice transplanted with syngeneic bone marrow (BM). This later effect also correlated with a significant increase in anti-tumor activity as evaluated by the resistance to metastasis in mice injected with syngeneic melanoma cells. These data indicate that RM06 is able to modulate the NK cell activity as well as the antitumor resistance.
Adjuvants, Immunologic↗
In vivo effects of cytokines on development of natural killer cells and antitumor activity in lethally irradiated bone marrow transplanted recipients.
We have evaluated the effects of combinations of various cytokines on the reconstitution of natural killer (NK) cell activity and resistance to metastases from B16 melanoma, in lethally irradiated mice transplanted with syngeneic bone marrow. Treatment with some combinations of interleukin-2 (IL-2) and other cytokines (IL-2 + IL-1 + TNF alpha or IL-2 + IL-1 + LT) induced appreciably greater and more rapid augmentation of NK cell regeneration than IL-2 alone, as measured in vitro in the 4-h 51Cr release assay against YAC-1 or in vivo in an assay of lung clearance of 125IUdR-labeled tumor cells. The same treatments also induced significant augmentation of in vivo resistance against pulmonary metastases in C57BL/6 mice injected with B16 melanoma cells. These data indicate that stimulation of NK activity in tumor-bearing bone marrow transplanted recipients may be of value in the control of metastatic disease.
Animals↗
Hypothalamic control of the generation of mature natural killer lymphocytes in bone marrow and spleen of the mouse.
Following previous work showing that electrothermocoagulation of the median region of the hypothalamus (MH) caused a marked and permanent decrease in the cytotoxicity of natural killer (NK) cells and in the number of large granular lymphocytes, a study was made of the effect of such lesions on the generation of NK cells in the bone marrow (BM) and spleen of C57BL/6 mice. Fresh spleen and BM cells from MH-lesioned and sham-operated mice were cultured with 40 U of recombinant interleukin-2 (rIL-2). NK activity was significantly higher in BM of lesioned mice, whereas spleen NK activity was greater in the sham-operated controls. NK cells matured by culture with rIL-2 were characterized by assay with fluorescent monoclonal antibodies and found to display the typical NK phenotype. These results show that the number of NK precursors is greater in BM of MH-lesioned mice and that their migration into other organs is probably partially impeded. It can also be concluded that intactness of both BM and the hypothalamus is essential for the physiological generation of NK cells.
Animals↗
In vivo and in vitro effects of cytokines on the generation of NK cell-mediated antitumor activity.
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Animals↗
Synthetic biological response modifiers; Part 1. Synthesis and immunomodulatory properties of some N2-(omega-(hypoxanthin-9-yl)alkoxycarbonyl)-L-arginines.
The synthesis and the main chemical and physical properties of some N2-(omega-(hypoxanthin-9-yl)alkoxycarbonyl)-L-arginines are described. The ability of the synthesized compounds to modulate the natural cytotoxic response (NK cells) in mice has also been analyzed and described.
Adjuvants, Immunologic↗
Defective natural killer cell activity in puerperal hyperprolactinemia.
Prolactin (PRL) influences immune reactivity in animals and in humans and both T-cell abnormalities and reduced natural killer (NK) cell activity have been reported in women with pathological hyperprolactinemia. To investigate further the possible interactions between PRL and the immune system in humans, we analysed T-cell phenotypes and NK cell activity in 15 women with physiological hyperprolactinemia of the puerperium and in 45 age-matched healthy normal cycling women. Puerperal women displayed a normal T-cell phenotype but a significant reduction in the number of Leu-7+ and Leu-11+ cells, associated with a decreased NK cell activity, as measured against K-562 target cells. There was a significant inverse correlation between the raised serum PRL levels and both the number of Leu-7+ cells and NK cell activity. These data confirm an important immunoregulatory role for PRL in humans and suggest a direct inhibitory effect of the chronically raised PRL concentrations on the maturation of NK cells.
Female↗
Effect of Biostim (RU 41.740) on natural killer cell generation from bone marrow precursors.
We have evaluated the possible effect of RU 41.740 (Biostim), a mixture of two glycoproteins extracted from K. pneumoniae, on the in vitro interleukin-2 (IL-2)-induced generation of NK cells from bone marrow (BM) precursors and on the in vivo reconstitution of splenic NK activity in lethally irradiated (9 Gy) and BM reconstituted mice. Our results show that RU 41.740 is able to augment the generation of NK cells when added (1-0.01 micrograms/ml) to normal or 5-fluorouracil-resistant BM, cultured in the presence of recombinant IL-2. Also, in vivo treatment of lethally irradiated mice, transplanted with syngeneic BM cells, with RU 41.740 (1-0.1 mg/kg i.v.) from day 0 through day 4 after BM graft, resulted in a significant augmentation of NK activity reconstitution.
Animals↗