摘要:

AbstractWe reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T80G)2inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T80G is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T80G at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62 %) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T80G was administered in vivo. In addition to the spleen, 7T80G activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T80G elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c, i.v., and i.p. routes all induced activition of NK cells in spleen, BM and PE. 7T80G was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T80G, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T80G showed no such synergism.

ISSN:0892-3973    

DOI:10.3109/08923979209009210

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractIn a preceeding paper we characterized the in vivo and in vitro induction of cytotoxic effector cells elicited by a novel synthetic immuno-stimulator 7-thia-8-oxoguanosine (7T80G)2. In the present study we further characterized the cells responsible for the induced cytotoxicity and the mechanisms together with the lymphokines mediating the immunological response to 7T80G. Removal of macrophages from 7T80G activated spleen cell suspensions by various methods resulted in a significant increase in cytotoxicity to YAC-1 targets. 7T80G induced effectors did not exert cytotoxic effect on macrophage sensitive P815 target cells. In vivo activated effectors when incubated with anti-asialo-GM1antibody plus complement lost completely their ability to lyse YAC-1 targets. Together, these findings indicate that the 7T80G induced effector cells are not macrophage like. Spleen cells from nude mice were readily activated by 7T80G. The induced effectors were resistant to complement mediated lysis using anti-L3T4, anti-Lyt1 or anti-Lyt2 antibodies. Pretreatment of spleen cells with macrophage depleting agents both, in vitro and in vivo and subsequent activation of cells by 7T80G resulted in effectors with reduced cytotoxicity.When injected in vivo, 7T80G induced strong IFN production which paralelled the kinetics of NK cell activation. Furthermore, antibodies toα&β-IFN but not toγ-IFN diminished the induction of the cytotoxic activity. Although these findings suggest that activation of NK cells by 7T80G is most likely to be mediated byα&β-IFN involvement of other cytokines can not be ruled out.

ISSN:0892-3973    

DOI:10.3109/08923979209009211

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractThe effects of Taxol on some immunological parameters were investigated, in vitro, in the murine macrophage cell line J774.1. Mitochondrial dehydrogenase activity and (3H) TdR incorporation were shown to be increased in Taxol treated cells. Likewise, Taxol induced TNFαsecretion. But Taxol seemed to be a weak inducer of the two interleukins IL-1 and IL-2, since their detection occured late in the cell culture supernatants.

ISSN:0892-3973    

DOI:10.3109/08923979209009212

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractAcemannan, an antiviral agent with immune enhancement capabilities, was studied for its impact on cytotoxic T-lymphocyte (Tc) function generated in response to alloantigen. To investigate whether acemannan directly stimulated the generation of Tc from primary mixed lymphocyte cultures (MLC), the drug was added at the initiation of the MLC. There was a dose-related, statistical increase in killer T-cell generation produced by acemannan in the clinically relevant dose range. The lowest test dose of the drug (2.6×10-9M) increased chromium release nearly two-fold; the 2.6×10-8M dose gave a maximal 3.5 fold increase in cytotoxic T-cells. To study whether acemannan enhanced the capacity of Tc once generated to alloantigen to destroy targets bearing the sensitizing antigens, MLR were established in the absence of any drug. Acemannan at the two highest doses increased the functional capacity of Tc to destroy target cells to which they had been sensitized in the MLR. To control for the possibility that acemannan was directly cytotoxic to target cells, targets were incubated alone with drug and without sensitized killer T-cells. No dose of acemannan was found to be cytotoxic to these cells. In conclusion, acemannan did enhance the generation of cytotoxic T-cells when added at the initiation of the MLR. When acemannan was added at the completion of allostimulation, an increase of almost 50% killing by Tc was also observed. These effects can not be explained by direct drug related toxicity and suggest a functional correlate to the previously described immune enhancing properties of the agent. As this drug is being tested for the treatment of HIV infections, these data provide at least one immunologic mechanism by which acemannan may be clinically salutory.

ISSN:0892-3973    

DOI:10.3109/08923979209009213

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractThe effects of purified protein A from Staphylococcus aureus Cowan I strain on induction of lymphokine (IL-2) activated killer (LAK) activity were studied in normal as well as melanoma patient's lymphocyte. The coculture of peripheral blood mononuclear cells (PBMC) with various doses of protein A (0.001, 0.01 and 0.1μmlg/ml) and IL-2 (100 U/ml) for 4 days produced synergistic effect on the LAK cells mediated cytotoxicity. The potentiation of cytotoxicity and lytic ability of LAK cells against NK sensitive (K-562) and NK-resistant (M1 4) tumor cells were observed. Further there was potentiation of DNA synthesis in PBMC after 4 days culture. Similar results were found when PBMC from melanoma patients were cultured with PA and IL-2. The potentiation of LAK cell induction associated with its cytotoxic and lytic potential by low doses of IL-2/PA regiment may be helpful in the development of LAK immunotherapy of the cancer patients.

ISSN:0892-3973    

DOI:10.3109/08923979209009214

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractIn a transplantable solid tissue Dalton's lymphoma tumor model in mice we have studied the mode of antitumor action of protein A, a well known biological response modifier. Protein A (15 ug) was administered intravenously in normal and solid tissue Dalton's lymphoma tumor bearimg mice on day 3 and 7 after tumor inoculation. Incidence of mortality was more in untreated tumor bearing group than that in PA treated tumor bearers. There was a significant decrease (p<0.001) in tumor diameter in PA treated group compared to untreated group. Protein A treatment significantly enhanced the delayed type hypersensitivity (p<0.01), T-cell number in spleens (p<0.001) and lymph nodes (p<0.05) as well as phagocytosis (p<0.001) of opsonized SRBC by peritoneal macrophages of tumor bearing animals. Apart from the nonspecific immunopotentiation, Protein A also activates natural Killer (NK) cell activity and also splenic lymphocytes mediated killing of autologous tumor targets in a significant (p<0.001) manner. These results suggest that PA treatment activates cellular arc of the immune system in general, and macrophage, T cells and NK cells specifically. In the present communication, we have attemted to provide the information that these immune activations appear to be related to antitumor response induced by Protein A.

ISSN:0892-3973    

DOI:10.3109/08923979209009215

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractThe effect of the synthetic lecithin analogue, dimethyl-DL-2, 3-distearolyoxypropyl-2′hydroxylethylammonium acetate, on CTL cytolytic activity was studied. The analogue significantly inhibits H-2banti H-2dcytolytic T lymphocytes at concentrations which do not impair lymphocyte viability, protein synthesis, or RNA synthesis. At these concentrations the inhibition is reversible upon removing the analogue. Thus, the inhibition produced by analogue simply is not a result of analogue toxicity. At higher concentrations of the analogue, CTL inhibition is very pronounced; however at these higher concentrations there is evidence of nonspecific toxicity of the analogue on CTL.

ISSN:0892-3973    

DOI:10.3109/08923979209009216

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractAM3, a biological response modifier (BRM) of polysaccharide/protein nature, was given by the oral route to 13 patients with chronic active hepatitis B (CAHB). After 12 months of daily treatment, 8 patients cleared serum HBV-DNA and HBeAg together with ALT normalization. Immunohaemotologic studies showed how time of inhibition of viral replication was related to significant decreases of CD4, CD8 and B cell blood lymphocytes. After serum viral elimination, however, a significant haematologic rebound of peripheral blood mononuclear cells (PMNC): CD3, CD4 and CD8 lymphocytes was seen. These data, suggest that the antiviral activities of AM3 may be due to its immunodulatory capacities. These promising results, together with the absence of any side effects, justify the entry to trials with a larger number of patients. Furthermore, treatment with AM3 may help to elucidate the pathophysiology of CAHB.

ISSN:0892-3973    

DOI:10.3109/08923979209009217

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractRen-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NIN), a traditional Chinese medicine, is a drug made of spray-dried powder of hot water extract obtained from twelve species of medical plants. An intraperitoneal (ip) injection with NIN 2 days before intravenous (iv) infection withListeria monocytogenes (L. monocytogenes)accelerated elimination of viable bacteria in the spleen in the early stage of infection (from day 1) and protected mice from the lethal infection. It was suggested that the protective effect of NIN was mediated by the activation of nonimmune macrophages playing a principle role in resistance in the early stage of infection. Two days after ip injection with NIN just before infection, significantly increment in the number of monocytes in the peripheral blood was observed, though macrophage number in the spleen and their intracellular killing activity were unchanged. At 12 hours after infection withL. monocytogenesa significantly enhanced increase of splenic macrophage number was observed in NIN-treated mice, compared to controls. After ip injection of NIN, interleukin-1 (IL-1), IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) became detectable in the serum or peritoneal cavity. These results suggested that NIN stimulated macrophage-precursor cells in the bone marrow via the production of IL-1, IL-6, GM-CSF by macrophages, accelerated the supply of peripheral macrophages, and such macrophages accumulated into the site of infection in the very early stage of infection. Similar protective effects of NIN were observed by oral administration for 7 days till 1 day before iv infection withL. monocytogenes.

ISSN:0892-3973    

DOI:10.3109/08923979209009218

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

AbstractEpinastine caused an inhibition of histamine release from rat peritoneal mast cells induced by both antigen-antibody reaction and compound 48/80. Epinastine was similarly effective in inhibiting compound 48/80-induced histamine release not only from isolated rat peritoneal mast cells but also from rat mesenterial pieces. Also, histamine release from lung pieces obtained from actively sensitized guinea pigs after exposure to antigen challenge was markedly inhibited by epinastine. The drug was effective in inhibiting not only Ca2+uptake into lung mast cells in actively sensitized guinea pigs but also Ca2+release from the intracellular Ca store of rat peritoneal mast cells exposed to both compound 48/80 and substance P. No significant changes were observed in phosphodiesterase activity in rat peritoneal mast cells treated with epinastine, while adenylate cyclase activity was augmented by epinastine. Epinastine has no inhibitory effect on histamine release induced by Ca2+or IP3 from permeabilized mast cells. However, the drug significantly and dose-dependently suppressed calmodulin activity suggesting that histamine release inhibition due to epinastine may be partly attributable to Ca2+-calmodulin dependent process(es). The drug caused no visible changes in thermodynamic behavior of lipids, either in order parameter or in differential scanning calorimetry, indicating that the drug has no influence on membrane fluidity.

ISSN:0892-3973    

DOI:10.3109/08923979209009219

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor