Connection between lower natural killer function and susceptibility to viral infection in cluster headache.
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Adult↗
Biomedical subjects
E Bonmassar
Publications and source records attributed to E Bonmassar.
Increased susceptibility of peripheral mononuclear cells of leukemic patients to HTLV-I infection in vitro.
Peripheral mononuclear cells (MNC) collected from 12 healthy donors and 44 leukemic patients at various stages of the disease were tested for natural killer (NK) activity and for their susceptibility to HTLV-I infection in vitro, measured in terms of percentage of p19 positive cells. MNC from leukemic donors at any stage of leukemia (ie, onset or relapse, ON/REL; complete remission or off-therapy, CR/OT donors) were highly susceptible to HTLV-I infection. This was true for acute leukemias of lymphoblastic (ALL) or nonlymphoblastic (ANLL) type. MNC of ON/REL patients were more susceptible to HTLV-I than those of CR/OT donors. In addition, leukemic blasts were more rapidly infected (ie, within five to seven days) than the HTLV-I-susceptible normal cord-blood lymphocytes. However, the presence of circulating blasts was not essential to virus susceptibility, since CR/OT MNC, presumably free of leukemic blasts, were still more susceptible to HTLV-I than normal cells. Basal NK function of MNC from leukemic patients was significantly lower than that detectable in healthy controls. However, no correlation was found between susceptibility to HTLV-I infection and NK activity.
Adolescent↗
Differential susceptibility of human mononuclear cells to infection with HTLV-I.
Infection with human T-cell leukaemia/lymphoma (HTLV-I) preferentially affects T cells of the OKT-4 phenotype. The aim of the present study was to determine whether distinct T-cell subsets exhibit differences in susceptibility to virus infection. T cells from peripheral blood were separated according to cell densities by 7-step Percoll gradients. Separated T-cell subpopulations were infected with HTLV-I, using cocultivation with irradiated virus producer MT-2 cell line. Percentages of HTLV-I-infected cells and their phenotypes were assayed by immunofluorescence assay (IFA), using highly specific mouse monoclonal antibody directed against HTLV-I P-19 core protein, and other surface markers. The results showed that different T-cell subpopulations were susceptible to HTLV-I infection with the exception of large granular lymphocytes (LGL) which exhibit high cell-mediated natural cytotoxicity (CMNC).
Adult↗
Influence of interferon on the functional expression of natural killer target structures of murine lymphoma cells.
Murine lymphoma cells (YAC-1), induced by Moloney leukemia virus, nontreated (YAC) or pretreated in vitro with interferon (YAC-IF), were tested for their susceptibility to natural killer (NK)-mediated cytolysis. In line with previous reports YAC-IF were less susceptible to NK lysis than YAC cells. In cold competition assay, YAC-IF inhibited cytotoxicity to a lesser extent than YAC lymphoma when labeled target YAC cells were used. However, when radioactive YAC-IF cells were used as targets, cold competition attained with both YAC and YAC-IF was essentially the same. Furthermore, effector splenocytes, depleted of NK effector cells through immunoabsorption on YAC monolayer, were inactive against both YAC and YAC-IF targets. On the other hand, effector lymphocytes, absorbed on YAC-IF monolayer, retained NK activity against YAC cells but not against YAC-IF targets. These results are compatible with the hypothesis that interferon (IF) modulates negatively a subset of "interferon-susceptible" (IFS) NK target structure(s) (TS) of YAC cells, which would then express membrane determinants not functionally present on YAC-IF cells. On the other hand YAC and YAC-IF cells share "interferon-resistant" (IFR) TS not affected by pretreatment with IF. In order to test whether IFS X TS and IFR X TS are present on the same cell or clonally distributed, YAC cells were cloned and tested for NK susceptibility following IF pretreatment. The results did not support the hypothesis of a clonal distribution of both IFS X TS and IFR X TS since IF pretreatment of all clones, obtained by limiting dilution, resulted in a net impairment of target susceptibility to NK effector cells.
Animals↗
Natural resistance in mice against Friend leukemia cells. I. Studies with in vitro passaged interferon-sensitive and interferon-resistant cell clones.
Anti-lymphoma natural resistance (NR) has been detected in DBA/2 mice inoculated intravenously (iv) with syngeneic Friend leukemia cells (FLC). Interferon-sensitive 745 or interferon-resistant 3Cl-8 clones, passaged in vitro and exhibiting "low" tumorigenicity in syngeneic DBA/2 mice, were used. NR, measured as rapid clearance of radiolabeled cells from lung and liver of recipient mice, was age-dependent, was boosted by host pretreatment with polyinosinic-polycytidylic (poly I:C) acid or Friend leukemia virus, and was decreased by mice pretreatment with cyclophosphamide or i-carrageenan. Treatment of "target" FLC with interferon suppressed the susceptibility of 745 FLC, but not that of 3Cl-8 FLC to host's NR. These data suggest that the "low" in vivo tumorigenicity of in vitro passaged FLC is, at least in part, due to host's NR directed against target structures associated with leukemia cells.
Aging↗
A miniaturized cell-mediated cytotoxicity assay with human effector mononuclear cells.
A miniaturized method (Microtest, MIT) for detecting natural killer (NK) and antigen-elicited cell-mediated cytotoxicity has been developed. It retains the sensitivity and the efficiency of conventional macroassay (Macrotest, MAT). In comparison with the standard MAT, MIT provides a 5-fold reduction in the number of effector and target cells without changing the final reaction volume. This avoids the excessive relative evaporation that could occur in microassays employing limited reaction volumes. Moreover the use of V-bottom microtiter plates allows the recovery of 0.15 ml of supernatant, thus increasing the efficiency of 51Cr recovery. MIT was adopted for the evaluation of the NK activity of untreated or interferon (IFN)-treated human mononuclear cells (MNC) and for cold-inhibition and cytotoxic T-lymphocyte (CTL) assays. In the experiments performed with both macro and micro assays, comparable values of the percentage of specific lysis and of the number of lytic units were found. The slopes of the curves obtained with MIT are generally slightly lower than those detectable with MAT. The Pearson coefficient r2 is generally better for the macroassay although it can be considered acceptable in the microassay. The MIT described here appears to be a useful method, especially for providing information on natural resistance and cytotoxic T-lymphocyte systems in a number of pathological conditions characterized by a small recovery of effector cells from standard blood collection for analytical purposes.
Cell Line↗
An in vitro assay for evaluating chemosensitivity of leukaemia cells: preclinical studies.
The present study was aimed at defining the standard conditions for predictive chemosensitivity testing of human leukaemias. The in vitro cytotoxic potential of 11 anticancer drugs against L1210 murine leukaemia was comparatively determined 3 and 48 h after in vitro exposure of leukaemia cells to these agents. In preliminary testing, drug-induced damage was estimated in terms of percent inhibition of: tumour cell proliferation, by microscopic determination of viable cell numbers; and DNA synthesis, by measuring the extent of incorporation of the labelled nucleoside 125IUdR. Since the two tests appeared to yield comparable results, all subsequent experiments on the various murine tumours were performed using the radiolabel incorporation technique. The results obtained pointed out that this metabolic assay performed 48 hours after drug exposure appears to be capable of predicting both "spontaneous" and "induced" in vivo resistance of murine leukaemias.
Animals↗
Decline of natural cytotoxicity of human lymphocytes following infection with human T-cell leukemia/lymphoma virus (HTLV).
Cell-mediated natural cytotoxicity (CMNC) of fresh or long-term cultured lymphocytes collected from HTLV-positive patients or infected in vitro with the virus, was tested against K562 target cells. Severe depression of reactivity was found in fresh lymphocytes of three patients with advanced disease, in 12 in vitro established T-cell malignant lines, and two HTLV-infected cord blood (C5/MJ and C91/PL) lines. Moreover, all (eight) HTLV-1 infected cell lines listed showed a significant inhibition of CMNC of peripheral blood lymphocytes of healthy donors. Whether virus infection promotes the outgrowth of pre-existing suppressor cells and/or produce changes of the T-lymphocyte function is unknown.
Adult↗
Induction of natural killer cell activity by inactivated Candida albicans in mice.
Injection of merthiolate-inactivated yeast form cells of Candida albicans into the peritoneal cavities of mice induced the appearance of a cytolytic effector population against YAC-1 tumor cell lines. This induction was maximally manifested in 5- to 8-week-old animals 3 to 4 days after injection of 2 X 10(7)C. albicans cells, and the peritoneal lytic population exerted its optimum cytotoxic effect after 4 h of incubation. No significant natural cytotoxic activity was generated by C. albicans in the bone marrow or thymus, whereas there was a slight, transient, but significant depression of natural splenic cytotoxicity. Experiments performed to characterize the natural cytotoxic population elicited by the inactivated yeast showed that the effectors were nonadherent, nonphagocytic cells. Moreover, the anti-YAC-1 lytic activity was partially sensitive to anti-Thy1.2 serum and was completely abrogated by treatment of peritoneal nonadherent cells with monoclonal anti-asialo GM1 antibodies. Finally, the peritoneal population of cytotoxic cells induced by C. albicans was fully susceptible to Ly5.1 plus anti-immunoglobulin G2a and complement lysis. Although different cell populations could be induced by inactivated C. albicans, all of our data support the view that the anti-YAC-1 activity was entirely attributable to natural killer lymphocytes.
Adhesiveness↗
Evaluation of antibacterial activity in experimental meningo-encephalitis in mice.
Mice infected intracerebrally (ic) or intraperitoneally (ip) with Pseudomonas aeruginosa were treated subcutaneously with graded doses of five antibiotics all of which displayed anti-pseudomonal activity in vitro. The analysis of MIC, ED50 in the ip infection model (ED50-ip) and that in the ic system (ED50-ic) for each agent showed: gentamicin, the most active agent in vitro, was also active in vivo, with an ED50-ic nearly six-fold higher than ED50-ip; ceftazidime, considerably active both in vitro and in vivo, showed comparable values of ED50 in the two systems; ceftriaxone, also active in vitro, showed limited activity in vivo, its two ED50 values being similar; aztreonam, moderately active both in vitro and in vivo, showed comparable activity in the two infection models; carbenicillin, the least active agent in vitro, gave poor results in vivo, with an ED50-ic 2.6-fold higher than ED50-ip.
Animals↗
Natural cell-mediated cytotoxicity: a micro assay suitable for clinical tests.
A micro version (microtest, MIT) of the 51Cr release assay for detecting Natural Killer activity (NK) has been developed. The test retains the sensitivity and the efficiency of conventional macroassay (macrotest, MAT) and provides a 5-fold reduction in the number of effector and target cells employed. In experiments performed with peripheral blood mononuclear cells (MNC), untreated or treated with interferon (IFN) or with hydrocortisone (Hy), comparable values of the percentage of specific lysis and of the number of lytic units were obtained using both MAT and MIT methods. Therefore MIT appears to be useful in monitoring the NK function of patients characterized by low MNC counts.
Animals↗
Natural resistance against hematopoietic cells in lethally-irradiated mice infected with Friend leukemia virus.
The influence of in vivo infection with the polycythemic substrain of Friend leukemia virus on noninducible ('natural') resistance against allogeneic normal or malignant grafts was studied in lethally irradiated mice. Parallel studies were performed on the NK system in the same experimental conditions. The results indicate that FLV-P infection of mice with full (DBA/2) vs partial (BALB/c and CD2F1) susceptibility did not suppress their in vivo natural resistance against bone marrow or El-4 leukemia cells. On the other hand, a decline in NK activity paralleled the progression of leukemic disease in the more susceptible DBA/2 hosts.
Animals↗
Chemical xenogenization of murine lymphoma cells with triazene derivatives: immunotoxicological studies.
Equitoxic doses of 5-(3-3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) and aryl-triazene derivatives (compounds all capable of inducing a marked increase in murine tumor cell immunogenicity) were studied for their effects on the host immune system. At different times after drug exposure the animals were tested for allograft responses, competence in producing lymphocytes active in lethal graft-versus-host disease, delayed-type hypersensitivity, humoral antibody production, and mitogen responsiveness. While some of the aryl-triazenes tested (DM-COOK DM-NO2) showed a pattern of immunodepression similar to that of DTIC, others were less (MIC, MM-COOK, MM-Cl) or far less (DM-Cl, MM-NO2) active than DTIC in impairing host immunocompetence, although all retained or even augmented their ability to induce chemical xenogenization.
Animals↗
Natural resistance of mice pretreated with 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) + cyclophosphamide (Cy) against virus-induced lymphoma cells.
Virus-induced leukemia was inoculated into histocompatible or allogeneic hosts pretreated with 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) + Cyclophosphamide (Cy), which abrogate endogenous cell proliferation and T-dependent graft responses, but not selected "natural resistance" (NR) activities. Marked impairment of lymphoma cell growth occurred mainly in the spleen of allogeneic mice with respect to that of histocompatible controls. Tumor inhibition was still present when lymphoma challenge was performed on day + 3 after Cy administration. Parallel studies on "natural killer" (NK) activity in vitro or in vivo showed that complete abrogation of the NK function was detectable on day + 3 or + 6 after Cy treatment. It was concluded that in vivo inhibition of lymphoma growth in mice pretreated with DTIC + Cy could be a drug-resistant NR at least in part distinguishable from the NK function.
Animals↗
Increase of natural killer (NK) activity of mouse lymphocytes following in vitro treatment with cytosine-arabinoside.
The in vitro influence of cytosine-arabinoside (Ara-C) on mouse NK activity was studied treating effector cells, target cells or effector and target mixture with graded concentrations of the drug. Ara-C increased the NK efficiency of mouse splenocytes without enhancing the susceptibility of target cells or the cytolytic events when added to effector-target mixture. This phenomenon was confirmed with splenocytes collected from congenitally athymic (nude) or conventional donors of different ages, untreated or depressed or boosted for NK activity by various agents. In addition Ara-C increased the NK activity of spleen cells of nude mice deprived of nylon-adherent cells, and did not affect suppressor cells capable of inhibiting the lytic phase of NK process. The drug was able to significantly augment the binding ability of spleen cells to the NK-sensitive YAC-1 target. It was concluded that Ara-C would increase the efficiency of natural cytotoxicity presumably through a direct influence on effector lymphocytes.
Animals↗
Experimental studies on mice challenged intracerebrally with Pseudomonas aeruginosa.
Intact or immunodepressed mice of different strains were challenged with Pseudomonas aeruginosa cells by the peritoneal or intracerebral route, in order to establish experimental models which may mimic the clinical conditions of compromised hosts experiencing local or systemic invasion by the opportunistic pathogen. The possible role played by host sensitization alone or in combination with chemotherapy was also studied.
Animals↗
Interferon-induced changes in the susceptibility of murine and human lymphoma cells to natural cytotoxic lymphocytes.
Mouse YAC-1 and human K562 leukemic cells were treated in vitro with fibroblast interferon (IF) and tested for their susceptibility to NK effector lymphocytes. In both cases a decrease in target susceptibility was induced by the IF treatment. "Cold" competition experiments confirmed that loss or masking of NK target structures occurred in IF-pretreated cells. In fact, when radio-labeled untreated cells were used as targets, IF-pretreated leukemias produced inhibitory effects lower than those mediated by intact cells. However when IF-pretreated targets were used, cold cells either intact or preincubated with IF gave similar competitive effects. These data suggest that IF modulates differentially distinct subsets of NK target structures.
Animals↗
Modulation of natural killer (nk) cell activity during FLV-P virus infection of mice.
We analyzed the effects of a polycythemic substrain of Friend leukemia virus, i.e. the FLV-P virus, on splenic NK activity of DBA/2 susceptible mice. One day after virus injection a significant increase of NK activity was found, which persisted until day 10. On the other hand, 14-21 days after virus injection a marked and significant depression of activity was measured. This depression was associated with the appearance of suppressor cells able to inhibit the lytic activity of untreated splenocytes when mixed in vitro in the 4 h 51Cr-release assay. The suppressor cell population was insensitive to treatment with anti-Thy 1.2 plus complement, was adherent to Sephadex G-10 and nylon, but did not adhere to plastic, suggesting it is neither a T-cell nor a typical macrophage. The possible relevance of NK activity modulation in relation to the induction of leukemia is discussed.
Animals↗