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At least 19 recordsLinked to original sources
PubMed1989

IFN-beta 2/IL-6 augments the activity of human natural killer cells.

MHC nonrestricted cytotoxic cells play an important role in the killing of tumor cells in vitro and potentially in vivo. The activity of these cells is regulated by several cytokines such as IL-2 and IFN. In the present study we provide first evidence that IL-6 significantly augments the cytotoxic activity of human NK cells. IL-6 is produced by many different cells and is also known as IFN-beta 2, B cell stimulatory factor 2, hybridoma growth factor, hepatocyte-stimulating factor, and 26 kDa protein. IL-6 stimulates the activity of human CD3- NK cells but not that of CD3+ non-MHC-restricted cytotoxic T lymphocytes. As is the case with IL-2, the IL-6-mediated augmented cytotoxicity was a result of a more efficient lysis, but was not caused by an increased effector to target cell binding. Moreover, the effect of IL-6 on NK cell activity was blocked by a mAb directed against IL-2, and IL-6 itself was found to be a potent inducer of IL-2 production in cultured human PBMC. Thus it may be concluded that IL-6 enhances the cytotoxic activity of NK cells via IL-2. This newly recognized property of IL-6, which is produced by almost any cell, may be of importance in host defense against microbes and malignancies and therefore could contribute to improve the adoptive immunotherapy by using lymphokine-activated killer cells.

Adjuvants, Immunologic↗
PubMed1985

Elevated allogeneic cytotoxic T lymphocyte activity in peripheral blood leukocytes of homosexual men.

Peripheral blood leukocytes (PBL) from male homosexual and heterosexual volunteers who did not have evidence of acquired immunodeficiency syndrome (AIDS) were studied for their ability to generate cytotoxic T lymphocyte (CTL) responses in vitro to allogeneic stimulator PBL from a single individual or from a pool of donors (allo-pool). Seventeen of 39 homosexual donors generated strong primary CTL activity to a single randomly selected stimulator donor, whereas only two of 16 heterosexual donors generated a strong CTL response to the same stimulators. A more detailed study was performed by using PBL from 11 of the homosexual and five of the heterosexual donors, in which CTL responses to the allo-pool were repeatedly tested over a 14-mo period. The response status of the donors that were strong and weak or moderate responders did not change during this period. No correlation of strength of CTL activity was observed with the following: HLA mismatching between responder and stimulator; proportion of OKT4+ and OKT8+ subsets in peripheral blood; antibodies to HTLV-III; antibody titers to hepatitis B, Epstein Barr virus, cytomegalovirus, or HLA alloantigens; homosexual practices; or circulating immune complex levels, although a statistical correlation by multivariate analysis was observed between elevated allogeneic CTL and a combination of other factors. The findings are discussed with respect to possible relevance to AIDS susceptibility and development.

Adult↗
PubMed1975

[The lymphocyte cytotoxicity test in tumor immunology (author's transl)].

The cytotoxic action of lymphocytes on cancer cells in vitro indicates sensitization of the patient against his own tumor. The technical difficulities of this test and possibilities of standardization and simplifying the procedure are discussed. Critical steps are isolation of lymphocytes and culturing target cells without loosing their specific antigenic structure. The need for specificity controls both for lymphocytes and tumor cells is emphasized. Labelling tumor cells with isotopes represents a major improvement in evaluating the result. The role of thymus- and bone marrow-dependent lymphocytes as well as blocking factors in the serum of tumor patients can be analyzed in the cytotoxic assay. A better understanding of these mechanisms may facilitate a therapeutic approach by manipulating the interaction of tumor cells and host.

Animals↗
PubMed2001

Interleukin-7 and interleukin-12 have different effects in rescue of depressed cellular immunity: comparison of malignant and tuberculous pleural effusions.

The present study attempts to determine the role of interleukin-7 (IL-7) and IL-12 in recovering the functions of the lymphocytes of malignant effusion, in terms of cytokine production, proliferation, and cytolytic activity, compared with lymphocytes from tuberculous pleural effusion. Effusion-associated lymphocytes (EAL) were isolated from tuberculous (tEAL) and malignant (mEAL) pleural effusions. The EAL proliferate response was measured after 3 days in culture. Interferon-gamma (IFN-gamma) production and cytotoxicity against K-562 cells or autologous tumor cells were assessed after 6 days in culture. It was found that the mEAL had depressed proliferation, IFN-gamma production, and cytolytic activity, as compared with tEAL. Stimulation with IL-12 plus IL-2, but not with IL-7 plus IL-2, fully restored the IFN-gamma production of mEAL to that of tEAL levels. In contrast, the proliferate response of mEAL was enhanced significantly more with IL-7 plus IL-2 than with IL-12 plus IL-2. Both the IL-7 plus IL-2 and IL-12 plus IL-2 stimulation of mEAL showed a significant increase in cytolytic activity against autologous tumor cells, although the cytolytic activity against K-562 cells did not increase. These results suggest that tEAL had a higher cellular activity than mEAL. This depressed cellular function of mEAL could be reversed with cytokines. However, different cytokines had different effects on mEAL; for example, IL-7 had a better effect in the stimulation of lymphocyte proliferation compared with IL-12, which had a better effect in driving the lymphocytes to the T helper 1 (TH1) pathway and a higher IFN-gamma production. Both IL-7 and IL-12, in the presence of IL-2, can restore the immunosuppressed cytolytic activity of the lymphocytes of malignant pleural effusion against autologous tumor.

Adjuvants, Immunologic↗
PubMed1989

Physical exercise increases natural cellular-mediated tumor cytotoxicity in elderly women.

The influence of acute treadmill exercise on natural killer (NK) cell tumor cytotoxicity in vitro was studied in elderly women after participation in a program of physical exercise training (PET) (n = 7) or after participation in a paralleling nonexercise control (NEC) condition (n = 7). The two study groups were equated (p greater than 0.05) according to age, percent total body fat, functional status as measured by multi-inventory ranking, and exercise capacity. After the experimental period, the PET subjects had a greater basal level of NK activity than the NEC subjects (PET 38.2 percent specific lysis, %SL, vs. NEC 28.8 %SL; p less than 0.05). Both groups experienced an increase in NK activity after acute treadmill exercise (PET 38.2-57.4 %SL, p less than 0.01; NEC 28.8-37.8 %SL, p less than 0.05), but the increase in the PET subjects was significantly (p less than 0.05) greater than that observed in the NEC subjects. We conclude that natural cellular-mediated tumor cytotoxicity is increased in response to acute exercise and long-term PET in elderly women.

Activities of Daily Living↗
PubMed2000

Monophosphoryl lipid A and QS21 increase CD8 T lymphocyte cytotoxicity to herpes simplex virus-2 infected cell proteins 4 and 27 through IFN-gamma and IL-12 production.

We have shown previously that IFN-gamma pretreatment of human epidermal cells (ECs) cultured in vitro partially reverses down-regulation of surface MHC class I by HSV infection, allowing recognition by CD8 CTLs, and that HSV immediate early (IE)/early (E) proteins are the predominant targets for CD8 CTLs. In this study of 25 subjects, CD8 CTLs recognized the HSV-2 IE infected cell protein 27 (ICP27) (expressed in autologous IFN-gamma-pretreated, Vaccinia virus recombinant-infected ECs) in all subjects studied, ICP4 in 89%, and ICP0 in 11%. The main hierarchy of recognition was ICP27 > ICP4. ICP27 was the dominant target in 89% of subjects but showed great individual variability in the degree of cytotoxicity. CD8 cytotoxicity specific for HSV-2 IE proteins was enhanced by 48-67% when CD8 CTLs were coincubated with the combination of monophosphoryl lipid A and QS21 adjuvants at the time of Ag presentation. These adjuvants also significantly enhanced IL-12 and IFN-gamma production from nonadherent mononuclear cells stimulated by HSV-2-infected ECs. Addition of IL-12 and IFN-gamma at the time of initial Ag presentation enhanced CD8 cytotoxicity to levels comparable with those stimulated by the adjuvants. Addition of neutralizing Abs to IL-12 or IFN-gamma inhibited CD8 T cell cytotoxicity up to 95% when a combination of the Abs were added at the time of initial Ag presentation. Therefore, the mechanism for the enhancement of CD8 T cell cytotoxicity by adjuvants in this system appears to be via increased levels of IL-12 and IFN-gamma.

Adjuvants, Immunologic↗
PubMed1986

Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. I. Defective trigger on NK cells for NKCF production by target cells, and partial restoration by IL 2.

Peripheral blood from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) exhibits poor NK activity in the 51Cr-release assay. The present studies were undertaken to investigate the mechanism underlying the observed defective NK cytotoxic activity. On the basis of our studies on the mechanism of natural killer cell-mediated cytotoxicity (NKCMC), a defective NK cell can result from lack or decreased frequency of effector cells, inability to recognize and bind the target cell, failure to be activated for the release of NK cytotoxic factors (NKCF), and/or failure to synthesize or secrete NKCF. Each of these various possibilities was examined. Single cell analysis revealed that the frequency of NK cells was comparable to controls, and although the NK cells bind to the NK-sensitive target, the bound target is not lysed. These results suggested that the defect in NK cells was not due to depletion of NK cells or to a defect in recognition structures, but that it was located at the postrecognition event. We previously demonstrated that after binding to target, the NK cell is stimulated to release NKCF in the supernatants and NKCF lyse specifically NK-sensitive targets. Accordingly, we investigated the activation of NK cells from AIDS and ARC patients for release of NKCF. After coculture with the stimulator cell, the patients' NK cells failed to release active NKCF in the supernatant. However, the cells released NKCF after stimulation with the lectin Con A or a mixture of TPA and ionophore, albeit to a lesser extent than controls. These results suggested that AIDS and ARC NK cells are defective in the trigger involved in release of NKCF. Further studies were done to investigate whether the immunomodulator IL 2 can restore the functional activity of the defective NK cells. Treatment with IL 2 resulted in augmented NK cytolytic activity, but did not reach control levels of activated cells from normal controls. Furthermore, the patients' IL 2-treated cells recover partially the ability to be stimulated by NK cells and to release NKCF. These results suggest that the trigger for NKCF production and the cytolytic function of the patients' NK cells are regulated by IL 2. By delineating the stage at which the AIDS and ARC NK cells are defective, it is now possible to monitor their recovery and to investigate the effect of various biologic response modifiers in restoring NK activity.

Acquired Immunodeficiency Syndrome↗
PubMed1979

Decreased cell-mediated cytotoxicity against virus-infected cells in systemic lupus erythematosus.

Cell-mediated cytotoxicity, directed against virus-infected tissue culture cells, was studied with peripheral blood mononuclear cells from 11 patients with systemic lupus erythematosus (SLE) and 12 matched, normal subjects in a 51Cr release assay. Baseline (preimmunization) levels of cytotoxicity against target cells infected with influenza A/Victoria, influenza B/Hong Kong, Newcastle disease virus, and herpes simplex virus were significantly decreased in patients with SLE compared to normal subjects (P less than 0.001), although serum antibody levels to the respective viruses were similar in both groups. After intramuscular administration of inactivated influenza A/Victoria vaccine, SLE patients failed to generate elevated levels of cytotoxicity against A/Victoria-infected cells, in contrast to normal subjects. SLE patients responded with levels of serum hemagglutination-inhibition antibody which were similar to those of normal subjects. Thus, SLE patients manifest decreased cell-mediated cytotoxicity against virus-infected target cells, although humoral antibody responses appeared to be intact. Studies of SLE patients with influenza may help to define the role of cell-mediated immunity in the pathogenesis of certain viral infections.

Adolescent↗
PubMed1979

Effect of human serum from patients with haematological disorders on mouse pluripotent haemopoietic stem cells (CFU-S).

Sera from 25 individuals (9 healthy subjects, 6 patients with systemic lupus erythematosus, and 10 patients with a variety of haematological disorders) were tested for anti-CFU-S by incubating suspensions of mouse marrow cells with serum and then assaying the cell suspensions for their capacity to form spleen nodules in lethally irradiated mice. The sera from 2 patients (1 with a preleukaemic disorder and the other with a malignant 'histio'-lymphoproliferative neoplasm) had anti-CFU-S activity which behaved like antibodies, rather than like the non-specific cytotoxic activity found in various sera for heterologous tissues, which in the past has been attributed to 'natural antibodies' and which, in recent years, has, in some cases, been found to be related to activation of the alternative pathway of complement. The anti-mouse tissue activity in the sera of the 2 patients may be related either to cross-reactivities between certain mouse and human tissues or to cross-reactivities between exogenous agents such as bacteria and mouse tissues.

Absorption↗
PubMed2000

HLA-B2702 (77-83/83-77) peptide binds to beta-tubulin on human NK cells and blocks their cytotoxic capacity.

It has been described that peptides derived from a highly conserved region of the alpha1 helix of the first domain of HLA class I Ags exhibit immunomodulatory capacity blocking both T and NK cell cytotoxicity. In vivo treatment with these peptides prolongs survival of MHC-mismatched allografts. However, the molecular bases of these effects are still unclear. In this study, we further analyze the mechanisms by which the dimeric peptide HLA-B2702 (77-83/83-77) induces suppression of NK cell cytotoxicity. This peptide inhibits natural and redirected lysis mediated by NK cells without significantly affecting effector-target cell binding. We have also isolated and sequenced a protein that binds this inhibitory peptide, which structurally corresponds to beta-tubulin. Tubulin is the major protein of microtubules and is involved in target cell killing. Furthermore, B2702 peptide promotes GTP-independent tubulin assembly, producing aggregates that cannot be depolymerized by cold. Treatment of NK cells with Taxol or demecolcine, which interfere with microtubule organization, also prevents NK cell cytotoxicity. Taken together, these results support the hypothesis that the peptide B2702 (77-83/83-77) exerts its inhibitory effect on NK cell cytotoxicity by inducing polymerization of microtubules and interfering with their normal assembly/disassembly dynamics.

Adjuvants, Immunologic↗
PubMedDate not supplied

Study of mouse spleen "natural cytotoxic" (NC) cell activity related to in vivo administration of B4 coxsackievirus.

By using A2G 40-day-old mice as responders, the influence of in vivo infection with a human strain of B4 coxsackievirus on "natural cytotoxic" (NC) cell activity was assayed, in relation to other immunomodulating treatments (beta-interferon, interleukin-1, or prostaglandin-E2). A significant increase of NC cell cytolysis was noticed in virus-infected mouse group, as compared to the control. The NC cell stimulation exerted by in vivo administration of beta-interferon or of interleukin-1 was not modified in virus-infected groups, but coxsackievirus was able to prevent the inhibitory effects of prostaglandin-E2 at the NC cell activity level when the cytotoxic assays were performed with 20:1 and 10:1 effector/"target" cell ratios, respectively. A possible extrapolation of results in the human medical practice is discussed.

Adjuvants, Immunologic↗
PubMed1983

Enhancement of reactivity of HLA-Cw antisera by extending the incubation time.

HLA-Cw antisera showing weak cytotoxic activity when tested at 1 1/2 hours in the conventional HLA-A,B, Cw testing procedure, were found to react better in the test using an extended incubation period of 3 hours. Of the 71 sera which were tested, 15 (21%) sera demonstrated an increase in anti-HLA-Cw reactivity against cells from donors possessing the corresponding Cw antigen. In addition, the use of B cells in the testing procedure appeared to be more favorable than T cells in the enhancement of reactivity of weak HLA-Cw antisera.

B-Lymphocytes↗
PubMed2000

Stress renders T cell blasts sensitive to killing by activated syngeneic NK cells.

Exposure of primary T cell blasts to stress in the forms of heat, hydrogen peroxide, or high-density growth conditions resulted in a state of enhanced susceptibility to killing by syngeneic IL-2-activated NK cells or lymphokine-activated killer cells, but not to killing by CTL. Cytotoxicity was perforin mediated and was not due to decreased target expression of total MHC class I. The levels of stress used had little effect on cell viability. For thermal stress, sensitization increased with temperature, required a minimum exposure time, and disappeared when cells were given a long enough recovery time. Our data support a model that predicts that activated NK cells play a role in the immunosurveillance of nontransformed stressed cells in normal animals.

Animals↗
PubMed1989

Auto-tumor lysis by blood lymphocytes in vitro. Strongly activated lymphocytes lack selectivity.

Selectivity of the lysis of the tumor cells by autologous blood lymphocytes and its various subsets was investigated by means of the cold target competition assay. The effectors were autologous lymphocytes passed through a nylon-wool column (unfractionated: U) and their low- and high-density subsets, either without or after activation. The lymphocytes were activated (a) in autologous mixed lymphocyte tumor cell culture in autologous (MLTC), (b) in mixed lymphocyte culture (MLC), without and with interleukin-2, for 6 days, or (c) by phytohaemagglutinin for 3 days. Autologous-lymphocyte-mediated cytotoxicity (auto-tumor lysis: ALC) by the unfractionated, unmanipulated blood lymphocyte (U) population, its high-density fraction and those induced for auto-tumor lysis in the MLTC is regularly weak and affects only the autologous tumor cells. Their ALC function was inhibited only by the target identical unlabelled cells while the effect of separated low-density lymphocytes was inhibited also by allogeneic tumor cells. The cold-target competition assay indicated that several subsets with different specificities exist simultaneously in the effector populations activated in MLC, because the various targets did not cross-compete or did so only partially. Whenever interleukin-2 was added, at the start of the mixed cultures (MLTC or MLC), the lytic effects were no longer selective. Phytohaemagglutinin-activated effectors lysed several targets. These targets were inhibitory in a criss-cross fashion. Generally, populations showing auto-tumor selectivity had weak lytic effects, while the strongly activated effectors, with strong cytotoxic function, were not selective.

Cytotoxicity Tests, Immunologic↗