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Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 271 records · Page 15Linked to original sources
PubMed1984

Influence of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the susceptibility of K562 to natural cytotoxicity: evidence for clonal variation in differentiation-induced changes of lytic sensitivity.

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the sensitivity to NK cell-mediated lysis of two cloned populations of K562 which exhibit marked and stable differences in their susceptibility to natural cytotoxicity has been examined. Culture in medium supplemented with TPA concentrations of l ng/ml or more invariably caused a decrease in the susceptibility of the sensitive clone E10/P2, whereas treatment of the relatively resistant clone F9/P2 with TPA under identical conditions caused a significant increase in susceptibility to natural cytotoxicity. In both cases the change in susceptibility occurred within 1 day of culture in TPA and was rapidly reversible following removal of the inducing agent. The changes in resistance to natural cytotoxicity induced by TPA were independent of variations in osmotic fragility and were not attributable to alterations in NK cell binding capacity as determined by cold competition analysis. In contrast to the effect of TPA, exposure of E10/P2 and F9/P2 to interferon (IFN) caused a reduction in sensitivity to natural cytotoxicity of both populations which was associated with a decreased capacity to compete for lysis of labelled target cells. These data suggest that the effects of differentiating agents on target susceptibility to NK cell lysis are variable and that responses to TPA are clonally distributed within cell populations.

Cell Differentiation↗
PubMed1984

Enhanced K-cell activity in the peripheral blood of patients with malignant disease.

We have analysed the influence of human malignant, inflammatory and infectious disease on the capacity of peripheral lymphocytes to mediate antibody-dependent haemolysis. The application of an enzyme-like kinetic model for measurement of maximal cytotoxic function has permitted reproducible and sensitive determinations of the K-cell function. The results show that malignant disease is associated with enhancement of ADCC capacity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1984

K cell mediated haemolysis: influence of large numbers of unsensitized cells on the antibody-dependent lysis of anti-D-sensitized erythrocytes by human lymphocytes.

The inhibition of K cell mediated haemolysis of anti-D-sensitized human red blood cells by unsensitized erythrocytes has been demonstrated. Inhibition of lysis was non-competitive in nature and influenced by the size and number of unsensitized cells. However, even in the presence of high inhibitor: target cell ratios (50:1) haemolysis, although reduced, was still effected suggesting that K cells are highly motile and capable of recognizing and destroying minority populations of antibody-sensitized erythrocytes. These data are compatible with a role for cytotoxic lymphocytes in the intravascular lysis of autoantibody or alloantibody-sensitized red cells.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1984

Influence of lectin-free interleukin-2 on natural and antibody-dependent cellular cytotoxicity.

Supernatants derived from MLA-144, a gibbon T cell line that constitutively releases interleukin-2 (IL-2) and which lack detectable interferon (IFN) had the capacity to enhance the natural killer (NK) cells function of human peripheral blood lymphocytes. Percoll fractionation revealed that like IFN-inducible cytotoxic cells lymphocytes responding to MLA-144 supernatants cofractionate with native NK cells. Exposure to MLA-144 conditioned medium also potentiated the cytotoxic capacity of extravascular effector cells which are either unresponsive or weakly responsive to interferon-alpha (IFN-alpha). Moreover lymphocyte (K cell)-mediated antibody-dependent cellular cytotoxicity (ADCC) which is unresponsive to IFN-alpha was in most cases subject to a modest potentiation following treatment with MLA-144 supernatants. These data confirm previous reports that IL-2 can regulate peripheral blood NK cell function and also demonstrate that this lymphokine can also influence those natural cytotoxic mechanisms which are unresponsive to IFN-alpha.

Animals↗
PubMed1983

Variance in resistance to natural and antibody-dependent cellular cytotoxicity and to complement-mediated lysis among K562 lines.

Isolation of sub-populations of the NK-sensitive erythro-leukaemic cell line K562 by limiting dilution techniques has revealed marked clonal variation in susceptibility to natural cytotoxicity. Detailed examination of two such lines (E10/P2 and F9/P2) which differed significantly in their susceptibility to both native and activated NK-cell-mediated lysis revealed that their differences were stable and independent of culture conditions. The resistant (F9/P2) and sensitive (E10/P2) lines had comparable cold-inhibitory and effector-cell adsorption capacities, indicating that differential susceptibility was not attributable to variable expression of NK target structures. F9/P2 was also less susceptible to antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated lysis, indicating the existence of variants with a generalized capacity to resist several immunolytic processes.

Adsorption↗
PubMed1983

Native and inducible levels of natural cytotoxicity in lymph nodes draining mammary carcinoma.

Lymphocytes isolated from axillary nodes draining breast carcinoma possess variable natural cytotoxic capacity. Augmentation of lymph node cell (LNC) cytotoxicity by interferon (IFN) is also variable, with only some populations displaying potentiated lysis following exposure to either IFN-a or gene-cloned IFN-a2. Where present the IFN-induced augmentation of LNC cytotoxicity was invariably weaker than that observed following similar treatment of autochthonous peripheral blood mononuclear cells (PBMC). Irrespective of their responsiveness to IFN the cytotoxic activity of all LNC preparations examined was significantly increased following pre-incubation with either staphylococcal enterotoxin A (SEA) or factors elaborated by lectin-pulsed allogeneic LNC. THe induction or amplification fo LNC-mediated natural cytotoxicity by lymphokines may provide a local potentiation of natural immune function at the host : tumour interface.

Breast Neoplasms↗
PubMed1983

Naturally cytotoxic tonsillar lymphocytes: a manifestation of heterogeneity among human NK cells.

Lymphocytes isolated from human tonsils are capable of lysing cells of the natural killer (NK)-susceptible line K562. Although weak compared with that of autochthonous peripheral lymphocytes, cytotoxicity is invariably manifest at high effector-to-target ratios. Like peripheral NK cells, tonsillar cytotoxic lymphocytes possess a low buoyant density, which makes possible their partial enrichment from non-cytotoxic cells by centrifugation on discontinuous Percoll gradients. However, examination of cytotoxic fractions indicates that, unlike blood lymphocyte-mediated cytotoxicity, effector function is not associated with the presence of large granular lymphocytes. Furthermore, a functional distinction from classical NK cells is apparent since, although tonsillar cytotoxicity is significantly enhanced after exposure to supernatants from polyclonally activated allogeneic tonsils, pretreatment with lymphoblastoid (Namalva) interferon (IFN-alpha) at doses shown to potentiate maximally the cytotoxicity of peripheral blood lymphocytes fails to influence reactivity. These data provide preliminary evidence for the existence of, at least limited, heterogeneity among human NK cells.

Cell Separation↗
PubMed1983

Human K cell-mediated haemolysis: determination of the cytotoxic capacity and antibody sensitization requirements of T lymphocyte enriched and depleted populations.

We have examined the cytotoxic activity of unfractionated peripheral blood lymphocytes (PBL) and T cell-enriched and depleted populations for human red blood cells (HRBC) sensitized with anti-D. Although K cell function was frequently enriched in non-sheep red blood cell (SRBC) rosetting (E-) fractions in some cases cytotoxic activity was equivalent in SRBC rosetting (E+) and non-rosetting cells or greater in E+ populations. The distribution of antibody induced haemolytic activity was similar, but not identical, to that of natural killer (NK) cell-mediated lysis. The sensitization requirements of E- and E+ populations measured as the concentration of anti-D capable of inducing 50% of maximum lysis (Ab50) were similar or identical. In addition it was apparent that the differences in cytolytic potential of E- and E+ are quantitative rather than qualitative since E+ cells exhibited lytic profiles equivalent to E- populations following increase of the effector cell concentration. Despite the similar antibody requirements of E- and E+ effectors these populations exhibited markedly different sensitivity to inhibition of haemolysis by heat-aggregated gammaglobulin (HAG). We conclude that functional K cells are variably distributed between E- and E+ populations and that differences in cytotoxic activity are a reflection of the relative number of effector cells in each fraction. The differences in the sensitivity of E- and E+ K cells to HAG do not influence the apparently identical sensitization requirements of the 2 populations, possibly because receptors for aggregated IgG are independent of those involved in the induction of ADCC.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1983

The relationship between antibody concentration and target cell number in the induction of K cell-mediated haemolysis: evidence for asymmetry among reactants.

The cytotoxic capacity of peripheral blood mononuclear cells for anti-D sensitized human O Rh(D) + ve (R1R2) erythrocytes was measured under conditions where antibody concentrations and target cell number were varied with respect to each other. It was observed that where sensitization was limiting, due either to target cell excess or increased antibody dilution, the relationship between lysis and antibody concentration was non-linear, and that the end-point dilution of anti-D at which measurable cytotoxicity occurred was dependent upon the source or concentration of effector cells. The asymmetrical relationship between cytotoxic activity and the degree of sensitization suggests that, in this system at least, there is extensive heterogeneity either among target erythrocytes in terms of their degree of sensitization and consequent susceptibility to lysis, and/or among effector cells in terms of their sensitization requirements for induction of cytotoxicity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1983

Regulation of natural and antibody-dependent cellular cytotoxicity by staphylococcal enterotoxin A.

The capacity of staphylococcal enterotoxin A (SEA), a potent T cell mitogen and inducer of interferon-gamma (IFN-gamma), to modulate human lymphocyte cytotoxic function has been examined and compared with the influence of purified and/or gene cloned IFN-alpha. While the natural killer (NK) cell function of peripheral blood lymphocytes is significantly augmented after exposure to IFN-alpha, levels of cytotoxicity were even greater following pre-treatment with optimal concentrations (0 X 1 microgram/ml) of SEA. Moreover lymphocyte (K cell)-mediated antibody-dependent cellular cytotoxicity (ADCC), which is uninfluenced by exposure to IFN-alpha, was, in most instances, potentiated by SEA. However the efficacy with which SEA augmented natural cytotoxic function was most apparent from experiments utilizing extravascular lymphoid effectors in which basal NK activity is weak and the response to IFN-alpha variable (in the case of lymph node cells) or undetectable (in the case of tonsillar lymphocytes). Co-fractionation on Percoll gradients of lymphocytes responding to SEA with native NK cells suggested that SEA affects NK cells or their non-cytolytic precursors possibly by elaboration of soluble mediators rather than by the induction of a ligand binding mechanism analogous to lectin-dependent cytotoxicity. This system could have important implications for the regulation of NK cell function by lymphocyte stimulatory factors, particularly in lymphoid tissues where indigenous NK activity is low and relatively unaffected by IFN-alpha.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Selective enhancement of human mononuclear leucocyte cytotoxic function by interferon.

The influence of type I interferon (IFN) on leucocyte-mediated antibody-dependent cellular cytotoxicity (ADCC) has been examined in a system in which differential alloantibody sensitization of human erythrocyte target cells allows discrimination between lymphocyte and monocyte effector function. ADCC mediated by unfractionated mononuclear leucocyte populations was regularly enhanced by interferon pretreatment over a range of concentrations of the sensitizing antibody. The capacity of IFN-augmented reactivity was, however, removed with adherent cell depletion, suggesting that lymphocyte (K-cell) effectors are not modulated by IFN, even though such populations demonstrate IFN-potentiated natural killer (NK) reactivity against K562. These results suggest that monocyte and NK cell function but not K-cell activity was influenced by interferon.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Lysis of alloantibody-sensitized human erythrocytes by peripheral blood mononuclear cells: heterogeneity of effector populations.

Cell-mediated haemolysis of human erythrocytes (HRBC) mediated by sensitizing alloantibodies of two specificities was studied using the 51Cr release assay. Peripheral blood mononuclear cells (PBMC) were found capable fo lysing HRBC of phenotype ARh(D) + ve sensitized with either anti-D or "natural" anti-A antibodies. The characteristics of the effector population, however, were dependent upon the sensitizing antibody. HRBC sensitized with anti-A were lysed by a radioresistant, silica- and carrageenan-sensitive population which could be selectively removed by adherence. Sensitization with rhesus antibody induced cytotoxicity by a population which was radiosensitive and relatively unaffected by removal of adherent cells or by treatment with silica or carrageenan. The results demonstrate that the antigen-antibody interaction, rather than the target cell type, determines which effector cells participate in antibody-dependent cellular cytotoxicity (ADCC) against human red cells.

ABO Blood-Group System↗
PubMed1979

Inhibition of antibody-dependent cellular cytotoxicity by artificial immune complexes and pathological sera.

Detection of immune complexes by inhibition of antibody-dependent cellular cytotoxicity (ADCC) is based on the principle that soluble complexes can compete with target cell-bound antibody for receptors (FcR) on cytotoxic lymphocytes. The objective of this study was to define a cytotoxicity system for the determination of soluble immune complexes in the sera of patients with inflammatory bowel disease (IBD). For this purpose, the conditions under which soluble complexes of rat serum albumin (RSA) and rabbit anti-RSA inhibited human K-cell mediated lysis of sensitized Chang cells were examined, on the assumption that the behaviour in the system of circulating immune complexes putatively present in inflammatory bowel disease, is similar to that of artificial immune complexes. Inhibition of ADCC by a standard amount of artificial complex in different normal human sera was relatively uniform provided that the final concentration of the latter did not exceed 10% of the culture medium. In the absence of extraneous complexes, the effect of both normal and IBD sera on ADCC varied widely. Differential inhibition of ADCC by sera from patients with IBD and normal subjects was thus expressed as a function of ADCC in a standard batch of foetal bovine serum (FBS). Under these conditions differences between pathological (n = 51) and normal (n = 52) sera were highly significant (P less than 0.001), which could not be explained by the presence in the patients' sera of HL-A antibodies reactive with the effector cells, nor by a deficit in nutritional support of ADCC. The absence of a correlation between inhibition of ADCC and total serum IgG or IgM inferred that inhibition was attributable to immune complexes in the IBD sera. The limitations of this assay for assessment of the incidence of immune complexes in pathological sera are discussed.

Adult↗
PubMed1977

Leukocyte migration inhibition in human pulmonary neoplasia.

Peripheral blood leukocytes from 65 lung cancer patients, 69 healthy donors, 33 patients with malignant disease outside the lung, and 24 patients with nonmalignant pulmonary conditions were examined for immune reactivity, as measured by the leukocyte migration inhibition assay, to antigens in homogenates of lung tumor tissue and material derived from tumor-free lung areas and a nonmalignant lung lesion. A low level of reactivity with apparent specificity was detected in the lung cancer patient group, with 17/52 showing migration inhibition with extracts of lung tumor tissue. Reactivity was also detectable in this group against homogenates of tumor-free lung and nonmalignant lung lesion. The data supported the conclusion that sensitization at least in some patients with lung cancer might be directed not only against tumor-specific antigens but also against antigens of less confined disease association.

Adult↗
PubMed1977

The effects of halothane anaesthesia on antibody-dependent cellular cytotoxicity in rats.

Lymphocytes from rats killed while anaesthetized with 1-5 per cent halothane showed a significantly reduced capacity to induce lysis of antibody-coated target cells compared with those from untreated rats. This effect was short-lived however, being no longer apparent in lymphoid cells taken from rats 2 h after their recovery from such anaesthesia. Surgical procedures were not effective in extending the duration of reduced ADCC activity. The implication of these findings is that the post-operative depression of this in vitro assay of immunocompetence results from the influence of the anaesthetic agent per se or its metabolities with surgical trauma having little role.

Anesthesia, General↗
PubMedDate not supplied

Selective stimulation of cutaneous interleukin 6 expression by skin allergens.

Epidermal cells, both keratinocytes and Langerhans cells, are able to synthesize and secrete a variety of cytokines, many of which influence or are essential for the induction of skin sensitization and the elicitation of local inflammatory reactions. It has been proposed that it may prove possible to distinguish between contact allergens and skin irritants as a function of differential induction or upregulation of epidermal cytokine expression. In the present study we have addressed this by examination of the local cutaneous production of interleukin 6 (IL-6) following topical exposure of mice to oxazolone, a potent contact allergen, or to benzalkonium chloride (BZC), a skin irritant that is considered not to have a significant potential to cause skin sensitization. Both oxazolone and BZC could induce the production of IL-6 as measured by enzyme-linked immunosorbent assay in homogenates prepared from treated skin. However, when these chemicals were applied at concentrations that resulted in equivalent cutaneous inflammatory responses, based on induced oedema, only oxazolone provoked the production in skin of IL-6. Moreover, under these conditions exposure only to oxazolone resulted in the secretion by draining lymph node cells of measurable concentrations of this cytokine. These data suggest that the ability of oxazolone to stimulate local IL-6 production is not secondary simply to the induction of local inflammatory responses. As such, the results support the possibility that skin allergens and skin irritants may stimulate variable patterns of epidermal cytokine production.

Adjuvants, Immunologic↗
PubMedDate not supplied

The mouse IgE test for the identification of potential chemical respiratory allergens: considerations of stability and controls.

The mouse IgE test is a novel approach to the predictive identification of chemicals that have the potential to cause sensitization of the respiratory tract. The method is based upon measurement of induced changes in the serum concentration of IgE in BALB/c strain mice following topical exposure to the test chemical. The investigations described here were undertaken to examine the stability of the assay, to evaluate the utility of trimellitic anhydride (TMA) and 2,4-dinitrochlorobenzene (DNCB) as, respectively, positive and negative controls for use in the test and to consider criteria for the classification of chemicals as potential respiratory allergens based upon changes induced in serum IgE concentration. On the basis of fifteen independent experiments it was found that, while there was some intra- and inter-test variability with respect to absolute concentrations of IgE measured in the sera of individual mice, the relative pattern of reactivity observed following treatment of mice with TMA, DNCB or with vehicle (4:1 acetone:olive oil) alone remained consistent. In each experiment treatment with TMA provoked a very substantial increase in serum IgE relative to vehicle controls. In no instance did exposure of mice to DNCB cause an increase in the concentration of serum IgE, and in some instances treatment with this chemical resulted in reduced IgE levels. In a parallel series of experiments it was found that serum IgE concentrations in vehicle-treated mice were comparable with those found in the serum of untreated animals. It is concluded that the differential ability of chemicals to induce changes in the concentration of serum IgE in BALB/c mice is a stable phenomenon. It is recommended that, in practice, TMA and DNCB should be incorporated in mouse IgE tests as, respectively, positive and negative controls. Finally, it is proposed that activity in the test is assessed as a function of induced changes in serum IgE levels relative to concurrent vehicle controls, rather than by reference to historical normal range values.

Allergens↗