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Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 253 records · Page 14Linked to original sources
PubMed1989

The murine local lymph node assay for identification of contact allergens: a preliminary evaluation of in situ measurement of lymphocyte proliferation.

A murine local lymph node assay for the identification of contact allergens has been developed. Contact sensitizing activity is measured as a function of lymphocyte proliferation in the draining lymph node following repeated application of the test agent to the dorsum of the ear. In original studies, lymphocyte proliferative activity was measured in vitro. In an attempt to remove the requirement for tissue culture, and thereby enhance the utility of the local lymph node assay as a predictive screening method, a new protocol has been evaluated in which proliferation in draining nodes is measured following i.v. injection of 3H-thymidine.

Allergens↗
PubMed1989

Acute-phase proteins and the serological evaluation of experimental contact sensitivity in the mouse.

The evaluation of contact reactions in previously sensitized mice is assessed conventionally by measurement of increases in ear thickness following challenge. In an attempt to develop a serological method for the investigation of contact sensitization in mice, we have examined whether analysis of changes in the concentration of acute-phase proteins in response to challenge provides a reliable alternative means of evaluating elicitation reactions. Measurement of either the relative serum haptoglobin concentration, using radial immunodiffusion, or the absolute concentration of serum amyloid A, by an enzyme-linked immunosorbent assay, has been found to correlate well with induced increases in ear thickness following challenge. Changes in the concentration of acute-phase proteins proved to be of sufficient sensitivity to reflect the specificity of contact sensitization and its inhibition by antigenic competition.

Acute-Phase Proteins↗
PubMed1989

Dendritic cell accumulation in draining lymph nodes during the induction phase of contact allergy in mice.

Draining lymph node cells isolated from mice 24 h following topical exposure to a variety of contact-sensitizing chemicals, including the dinitrobenzene derivatives, 2,4-dinitrochlorobenzene and 2,4-dinitrothiocyanobenzene, contained increased numbers of dendritic cells (DCs). The increase in frequency of DCs was time-dependent and preceded significant changes in either lymph node cellularity or lymph node cell proliferative activity. The degree of DC accumulation was also influenced by the chemical used and the concentration employed for sensitization. In the context of contact allergy, the biological relevance of this phenomenon to the induction of hapten-specific responses is indicated by the fact that relatively small numbers of DC--enriched fractions of lymph node cells (comprising approximately 70% DCs), but not unfractionated or DC--depleted populations, transferred sensitization to naive animals. Moreover, using the skin-sensitizing fluorochrome, fluorescein isothiocyanate, it was observed that 24 h following exposure the majority of lymph node cells bearing high concentrations of antigen were within the DC-rich fraction.

Animals↗
PubMed1989

Assessment of the functional activity of antigen-bearing dendritic cells isolated from the lymph nodes of contact-sensitized mice.

The immunostimulatory properties of dendritic cells (DC) which rapidly accumulate within the draining lymph nodes of mice topically exposed to contact allergens have been assessed as a function of their ability to initiate proliferative responses by sensitized lymph node cells (LNC) in vitro. A proportion of such DC bear antigen which is in a highly immunogenic form. Thus, at low stimulator:responder ratios, DC-enriched populations prepared from the draining nodes of mice exposed to the skin-sensitizing fluorochrome fluorescein isothiocyanate (FITC) induced significant proliferative responses by FITC-primed responder lymphocytes. Under the same experimental conditions, unfractionated or DC-enriched LNC isolated from naive mice and coated with at least equivalent amounts of FITC in vitro were without effect. The influence of DC populations on lymphocyte proliferation was largely, but not wholly, antigen-specific in nature. Dendritic cell fractions isolated 18 h following topical exposure to high concentrations of FITC or oxazolone induced a marked proliferative response by lymphocytes sensitized to the homologous chemical and a significantly less vigorous response by lymphocytes primed to unrelated haptens. In contrast DC isolated from the nodes of mice sensitized with 2,4-dinitrochlorobenzene (DNCB) caused proliferation only of DNCB-primed lymphocytes. The relative potential of DC populations prepared from FITC- and oxazolone-primed mice to induce antigen-specific and non-specific stimulation was dependent upon both the concentration of chemical used for sensitization and the period of exposure.

Animals↗
PubMed1989

Regulation of lymphocyte proliferation in contact sensitivity: homeostatic mechanisms and a possible explanation of antigenic competition.

Epicutaneous exposure of mice to the contact sensitizing chemicals 4-ethoxymethylene-2-phenyl-oxazol-5-one (oxazolone) and 2,4,6-trinitrochlorobenzene (picryl chloride) causes an inhibition of proliferative responses induced following subsequent topical challenge. The effects on lymphocyte proliferation comprise both transient antigen non-specific and more persistent hapten-specific mechanisms. Pretreatment of mice with one chemical 5 days prior to sensitization with a second, at which time antigen non-specific influences on proliferative responses are manifest, results in depression of contact sensitization as measured by changes in ear thickness following challenge. If, however, the period between pretreatment and sensitization is extended the inhibition of contact sensitization disappears in parallel with a decline in the antigen non-specific depression of lymph node cell proliferation. These data reveal that there exist two homeostatic mechanisms which control proliferation in response to challenge with at least some antigens, and that the extent of lymphocyte proliferation directly influences the degree of contact sensitization achieved. Moreover these results demonstrate that, in some instances at least, competition between antigens may be a function of immunoregulatory influences on lymphocyte proliferation.

Animals↗
PubMed1989

Differential susceptibility of haemolysin-sensitized erythrocytes to complement-mediated cytotoxicity: a biological manifestation of the relationship between antibody availability and complement fixation.

The influence of the concentration of membrane-bound antibody on the susceptibility of individual human erythrocyte populations to complement-mediated haemolysis has been examined using cold competition analysis. It was observed that under conditions where complement is limiting, the relative susceptibility of erythrocytes to complement lysis is dependent on the availability of sensitizing antibody, even when all target red cells possess sufficient membrane antibody to permit maximal lysis in the presence of excess complement. Furthermore, preliminary evidence is presented which suggests that, where the availability of complement is limiting, sensitized blood group A erythrocytes are more susceptible to complement lysis than are sensitized group B cells. Taken together the data indicate that the quantity, and possibly the distribution, of the membrane antibody dictates the relative susceptibility of erythrocytes to complement haemolysis.

ABO Blood-Group System↗
PubMed1988

The influence of antibody sensitization on target cell selection in monocyte-mediated antibody-dependent cellular cytotoxicity.

The role of sensitizing antibody in monocyte-mediated antibody-dependent cellular cytotoxicity (ADCC) has been investigated using human erythrocyte target cells and hyperimmune anti-A and anti-B antisera. The influence of sensitizing antibody concentration on target cell selection by effector monocytes was measured using a cold target competition assay. It was observed that even when red cells were saturated with sensitizing antibody with respect to lytic susceptibility further increases in the density of membrane bound IgG continued to influence their capacity to inhibit lysis in cold target competition assays. It is suggested that although a critical level of sensitization is required for the initiation of lysis, the avidity of interaction between monocyte and target erythrocytes is significantly influenced by further increases in the availability of target-bound antibody.

ABO Blood-Group System↗
PubMed1987

Depression of lymph node cell proliferation induced by oxazolone.

The influence of topical exposure to two sensitizing chemical on draining lymph node cell proliferative responses in BALB/c mice has been examined. Conventional contact sensitization with 4-ethoxymethylene-2-phenyloxazol-5-one (oxazolone) has been shown to induce a rapid and systemic suppression of subsequent proliferative responses to topically applied chemical which can be adoptively transferred to recipient mice with immune lymph node cells. In contrast to some previous reports in which such suppression was found to be largely antigen-specific in nature, we report that, at least initially, the inhibition of lymphocyte proliferation induced by skin sensitization is hapten-non-specific. The relevance of this phenomenon to the regulation of contact sensitization is discussed.

Animals↗
PubMed1987

The effects of interferon on the recirculation of lymphocytes in the rat.

Lymphocytes from the thoracic duct (TDL) were incubated with interferon (IFN) prior to i.v. injection into syngeneic or allogeneic recipient rats. The effect of IFN treatment on the ability of lymphocytes to migrate was studied using 'standard' TDL collected overnight at 4 degrees or an 'optimal' collection of passaged TDL which recirculate with an accelerated tempo (Smith & Ford, 1983). Interferon treatment resulted in an increase in early (30 min) localization of both standard and optimal TDL into lymph nodes. Entry of standard IFN-treated TDL was increased by 91% and 54% in cervical and mesenteric lymph nodes, respectively; increases of 50% and 22% in the same lymph nodes were recorded for optimal IFN-treated TDL. Enhanced entry of standard TDL was contrasted with a reduced ability of IFN-treated TDL to migrate out of lymph nodes; there was a reduced output into the thoracic duct and a surplus of IFN-treated lymphocytes in cervical lymph nodes despite 24 hr continuous thoracic duct drainage. Incubation with interferon did not, however, alter the ability of optimal TDL to reach the thoracic duct rapidly after injection. Allogeneic lymphocytes, which are eliminated soon after injection by an NK-like cytotoxicity, a phenomenon termed ALC, were unaffected by incubation with interferon, thus IFN-treated allogeneic lymphocytes were killed after i.v. injection as rapidly as untreated cells.

Animals↗
PubMed1986

Influence of chronic low-level exposure to lead on plasma immunoglobulin concentration and cellular immune function in man.

The immunological status of individuals occupationally exposed to low levels of inorganic lead has been examined and compared with that of non-exposed, age and sex-matched controls. At the time of testing the exposed population had a mean (+/- SD) blood lead concentration of 38.4 +/- 5.6 micrograms X 100 ml-1 (n = 39) compared with a mean value of 11.8 +/- 2.2 micrograms X 100 ml-1 (n = 21) for the control group. No differences in the serum concentrations of IgG, IgA and IgM between the populations were observed and there existed no correlation between blood lead concentration and serum immunoglobulin levels. In addition assessment was made of the capacity of peripheral blood mononuclear cells to respond to the mitogen phytohaemagglutinin (PHA), a correlate of T cell function, and to spontaneously lyse cells of the erythroleukaemic cell line K562, a measure of NK cell function. In neither case was there a difference between exposed and control populations and no correlation between reactivity and blood lead concentration. Although previous studies in rodents have indicated that exposure to inorganic lead resulting in similar blood lead concentrations may compromise immune competence our data suggest that no similar effect occurs in man.

Humans↗
PubMed1986

The influence of chemical carcinogens on natural killer cell function in rats. A comparison of 2-acetylaminofluorene with 4-acetylaminofluorene.

The influence of the carcinogen 2-acetylaminofluorene (2AAF) administration on splenic natural killer (NK) cell function in two strains of rats has been examined and compared with that of the non-carcinogenic analogue 4-acetylaminofluorene (4AAF). In both strains it was observed that daily exposure to 25 mg kg-1 2AAF induced a significant depression of both native and interferon (IFN)-activated NK cell function which was first apparent between 7 and 13 days following initiation of treatment. In contrast 4AAF failed to influence NK cell activity. These data indicate that 2AAF in common with some other carcinogens has the capacity to influence natural cytotoxic function and lend support to the hypothesis that carcinogenic potential may in some cases be associated with immunosuppressive properties.

2-Acetylaminofluorene↗
PubMed1986

Failure of inorganic lead exposure to impair natural killer (NK) cell and T lymphocyte function in rats.

Natural killer (NK)-cell and T-cell functions have been measured in rats following exposure to either 100 or 1000 ppm lead as lead acetate in drinking water. The capacity of splenocytes isolated from exposed animals to mediate native and interferon (IFN)-activated natural cytotoxicity was measured at three effector:target-cell ratios and found to be normal at all time points examined. Furthermore, splenic T-cell function of treated animals as determined by phytohaemagglutinin (PHA)-induced proliferation was comparable to control values. We conclude that low-level lead exposure is not associated with an impairment of either T-or NK-cell function.

Aminolevulinic Acid↗
PubMed1986

Contact-sensitizing and tolerogenic properties of 2,4-dinitrothiocyanobenzene.

Epicutaneous application of 2,4-dinitrothiocyanobenzene (DNTB) is said to result in specific immunological hyporesponsiveness and fails to induce contact sensitization. However, we demonstrate that topical exposure to DNTB causes activation of the draining lymph node in mice and the induction of contact sensitization in both rodents and a single human volunteer. In mice and rats, pre-exposure to DNTB failed to impair subsequent responsiveness to the cross-reactive allergen 2,4-dinitrochlorobenzene. These data provide evidence that DNTB cannot be regarded as an exclusive tolerogen when applied epicutaneously and indicate that attempts to define the characteristics of tolerising chemicals from analysis of this agent may be misleading.

Administration, Topical↗
PubMed1986

The influence of 7,12-dimethylbenzanthracene on natural killer (NK) cell function in rats.

The administration to 2 strains of rat (Alderley Park and Sprague Dawley) of 40 (2 X 20) mg of 7,12-dimethylbenzanthracene (DMBA) on a single day caused a transient depression of NK cell function. The splenic natural cytotoxic capacity of both DMBA treated and control animals was augmented by inclusion within the assay of interferon (IFN) but IFN failed to restore carcinogen-treated splenocyte cytotoxicity to normal values. Splenocyte populations from DMBA treated animals exhibiting reduced cytotoxic activity possessed normal frequencies of target-binding lymphocytes suggesting that the impairment of reactivity was attributable to a defect in the post-recognitive stage of NK mediated lysis. Administration of DMBA was not associated with a reduction in spleen weight or cellularity or with an impairment of splenic lymphocyte responsiveness to phytohaemagglutinin (PHA) indicating that depressed NK cell function was not a result of general lymphotoxicity. These data confirm previous reports that administration of chemical carcinogens may be associated with a depression of NK cell function.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Mechanism and regulation of natural cytotoxicity. Minireview on cancer research.

Natural killer (NK) cells comprise a heterogeneous population of effector cells functionally and phenotypically distinct from B cells and mature antigen-sensitive T cells, with the capacity to spontaneously lyse target cells of widely different tissue provenance in a genetically unrestricted fashion. As such they have been widely implicated in immunosurveillance against neoplastic and virus-infected cells, as well as in the homeostasis of haematopoietic differentiation and regulation of immune function. In common with cytotoxic T cells, the lytic mechanism may be resolved into several discrete stages. Target cell recognition appears to involve several chemical entities, while susceptibility is also influenced by a multiplicity of factors operative at post-recognition stages of the lytic process. NK activity is subject to both positive and negative regulation. The potentiating effects of interferons and interleukin-2, products of activated T cells, indicate a possible pathway by which adaptive immune responses may augment natural cytotoxicity under local physiological conditions. Negative regulation is mediated by certain prostaglandins and a variety of cell types including macrophages, granulocytes and thymocytes as well as subsets of peripheral blood lymphocytes.

Animals↗
PubMed1985

The rapid rejection of allogeneic lymphocytes by a non-adaptive, cell-mediated mechanism (NK activity).

The fate of allogeneic lymphocytes (AO or DA) transferred to non-immune PVG recipients was studied in the light of previous evidence (Heslop & McNeilage, 1983; Rolstad & Ford, 1983) that allogeneic lymphocytes can be rapidly destroyed in certain strain combinations of rats and mice by a mechanism that is distinct from either T-cell mediated immunity or an alloantibody response. AO lymphocytes injected into PVG recipients were discriminated from syngeneic lymphocytes within 15-30 min of i.v. injection, as testified by the excess release of 51Cr into the lymph plasma of the recipient. The following experiments were intended to distinguish between natural antibody and natural killer (NK) cells as the mechanism responsible for the allogeneic lymphocyte cytotoxicity (ALC) displayed by PVG rats. Nude rats treated from birth with anti-mu chain serum and shown to be lacking B and T lymphocytes, as well as being profoundly deficient in immunoglobulin, displayed more aggressive ALC than did control nude rats which, in turn, showed stronger ALC than did euthymic rats. Serum from PVG nude rats exerted no inhibitory or destructive effect on allogeneic lymphocytes in an antibody-dependent cellular cytotoxicity system, an assay of graft-versus-host activity, or when injected into 3-4-week-old PVG rats which had not yet developed ALC. Treatment of nude rats with anti-asialo GM 1 antiserum depressed ALC and NK activity in parallel, thus adding to a wide range of circumstances in which ALC and NK activity are closely correlated. In conclusion, ALC is implemented by a non-adaptive, cell-mediated mechanism independent of immunoglobulin, but the precise identity of the effector cell in the recipients' lymphatic tissues remains to be settled.

Animals↗