Search PubMed⌕ Search

Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 199 records · Page 11Linked to original sources
PubMed1993

Influence of sodium lauryl sulphate on 2,4-dinitrochlorobenzene-induced lymph node activation.

The influence of the anionic surfactant sodium lauryl sulphate (SLS) on the ability of the contact allergen 2,4-dinitrochlorobenzene (DNCB) to provoke draining lymph node cell proliferative responses, a correlate of skin sensitizing potential, has been examined in mice. Topical application of 10% SLS with 0.1% DNCB caused a more vigorous proliferative response than did exposure to 0.1% DNCB alone. Lower concentrations (0.1% or 1%) of SLS were ineffective and 10% SLS failed to influence proliferative responses to higher concentrations (0.5% or 1%) of DNCB. Using an in vitro model for measurement of percutaneous absorption 10% SLS was shown not to increase the skin penetration of 0.1% DNCB. We therefore examined the influence of SLS on the accumulation of dendritic cells (DC) in lymph nodes draining the site of exposure, an important early event during the induction phase of skin sensitization. The frequency of DC in draining nodes was measured following topical application of SLS, DNCB or a combination of both. Epicutaneous exposure to 0.1% DNCB caused only a modest increase in the number of lymph node DC. However, 10% SLS or a mixture of 10% SLS with 0.1% DNCB each resulted in a significant elevation of DC numbers. It is proposed that SLS augments the skin sensitizing potential of sub-irritant concentrations of DNCB via an increase in the number of immunostimulatory DC which reach the draining nodes.

Administration, Cutaneous↗
PubMed1993

Regulation of mouse peritoneal mast cell secretory function by stem cell factor, IL-3 or IL-4.

We examined whether three cytokines that promote mouse mast cell development, the c-kit ligand stem cell factor (SCF), IL-3, or IL-4, also can directly stimulate or modulate mouse peritoneal mast cell (PMC) mediator release. Challenge of purified PMC with rat rSCF164 at 20 to 100 ng/ml for 30 min induced a modest release of serotonin (5-HT), whereas IL-3 or IL-4 did not directly stimulate 5-HT release. Experiments in which PMC were exposed to each cytokine for 15 min, and then to DNP-HSA Ag or anti-IgE antibody for a further 15 min, showed that SCF, but not IL-3 or IL-4, had an additive effect on the 5-HT release induced by either of the IgE cross-linking agents. In longer term experiments, SCF (0.16 to 500 ng/ml), IL-3 (2.5 to 100 ng/ml), or IL-4 (0.06 to 2.5 ng/ml) was added to peritoneal cell cultures for 48 h, during which the cells were passively sensitized with IgE anti-DNP antibody. Incubation of either unfractionated or highly purified PMC preparations with each of the three cytokines resulted in a concentration-related increase in 5-HT release upon subsequent challenge of the cells with DNP-HSA Ag. However, after pretreatment of peritoneal cells for 48 h with each cytokine, only IL-4 (10 ng/ml) enhanced release of 5-HT induced by calcium ionophore A23187 (0.25 microM); IL-3 (100 ng/ml) had no effect, whereas SCF (100 ng/ml) significantly inhibited ionophore-induced release. Although IL-3 or SCF up-regulate responsiveness to IgE-dependent stimuli, we detected no effect of these cytokines on the binding of [125I]IgE to PMC. This suggests that the enhancing effects of SCF or IL-3 on IgE-dependent 5-HT release did not simply reflect changes in the amount of IgE bound to the cells. In conclusion, we found that SCF, IL-3, or IL-4 each exerted a different spectrum of stimulatory, costimulatory, or regulatory effects on the secretory function of mouse PMC.

Animals↗
PubMed1993

Results with OECD recommended positive control sensitizers in the maximization, Buehler and local lymph node assays.

The guinea pig maximization test and the Buehler occluded patch test are used widely to identify the sensitization potential of new chemicals. This information enables toxicologists and/or regulatory authorities to determine whether a chemical should be classified formally as a skin sensitizer. Both to improve and to harmonize these assessments internationally, the OECD has recommended recently that moderate rather than strong contact sensitizers are used as positive control substances. The purpose is to ensure an adequate level of sensitivity in sensitization assays performed at specific testing establishments. Results from two laboratories reported here show that the minimum acceptable standard laid down by the OECD can be achieved and indeed commonly exceeded by a substantial margin. Furthermore, results with these positive controls in a new method, the local lymph node assay, also appear to satisfy similar criteria, suggesting results from this assay, including negative data, should be acceptable for classification purposes. However, a review of the way in which results with new chemicals will be interpreted for regulatory purposes, in the context of positive control data, reveals that considerable inadequacies still exist. It is recommended that ultimately, sensitization data can only be interpreted meaningfully (i.e. to protect humans from sensitization hazards) by considering the potency of the contact allergen in the context of the sensitivity of the assay performed at the particular testing institution.

Acrolein↗
PubMed1993

Approaches to the identification and classification of chemical allergens in mice.

During the last 10 years understanding of the immunobiological mechanisms whereby chemicals induce allergy has increased significantly. In parallel there have emerged opportunities to develop alternative methods for the prospective identification and classification of chemical contact and respiratory allergens. Attention has focused largely on the mouse, and several novel approaches to the identification of contact allergens have been described, among them the local lymph node assay, the mouse ear swelling test and, most recently, the noninvasive mouse ear swelling assay (MESA). Progress has been made also in defining methods for measuring respiratory sensitization potential in mice. Recent evidence indicates that respiratory and contact allergens provoke qualitatively different immune responses characteristic of selective T helper (Th) cell activation. Evaluation of the nature of immune responses induced in mice by chemicals may permit not only assessment of allergenic potential, but also prediction of the form allergic reactions will take.

Allergens↗
PubMed1993

Characterization of a monoclonal antibody to cis-urocanic acid: detection of cis-urocanic acid in the serum of irradiated mice by immunoassay.

Cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans-isomer on ultraviolet (UV) irradiation, has been suggested as a photoreceptor for and mediator of the suppressive effects of UV irradiation on systemic immune responses. Trans-UCA is located predominantly in the stratum corneum, and the extent of isomerization to cis-UCA may be analysed by high-performance liquid chromatography (HPLC) of skin extracts. Such an analysis is not suitable for other tissues. In this study a murine monoclonal antibody to cis-UCA was prepared and tested by ELISA using UCA isomers conjugated to protein as antigens. The interaction of the antibody with structural analogues of UCA was assessed by competitive inhibition ELISA which indicated that the antibody had a high specificity for cis-UCA. Screening of sera at various times after UVB irradiation of mice by competitive inhibition ELISA using the monoclonal antibody showed that cis-UCA was present, probably in an unbound form, for at least 2 days after the exposure. Thus, cis-UCA produced in the epidermis following UVB irradiation reaches the serum a few hours later. The implications of this finding for the generation of suppressed immune responses are discussed.

Animals↗
PubMed1993

Sensitization of mice to chemical allergens modulates the responsiveness of isolated mast cells to IgE-dependent activation.

It is known that the release of granule-associated inflammatory amines by isolated mouse tissue-type mast cells is subject to regulation in vitro by a number of cytokines that are produced during the immune response. In this study we investigated whether mast cell secretory function might also be subject to regulation in vivo during active sensitization. Mice were sensitized with one of three chemical allergens (trimellitic anhydride, TMA; 2,4-dinitrochlorobenzene, DNCB; or oxazolone) all of which induce contact sensitization and one of which (TMA) in addition causes immediate hypersensitivity. Peritoneal mast cells isolated from treated mice and sensitized passively with IgE released a greater proportion of cellular serotonin (5-HT) on stimulation either by anti-IgE or by specific antigen than did cells isolated from vehicle-treated controls. These results show that the function of mast cells is susceptible in vivo to regulatory influences that result from induction of an immune response.

Allergens↗
PubMed1992

The cellular and molecular basis for divergent allergic responses to chemicals.

Chemicals vary with respect to the nature of allergic reactions which they will elicit preferentially. A wide variety of environmental and industrial chemicals are known to cause allergic contact dermatitis (contact sensitivity). Some of these are able also to induce respiratory allergy. This article reviews the characteristics of immune responses to different classes of chemical allergens and the role which functional subpopulations of T helper (TH) cells and their soluble cytokine products play in the induction of allergic sensitization. In addition, new opportunities to identify and classify chemical allergens based upon characterization of divergent allergic responses is discussed.

Allergens↗
PubMed1992

The local lymph node assay: results of a final inter-laboratory validation under field conditions.

The local lymph node assay (LLNA) assesses the sensitizing activity of chemicals by measurement of primary lymphocyte proliferation in lymph nodes draining the site of application. In this final inter-laboratory study the consistency of LLNA results between laboratories and with guinea pig maximization test (GPMT) data was examined under 'field' conditions. Nine chemicals were evaluated independently by each laboratory according to guidelines for test concentration and vehicle selection developed during previous validation studies to ensure assay optimization. Equivalent predictions of sensitization potential were obtained by all laboratories for eight chemicals. Five of seven chemicals identified as sensitizers in the GPMT were correctly identified in the LLNA--four by all laboratories and 1 (4-chloroaniline) by one laboratory only--although in this latter case, two other laboratories obtained clear dose responses, suggestive of sensitization. The LLNA identified correctly those chemicals predicted to be extreme or strong sensitizers in the GPMT. The remaining two chemicals were non-sensitizers in the guinea pig and failed to elicit positive proliferative responses in the LLNA. These data demonstrate that sensitivity and reliability of the LLNA is retained when chemicals are evaluated independently, and that it provides a reliable pre-screen for the identification of chemicals with significant sensitization potential.

Animals↗
PubMed1992

Variable effects of chemical allergens on serum IgE concentration in mice. Preliminary evaluation of a novel approach to the identification of respiratory sensitizers.

A wide variety of chemicals may induce allergic contact dermatitis (contact sensitivity). Some chemical allergens may, in addition, cause respiratory sensitization. Topical exposure of mice to contact and respiratory chemical sensitizers results in the initiation of divergent immune responses characteristic of preferential activation of different functional subpopulations of T helper (TH) cells. In the present study we have sought to make use of these differences, particularly differences in the ability of contact and respiratory allergens to provoke IgE responses, and to question whether opportunities exist for the identification of chemicals with the potential for respiratory sensitization. We have examined alterations in the serum concentration of IgE following topical exposure of mice to seven chemical allergens; trimellitic anhydride (TMA), phthalic anhydride, diphenylmethane-4,4'-diisocyanate (MDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (IPDI), oxazolone and 2,4-dinitrochlorobenzene (DNCB). Three of these--TMA, phthalic anhydride and MDI--are known human respiratory sensitizers. The other four--HMDI, IPDI, oxazolone and DNCB--appear not to cause respiratory allergy, or at least have a very limited potential to do so. At the concentrations tested, exposure to all chemicals caused a lymphocyte proliferative response in lymph nodes draining the site of application. However, exposure only to TMA, phthalic anhydride and MDI resulted in a substantial increase in the concentration of serum IgE. Treatment with HMDI and IPDI failed to induce any change in serum IgE concentration. DNCB and oxazolone caused only small and transient elevations of IgE that were considerably less marked than those observed with respiratory sensitizers.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens↗
PubMed1992

Function of dendritic cells and changes in T cell proliferation in antigen-induced nonresponsiveness.

The ability of dendritic cells (DC) to acquire and present antigen to T cells during antigen-induced nonresponsiveness (AINR) in contact sensitivity was examined by studying cells from lymph nodes draining the sites of antigen challenge. Mice were pretreated on the right flank with either vehicle (AOO), oxazolone (Ox), or fluorescein isothiocyanate (FITC) and challenged 5, 10, or 20 days later with FITC on the left flank. At 5, 10, and 20 days, compared with animals pretreated with vehicle and challenged with FITC, those pretreated and challenged with FITC showed reduced acquisition of antigen by DC and the DC showed a reduced ability to stimulate naive T cells in vitro. Proliferation of T cells immediately on isolation (reflecting in vivo activity) was also reduced. When the time between pretreatment and challenge was extended to 40 days, the proliferative responses and antigen acquisition returned to normal. Animals sensitized with Ox and challenged with FITC showed nonspecific inhibition of T cell proliferation at 5 days only and not at later times and antigen levels on the DC from these animals were normal. The results show that low T cell proliferation during specific AINR in contact sensitivity may be a consequence of reduced acquisition and presentation of antigen by DC.

Animals↗
PubMed1992

Characterization of murine immune responses to allergenic diisocyanates.

Chemicals may cause contact allergy. Some allergens may, in addition, cause respiratory sensitization. In previous investigations we have found that contact and respiratory sensitizers induce differential immune responses in mice characteristic of TH1 and TH2 T helper cell activation, respectively. In the present study we have examined immune responses in mice following topical exposure to three allergenic diisocyanates; diphenylmethane-4,4'-diisocyanate (MDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), and isophorone diisocyanate (IPDI). All three chemicals are contact allergens. MDI is in addition a known human respiratory allergen. HMDI and IPDI appear not to induce respiratory sensitization or at least do so very rarely. Exposure of mice to all chemicals resulted in a vigorous lymphocyte proliferative response in lymph nodes draining the site of application, and each caused contact sensitization. In common with other respiratory allergens, MDI induced an increase in the serum concentration of IgE and provoked considerably more IgG2b than IgG2a anti-hapten antibody; responses consistent with a preferential activation of TH2 cells. In contrast, under conditions where both caused lymph node cell proliferation and contact sensitization, neither HMDI nor IPDI induced a measurable antibody response of any class. These data provide additional evidence that different classes of chemical allergen cause divergent immune responses in mice. The possibility that these characteristics may facilitate not only the identification, but also classification, of chemical allergens is discussed.

Allergens↗
PubMed1992

Dendritic cells and cutaneous immune responses to chemical allergens.

This article reviews the role of epidermal Langerhans cells (LC) in the development of cutaneous immune responses to chemical allergens. Following topical exposure to sensitizing chemicals, LC, many of which bear allergen, are induced to migrate from the skin, via the afferent lymphatics, to the draining lymph nodes. The phenotypic and functional changes to which LC are subject during this process and their development into active immunostimulatory cells closely resembling lymphoid dendritic cells is discussed. The migration and maturation of LC following skin sensitization is of critical importance to the effective presentation of chemical allergens to T lymphocytes and the induction of allergic responses. Evidence is reviewed which suggests that these events are initiated and regulated by epidermal cytokines. The conclusion drawn is that an early event during the induction of skin sensitization is the production by keratinocytes of cytokines which stimulate the migration of LC from the skin and which also result in the functional maturation of LC into potent antigen-presenting cells.

Allergens↗
PubMed1992

Intercellular adhesion molecule-1 (ICAM-1) expression by lymph node dendritic cells: comparison with epidermal Langerhans cells.

Following skin sensitization of mice, epidermal Langerhans cells (LC) are stimulated to migrate via the afferent lymphatics to the draining lymph nodes. Previous studies have demonstrated that, while in transit, LC acquire the characteristics of mature dendritic cells (DC) and develop into potent immunostimulatory cells. In the present study the expression by LC and lymph node DC of intercellular adhesion molecule-1 (ICAM-1) has been compared. Freshly-isolated LC expressed only very low levels of ICAM-1. In contrast lymph node DC, irrespective of whether they were isolated from resting lymph nodes or from activated lymph nodes draining the site of sensitization with oxazolone, exhibited significant membrane ICAM-1. As a substantial proportion of the DC found within the draining nodes of skin sensitized mice derive from epidermal LC it is apparent that, during migration from the skin, LC are induced to express increased ICAM-1. Such is compatible with the development of LC into effective antigen presenting cells.

Animals↗
PubMed1992

Chemical allergy: molecular mechanisms and practical applications.

Allergic reactions can be defined as the adverse, tissue-damaging, and sometimes fatal consequences of specific immune responses, usually to exogenous antigens. In the context of toxicology it is allergic reactions resulting from immune responses to chemicals and drugs which are of greatest relevance. The allergy may take a variety of forms including contact hypersensitivity (allergic contact dermatitis), respiratory hypersensitivity (with symptoms ranging from mild rhinitis to severe asthma), and various types of comparatively ill-defined reactions which in many respects resemble autoimmunity. Of these contact hypersensitivity is the most frequently encountered health problem resulting from the interaction of chemicals with the immune system. A wide variety of chemicals are able to induce contact sensitization. Some of these are, in addition, known to cause respiratory hypersensitivity, a less frequent, but no less important, form of chemical allergy.

Animals↗
PubMed1992

The murine local lymph node assay: a commentary on collaborative studies and new directions.

The murine local lymph node assay is a predictive test for the identification of contact allergens. This paper provides a historical background to the development of the assay and describes the performance of a recently completed interlaboratory trial designed to evaluate further the utility of the method as an alternative or adjunct to guinea-pig predictive tests. On the basis of these and supplementary investigations, a number of recommendations can be made regarding the use and interpretation of the local lymph node assay. Finally, a number of issues arising from recent studies are discussed, including comparisons of the local lymph node assay with guinea-pig methods.

Allergens↗
PubMed1992

The mechanisms and evaluation of chemically induced allergy.

Many chemicals are able to induce contact allergy, a delayed-type hypersensitivity reaction. Some of these have, in addition, the potential to cause respiratory allergy, an immediate hypersensitivity reaction effected by IgE antibody. The characteristics of immune responses provoked by chemical allergens determine the type of hypersensitivity reaction which will predominate. Recent evidence indicates that contact and respiratory allergens stimulate qualitatively different immune responses in mice consistent with the selective activation of T helper (TH) cell subpopulations. Contact allergens which lack the potential for respiratory sensitization preferentially activate TH1 cells which effect delayed-type hypersensitivity reactions. A soluble product of TH1 cells, interferon gamma (IFN-gamma), inhibits IgE antibody responses, and thereby the induction of respiratory sensitization. Conversely, chemical allergens which are known to cause respiratory hypersensitivity stimulate preferentially TH2-type responses. TH2 cells promote the development of respiratory allergy through the production of interleukin 4 (IL-4), a cytokine which is required for the initiation and maintenance of IgE responses. Although the molecular basis for the selective activation by contact and respiratory allergens of TH1 and TH2 cells, respectively, awaits clarification, these qualitative differences in immune response provide opportunities for the identification and evaluation of chemical sensitizers.

Animals↗
PubMed1992

Stimulation of Langerhans cell migration by tumor necrosis factor alpha (TNF-alpha).

Following topical exposure of mice to skin-sensitizing chemicals, Langerhans cells (LC), many of which bear antigen, are stimulated to migrate via the afferent lymphatics to draining lymph nodes. Consistent with the acquisition of potent immunostimulatory activity, LC while in transit to lymph nodes, are subject to a functional and phenotypic maturation thought to be mediated by granulocyte/macrophage colony-stimulating factor (GM-CSF) and possibly other epidermal cytokines. An interesting question is the nature of the stimulus that initiates the migration of LC from the epidermis. We have examined the influence of intradermal tumor necrosis factor alpha (TNF-alpha), another epidermal cytokine, on the accumulation of dendritic cells (DC) in draining lymph nodes. Murine, but not human, recombinant TNF-alpha caused a rapid and concentration-dependent increase in the frequency of DC in draining nodes. The conclusion drawn is that local production of TNF-alpha provides one signal for LC migration during cutaneous immune and inflammatory responses.

Cell Movement↗