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Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 181 records · Page 10Linked to original sources
PubMed1995

Differential cytokine production following chronic exposure of mice to chemical respiratory and contact allergens.

It has been demonstrated previously that a selective pattern of mitogen-inducible interleukin-4 (IL-4) production becomes apparent in mice after temporal evolution of the immune response to different classes of chemical allergen. Mitogen-stimulated draining lymph node cells (LNC) isolated after primary exposure to both the respiratory allergen trimellitic anhydride (TMA) and oxazolone, a contact allergen, secreted similar amounts of IL-4. Following secondary exposure, however, TMA, but not oxazolone, caused a marked increase in IL-4 production, consistent with the stimulation by TMA of a T-helper type-2 (Th2)-type response. In the present study, cytokine production characteristic of Th1 (interferon-gamma; IFN-gamma) and Th2 (IL-4 and IL-10) cell activation was examined following chronic exposure of mice to allergen over a 13-day period. In accord with previous studies, chronic exposure to TMA, but not to oxazolone, resulted in a substantial potentiation of mitogen-inducible IL-4 secretion. In addition, spontaneous IL-10 production by TMA-activated LNC was significantly higher than by cells prepared from oxazolone-exposed animals. The lower levels of Il-4 and IL-10 elaborated by oxazolone-activated LNC were not attributable to a reduced potential to secrete cytokine per se, as significantly more IFN-gamma was produced compared with TMA-activated LNC. It is proposed that these divergent cytokine production patterns reflect the selective stimulation of Th1- and Th2-type responses by contact and respiratory chemical allergens.

Allergens↗
PubMed1994

Cytokines and regulation of allergic sensitization to chemicals.

Sensitization to chemicals and the elicitation of allergic reactions results from the stimulation of specific immune responses. Adaptive immunity is orchestrated by cytokines, a family of inducible glycoproteins that influence in many ways the behaviour of, and interaction between, cells which mediate immune and inflammatory responses. In this article the role of cytokines in the development of cutaneous immune responses to chemical allergens and in directing the quality of immune responses provoked by such materials is discussed.

Animals↗
PubMed1994

The local lymph node assay: developments and applications.

The murine local lymph node assay is a predictive test method for the identification of contact allergens in which sensitizing activity is measured as a function of induced proliferative responses in lymph nodes draining the site of application. In this article the development and validation of the assay are described and comparisons with guinea pig predictive test methods discussed. In addition we examine the advantages and limitations of the method and consider new opportunities and applications of the assay in the context of the toxicological evaluation of sensitizing potential.

Allergens↗
PubMed1994

Induction of respiratory hypersensitivity to diphenylmethane-4,4'-diisocyanate (MDI) in guinea pigs. Influence of route of exposure.

The induction of respiratory sensitization in guinea pigs to diphenylmethane-4,4'-diisocyanate (MDI), a known human respiratory allergen, has been investigated and different routes of exposure compared. Guinea pigs were exposed to MDI by i.d. injection, by topical application or by inhalation. Pulmonary hypersensitivity was measured subsequently as a function of changes in respiratory rate following challenge with atmospheres containing MDI. In addition, contact hypersensitivity was measured by topical challenge and antibody responses evaluated by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis (PCA). Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful. Antibody responses and contact sensitization were both infrequent and low grade, and no animals exhibited pulmonary responses following challenge with atmospheric MDI. In contrast, sensitization by either i.d. injection or topical application of MDI induced antibody responses in the majority of animals. Moreover, a proportion of animals in each case exhibited pulmonary responses following subsequent inhalation challenge. These data indicate that the route of exposure influences markedly the effectiveness of sensitization to respiratory allergens such as MDI and that skin contact may be an important cause of occupational respiratory allergy.

Administration, Inhalation↗
PubMed1994

Cytokine-mast cell interactions: relevance to IgE-mediated chemical allergy.

Recent work has shown that certain cytokines (inducible secreted proteins) are potent regulators of mast cell development and secretory function. We know also that sensitization of mice to chemical allergens induces T cell-dependent immune responses in which cytokines play an important role. Combining these observations, we postulate that in vivo T cell responses might influence, via the production of cytokines, the behaviour of mast cells in situ. In support of this hypothesis we have found that mast cells isolated from chemical allergen-sensitized mice show enhanced responsiveness to IgE-dependent activation in vitro. This effect is seen with chemical allergens that are either contact or respiratory sensitizers in man. Although respiratory and contact allergens cannot be distinguished according to their ability to modulate mouse mast cell function in vivo, they can be separated on the basis of their differential ability to induce specific IgE-dependent mast cell sensitization. In conclusion, the mouse may offer a useful model for investigating and predicting the potential of chemicals to act as mast cell promoting agents and/or respiratory sensitizers.

Allergens↗
PubMed1994

Respiratory allergy: hazard identification and risk assessment.

Various chemicals and proteins of industrial importance are known to cause respiratory allergy, with occupational asthma being the most important manifestation of the disease. This paper describes clinical syndromes, mechanisms associated with occupational respiratory hypersensitivity, and methods available currently for the prospective identification of potential respiratory allergens. Certain classes of chemicals are commonly associated with occupational respiratory allergy. There is insufficient information, however, to predict respiratory sensitization potential from analysis of structure alone, although reactivity with proteins is likely to be relevant. As yet there exist no fully validated or widely applied predictive methods or internationally harmonized guidelines. The most promising predictive animal methods are the mouse IgE test and guinea pig models. Work in mice has focused upon events occurring during the induction phase of sensitization following primary encounter with the test chemical. In contrast, guinea pig models have been used primarily to identify respiratory allergens (chemicals or proteins) as a function of elicitation reactions induced in previously sensitized animals. Given the possible serious health manifestations of respiratory allergy, early identification of respiratory sensitizers is urgently required. The two methods should, as a priority, be developed further and the production of a detailed protocol for these methods be undertaken to facilitate further validation. Together, this information will allow for two types of risk assessment associated with respiratory allergy: the risk that exposure to a material will (1) induce sensitization in an individual and (2) elicit allergic reactions in a previously sensitized individual.

Allergens↗
PubMed1994

The performance of the local lymph node assay with chemicals identified as contact allergens in the human maximization test.

For many years, tests in the guinea pig have been the favoured option for the identification of the skin sensitization potential of chemicals. However, the mouse has been used widely in immunology research and can represent a viable alternative. A variety of murine assays have been described, including several methods based on ear swelling as an endpoint. Another option is to assess induced lymph node cell proliferation and it is this which forms the basis of the murine local lymph node assay (LLNA). The LLNA has undergone several successful interlaboratory validations and compares well with standard guinea pig assays. In the present study, the performance of the LLNA was examined with chemicals tested previously in the human maximization test (HMT). 30 chemicals, 23 of which proved positive in the HMT and seven of which were negative, have been tested. All but four of the materials found positive in the HMT also tested positive in the LLNA. Of these four, sulfanilamide and paraben esters would not classify as skin sensitizers in the guinea pig maximization test and nickel has been found to yield variable results in a number of predictive animal tests. Of the seven substances which proved negative in the HMT, six were also negative in the LLNA, the exception being sodium dodecyl sulfate. These data demonstrate that the LLNA is able to identify accurately chemicals which have the potential to cause significant allergic contact dermatitis in humans.

Allergens↗
PubMed1994

The identification of chemicals with sensitizing or immunosuppressive properties in routine toxicology.

In the context of this paper, immunotoxicity is taken to encompass immunosuppression/immunopotentiation and allergy. Over the last 10 to 15 years, well characterized methods for the assessment of altered immune competence have been reported. This has led to proposals for tiered testing schemes. This review examines the suitability of immunotoxicity parameters for inclusion in routine 28-day studies and comments on methods that have been proposed for incorporation within the guidelines issued by the US FDA and US EPA and OECD. It is recommended that the existing OECD Guideline 407 is modified to incorporate total and differential blood cell counts, spleen and thymus weight and histopathology, and draining and distal lymph node histopathology for Tier I level testing. Data so generated will provide a reliable and accurate means of identifying at an early stage potential immunotoxic effects. Tier II testing should be carried out on a case by case basis and only assuming positive results are obtained at Tier I. An increasingly sophisticated understanding of the nature of immune responses to chemical allergens has facilitated the design of novel predictive methods for the identification of sensitizing activity. Opportunities which arise from these new developments in allergy testing such as the local lymph node assay, mouse ear swelling test, and the mouse IgE test should be monitored closely.

Adjuvants, Immunologic↗
PubMed1994

Serological responses induced in mice by immunogenic proteins and by protein respiratory allergens.

It is known that a variety of materials, including both low molecular weight chemicals and proteins, is able to induce occupational respiratory allergy. We have shown previously that exposure of mice to chemical respiratory sensitizers results in both a marked increase in the serum concentration of IgE and the appearance of specific IgE antibody. In the present study we have examined the characteristics of immune responses induced in mice following intraperitoneal exposure to 3 protein respiratory allergens, ovalbumin (OVA), a lipase from Aspergillus oryzae (LP) and an amylase from Bacillus subtilis (AM) and to a fourth protein, bovine serum albumin (BSA), which is considered usually not to cause respiratory sensitization. Under conditions where all proteins provoked IgG antibody responses, only OVA, LP and AM elicited specific IgE antibody. As judged by passive cutaneous anaphylaxis (PCA) assay, BSA failed to induce an IgE response. In contrast to chemical respiratory sensitizers, the protein allergens examined here failed to cause a substantial increase in the serum concentration of IgE; OVA and AM induced no increase in serum IgE and LP only a comparatively modest increase relative to control values. In conclusion, these data demonstrate that while protein respiratory allergens are able to provoke specific IgE antibody, they fail to cause a marked increase in the concentration of this immunoglobulin in the sera of treated mice. It would appear, therefore, that the mouse IgE test, which seeks to evaluate chemical respiratory sensitization potential as a function of induced changes in the concentration of serum IgE, will be inappropriate for the identification of protein respiratory allergens. Nevertheless, identification of protein allergens may be possible by exploiting the observations reported here that such proteins induce in mice specific IgE antibody responses.

Allergens↗
PubMed1994

Interleukin-6 production by draining lymph node cells following primary contact sensitisation of mice: relationship to the proliferative response.

Interleukin-6 (IL-6) production and proliferative responses by draining lymph node cells were studied in mice exposed topically to a series of chemicals. Chemicals with the capacity to induce sensitisation, but not non-sensitisers, promoted both IL-6 production and lymph node cell proliferation ex vivo. The responses exhibited similar kinetics, were dependent upon the dose of topically applied allergen, and correlated significantly. We demonstrate that the main source of IL-6 within draining lymph nodes is not proliferating T lymphocytes. The induction of a strong IL-6 response, and the relationship of this to cellular proliferation indicate that production of this cytokine within the lymph node is closely associated with the induction of contact sensitivity in mice.

Animals↗
PubMed1994

The kinetics of cytokine production by draining lymph node cells following primary exposure of mice to chemical allergens.

Skin sensitization with chemical allergens is associated with the activation and proliferation of lymphocytes in lymph nodes draining the site of exposure. As lymphocyte activation is regulated by the action of cytokines, we have investigated the nature and kinetics of cytokine production by draining lymph node cells (LNC) from mice, following their primary exposure to chemical allergens. Both interleukin-1 (IL-1) and IL-6 were induced in a biphasic manner following primary exposure of mice to oxazolone or to dicyclohexylmethane-4,4'-diisocyanate (HMDI). The initial phase of production occurred when LNC were prepared from mice 8-20 hr following exposure, while the second peak was coincident with the maximal proliferative response at 72 hr. Increased IL-4 production was observed only when LNC were prepared 96 hr following sensitization. Despite vigorous lymphocyte proliferation there was no evidence for IL-2 production by draining LNC. The ordered and transient pattern of cytokine production that occurs during the afferent phase of contact sensitization suggests that sequential cytokine signals may be involved in regulating the characteristics of the response generated within the draining lymph node.

Allergens↗
PubMed1994

Differential function of dendritic cells isolated from blood and lymph nodes.

Dendritic cells (DC) isolated from the lymph nodes or spleens of mice and pulsed with contact sensitizers or protein antigens stimulate primary proliferative responses by syngeneic T cells and responses to alloantigens in the mixed leucocyte reaction (MLR). Using enriched human peripheral blood DC, we attempted to stimulate primary immune responses to contact sensitizers by autologous lymphocytes in vitro. No significant proliferation above background levels or CD69 expression (an early activation antigen on lymphocytes) was detected despite using a wide range of donors, chemicals, antigens and cell concentrations. Culture of DC for up to 5 days in vitro in the presence of phytohaemagglutinin (PHA)-conditioned culture supernatants, or recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) also failed to induce primary proliferative responses to contact sensitizers. Comparisons were made between blood and lymph node DC from mice to explore whether the lack of stimulation was the result of differences between mouse and human DC or between DC isolated from different tissues. DC from lymph nodes stimulated primary responses to contact sensitizers in both blood and lymph node lymphocytes whereas blood DC did not stimulate responses. Both lymph node and blood DC stimulated an allogeneic MLR, although blood DC were less efficient than those from lymph node. The data show that DC from different tissues exhibit variable functional activity. DC from blood and lymph nodes were examined to determine whether surface antigen expression is related to functional activity. Murine blood DC expressed similar levels of LFA-1, LECAM-1 and CD44 compared with lymph node DC but lower levels of MHC class II, B7 and ICAM-1. These results may therefore have important implications for antigen processing and presentation in cells from different tissue compartments.

Allergens↗
PubMed1994

Modulation of epidermal Langerhans' cell frequency by tumour necrosis factor-alpha.

During the induction phase of skin sensitization, dendritic cells (DC), many of which bear high levels of antigen, accumulate in lymph nodes draining the site of exposure. These DC derive from epidermal Langerhans' cells (LC) which are induced to migrate from the skin, via the afferent lymphatics, to lymph nodes. We demonstrated previously that intradermal exposure of mice to homologous, but not human, recombinant tumour necrosis factor-alpha (TNF-alpha) also causes an accumulation of DC in draining nodes, the implication being that the local production of this cytokine by epidermal cells provides one stimulus for LC migration. In the present study we have examined the influence of dermal TNF-alpha on the frequency of LC within the epidermis. Intradermal injection of mice with 25 ng or greater murine recombinant TNF-alpha caused a significant reduction in LC numbers within 30 min of exposure. The same treatment did not influence the frequency of Thy-1+ epidermal DC. The density of LC was unaffected by the same amount of human TNF-alpha of comparable specific activity or by murine granulocyte-macrophage colony-stimulating factor (GM-CSF). These data provide additional evidence that TNF-alpha provides an important signal for the migration of LC from the epidermis.

Animals↗
PubMed1994

Inducible interleukin-4-secreting cells provoked in mice during chemical sensitization.

It has been demonstrated previously that chemical contact and respiratory allergens differ with respect to the quality of immune responses they will provoke in mice. Trimellitic anhydride (TMA), a human respiratory allergen, induces in mice responses consistent with the preferential activation of Th2-type cells, resulting in the production of IgE anti-hapten antibody and an increase in the serum concentration of IgE. In contrast, oxazolone (OX), a potent contact allergen considered not to cause respiratory hypersensitivity, induces instead Th1-type responses in mice characterized by vigorous IgG2a antibody production and a failure to elicit IgE. In the present study we have extended these investigations and have examined the capacity of these chemicals to stimulate inducible interleukin-4 (IL-4) production by draining lymph node cells (LNC). IL-4 was measured in the supernatants of draining LNC cultured for various periods in the presence or absence of concanavalin A (Con A). Following primary topical exposure to the chemical allergens, Con A-stimulated LNC from OX-treated mice secreted significantly more IL-4 than did LNC from mice exposed to trimellitic anhydride (TMA). A different pattern of IL-4 secretion was observed following culture with Con A of LNC prepared from lymph nodes draining the sites of secondary exposure to these chemicals. In this case significantly higher concentrations of IL-4 were produced by TMA-treated mice. Detectable levels of IL-4 (> 300 pg/ml) were not found following culture of draining LNC from sensitized mice in the absence of Con A or following culture of LNC from naive mice with or without Con A. These data demonstrate that chemical allergens of different types stimulate discrete and changing patterns of inducible IL-4 synthesis consistent with the selective activation of Th-cell subpopulations.

Allergens↗
PubMed1994

Interactions of IFN-gamma with IL-3 and IL-4 in the regulation of serotonin and arachidonate release from mouse peritoneal mast cells.

We have examined the interactions between interferon-gamma (IFN-gamma), interleukin-3 (IL-3) and interleukin-4 (IL-4) in the regulation of IgE/antigen-induced secretory responses of mouse peritoneal mast cells. The cytokines were added either alone or in various combinations to cultured mast cells sensitized passively with IgE antibody. In experiments with unfractionated peritoneal cells (containing approx. 1% mast cells), IL-3 and IL-4 enhanced in an additive manner antigen-induced release of serotonin (5-HT), while IFN-gamma inhibited release regardless of whether IL-3 and/or IL-4 were present. In experiments employing mast cells purified to > 90%, IL-3 and IL-4 retained their enhancing activities whereas the inhibitory effect of IFN-gamma was considerably diminished. Nevertheless, IFN-gamma still inhibited significantly IL-4-enhanced secretion. The effects of IL-3 and IL-4 +/- IFN-gamma on arachidonate release were identical to those seen for 5-HT release, indicating that the secretion of both preformed mediators and newly synthesized eicosanoids is regulated in a similar way by these cytokines.

Animals↗
PubMed1994

Role of tumour necrosis factor-alpha in ultraviolet B light-induced dendritic cell migration and suppression of contact hypersensitivity.

Irradiation with ultraviolet B light (UVB) is known to suppress contact and delayed hypersensitivity response to a variety of antigens encountered within a short period following exposure. Such irradiation results in loss of Langerhans' cells and in synthesis of tumour necrosis factor-alpha (TNF-alpha) in the epidermis. In the present study the effect of broad-band (270-350 nm) and narrow-band (311-312 nm) UVB on the induction of contact hypersensitivity (CH) and on dendritic cell (DC) numbers in draining lymph nodes (DLN) of mice was examined. Broad-band UVB induced the accumulation of DC in DLN and this increase was substantially abrogated by treatment of mice with neutralizing antibody to TNF-alpha before irradiation. In addition, irradiation before sensitization with oxazolone resulted in a suppressed CH response. The suppression was negated to a considerable extent by TNF-alpha antibodies, administered before irradiation. Thus, one of the major effects of broad-band UVB is likely to be the synthesis of epidermal TNF-alpha which, in turn induces the migration of Langerhans' cells to DLN and leads to an impairment of their activity or function. Conversely narrow-band UVB did not result in an accumulation of DC in DLN or in a suppressed CH response. Such irradiation does, however, cause the isomerization from trans to cis-UCA in the epidermis. Cis-UCA has been proposed as a photoreceptor for UV and suppresses immune responses in a variety of experimental systems. Thus cis-UCA does not act through TNF-alpha induction or by influencing DC migration, and other studies indicate that histamine-like receptors in the skin may be involved.

Animals↗
PubMed1993

Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity.

Twenty organic Salmonella mutagens, seven of which (including benzo[a]pyrene) are established skin carcinogens, and one of which (2-chloroethanol) is a well-defined noncarcinogen to skin, have been evaluated for skin-sensitizing activity using the local lymph node assay. The relative mutagenicity of the agents to Salmonella was also established. Fourteen of the chemicals were positive in the local lymph node assay, including the seven skin carcinogens. 2-Chloroethanol was inactive as a sensitizing agent. We suggest that a variety of factors contributes to the lack of sensitizing activity of the remaining six bacterial mutagens: extremes of intrinsic chemical reactivity, high water solubility reducing dermal translocation, and inappropriate dermal metabolism. Two reference skin-sensitizing agents (an oxazolinone and fluorescein isothiocyanate) were established as in vitro clastogens after their recognition as nonmutagens to Salmonella. These data imply that mutagenicity, rather than simply activity in the Salmonella assay, is a primary stimulus for electrophilic sensitization and carcinogenic initiation in the skin. We conclude that genotoxicity data for an agent can provide indications of the agent's potential to induce skin sensitization and that genotoxins which are skin-sensitizing agents have an enhanced potential to initiate skin carcinogenesis. We suggest that common, albeit individually distinct, structure-activity relationships underpin genotoxicity, skin sensitization, and the initiation of skin carcinogenesis. These relationships should simplify the hazard evaluation of chemicals and contribute to a reduction in animal usage. Several predictions of skin carcinogenicity are made based on the data presented.

Animals↗