Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 217 records · Page 12Linked to original sources

PubMed1992

Langerhans cells, antigen presentation, and the diversity of responses to chemical allergens.

Respiratory and contact chemical allergens provoke differential immune responses in mice, stimulating preferentially T helper-2 (TH2) and TH1 cells, respectively. In an attempt to discover whether such differences are effected at the level of antigen handling and presentation we have examined the effect of topical exposure to trimellitic anhydride (TMA), a respiratory allergen, and 2,4-dinitrochlorobenzene (DNCB), a contact allergen, on Langerhans cell (LC) MHC class II (Ia) expression. Neither chemical caused a significant change in LC size. As measured by analytical flow cytometry, exposure to DNCB resulted in a time-dependent increase in LC Ia expression that exceeded 160% of control values within 24 h. Exposure to concentrations of TMA that caused an equivalent activation of draining lymph nodes failed to affect Ia expression by LC. Application of sodium lauryl sulfate at concentrations that caused edema also failed to influence LC Ia. These data demonstrate that TMA and DNCB exert differential effects on epidermal LC, possibly indicative of differences in antigen handling.

Allergens↗

PubMed1992

Divergent immune responses to respiratory and contact chemical allergens: antibody elicited by phthalic anhydride and oxazolone.

In previous studies we observed that exposure of mice to the contact allergen 2,4-dinitrochlorobenzene (DNCB) and the respiratory allergen trimellitic anhydride (TMA) resulted in qualitatively different immune responses characteristic of selective Th1- and Th2-type T helper cell activation respectively. The purpose of the present investigation was to determine whether the effects recorded with DNCB and TMA are characteristic of immune responses to contact and respiratory chemical allergens in general. Experiments have been performed with phthalic anhydride, a known human respiratory sensitizer, and with oxazolone, a potent contact allergen. Under conditions of exposure where both chemicals elicited an IgG anti-hapten antibody response, only phthalic anhydride caused an increase in the serum concentration of IgE. Furthermore, like TMA, phthalic anhydride preferentially induced IgG2b rather than IgG2a antibody. In contrast, oxazolone, like DNCB, induced a markedly stronger IgG2a than IgG2b antibody response. These data provide confirmatory evidence that chemical respiratory allergens and chemical contact allergens elicit qualitatively different immune responses which reflect their clinical effects in man.

Allergens↗

PubMed1992

Sulphanilic acid: divergent results in the guinea pig maximization test and the local lymph node assay.

The guinea pig maximization test (GPMT) has proven to be a valuable tool for the identification of the skin sensitization potential of chemicals. The method identifies a hazard which can lead in the EC to compulsory labelling of that chemical. In the present study, data on sulphanilic acid derived from the GPMT has been compared with results from a second guinea pig assay (the cumulative contact enhancement test) and the murine local lymph node assay, both of which require only topical application of chemical. Except for the GPMT, no test identified any sensitizing activity associated with exposure to sulphanilic acid. These latter results are consistent with the experience gained from substantial human exposure in an occupational setting and from which no cases of allergic contact dermatitis to sulphanilic acid have arisen over a 20-year period. In consequence, it is questioned which test protocol in practice has given the more accurate identification of sensitization hazard relevant to man.

Administration, Topical↗

PubMed1992

Differential ability of occupational chemical contact and respiratory allergens to cause immediate and delayed dermal hypersensitivity reactions in mice.

Trimellitic anhydride (TMA) is known to cause occupational respiratory allergy associated with the presence of specific IgE antibody. Other chemicals, such as 2,4-dinitrochlorobenzene (DNCB), while exhibiting a clear potential for contact sensitization, apparently lack the ability to induce respiratory allergy in man. It has been shown previously that although both chemicals are immunogenic in mice, each provoking contact sensitization, exposure only to TMA results in an IgE antibody response. In the present study, to examine further the characteristics of human allergens, we have compared the ability of TMA and DNCB to elicit immediate and delayed cutaneous hypersensitivity reactions in mice. Topical exposure to both chemicals resulted in delayed (24 h) hypersensitivity. However, only TMA induced, in addition, an immediate (1 h) dermal reaction following local challenge. Serum from TMA-immune mice, but not from untreated mice or mice sensitized with DNCB, was able to transfer immediate hypersensitivity to naive recipients. The kinetics of passive sensitization with TMA-immune serum, together with the fact that immediate hypersensitivity to DNCB could be induced with monoclonal IgE anti-dinitrophenol (DNP) antibody, suggests that the immediate dermal responses caused by TMA are effected by hapten-specific IgE. These data demonstrate that different classes of occupational chemical allergen exhibit a variable potential to elicit immediate and delayed dermal hypersensitivity reactions in mice, and provide a novel approach to the classification and characterization of human allergens.

Administration, Topical↗

PubMed1992

Influence of topical exposure to chemical allergens on murine Langerhans cells. Comparison of 2,4-dinitrochlorobenzene with trimellitic anhydride.

Chemical allergens differ with respect to the type of hypersensitivity reactions they preferentially elicit. Some chemicals, such as trimellitic anhydride (TMA), have the potential to induce both contact and respiratory hypersensitivity. Other chemicals cause only contact allergy. For example, 2,4-dinitrochlorobenzene (DNCB), a potent contact allergen, appears not to induce respiratory sensitization. In previous studies we have shown that topical exposure of mice to TMA and DNCB, under conditions of equivalent immunogenicity with respect to draining lymph node activation and contact sensitization, caused qualitatively different antibody responses. While the chemicals provoked IgG anti-hapten antibody responses of equivalent magnitude, only TMA induced an IgE response, and DNCB caused a significantly stronger IgG2a response. These data are consistent with the preferential activation by DNCB and TMA of Th1 and Th2 cells respectively. The purpose of the present study was to examine whether the qualitative differences in immune responses stimulated by these chemicals is reflected by variable affects on Langerhans cells (LC) in situ. Mice were exposed to concentrations of DNCB (1%) and TMA (50%) which caused equivalent levels of contact sensitization. Under these conditions topical exposure to DNCB, but not to TMA, or to vehicle alone, resulted in increased expression by LC of Ia antigen. Similar treatment with an irritant concentration (20%) of sodium dodecyl sulphate failed to influence Ia expression by LC. These data indicate that, at concentrations which induce similar levels of skin sensitization, not all contact allergens cause rapid changes in LC Ia expression, and that the qualitative differences in immune responses elicited by chemical allergens DNCB and TMA is associated with variable effects on LC.

Administration, Topical↗

PubMed1992

The effect of ultraviolet B irradiation and urocanic acid isomers on dendritic cell migration.

Irradiation with ultraviolet-B light (UV-B) suppresses some cell-mediated immune responses to a variety of antigens, including contact sensitizers. Following UV irradiation there is modulation of Langerhans' cells' markers and keratinocytes are induced to synthesize and secrete tumour necrosis factor-alpha (TNF-alpha). Cis-urocanic acid (cis-UCA) has been suggested as a photoreceptor for UV and has been demonstrated to suppress immune responses in several experimental systems. UCA is found naturally in the stratum corneum as the trans-isomer and converts to the cis-isomer on irradiation. In the present study the migration of dendritic cells (DC) to lymph nodes following UV-B irradiation or epicutaneous application of UCA isomers was examined in unsensitized mice and mice sensitized with fluorescein isothiocyanate (FITC). It was found that UV-B irradiation alone induced DC migration to draining lymph nodes (DLN) and that UV-B irradiation prior to skin sensitization at the same site enhanced DC migration. A maximum number of DC was present in DLN 48 hr following irradiation. In sensitized mice, the percentage of DC bearing FITC and the quantity of FITC per DC was unaltered by prior UV exposure. In contrast, neither isomer of UCA had any significant effect on DC numbers in sensitized or unsensitized mice. It was concluded that UV-B irradiation induced the migration of DC from the epidermis to draining lymph nodes, an effect possibly mediated by TNF-alpha release, while UCA may act by a different mechanism, perhaps via histamine-like receptors in the epidermis.

Animals↗

PubMed1992

Dermal tumour necrosis factor-alpha induces dendritic cell migration to draining lymph nodes, and possibly provides one stimulus for Langerhans' cell migration.

Previous studies have shown that following skin sensitization there is an accumulation of dendritic cells (DC) in lymph nodes draining the site of exposure. A significant number of the DC which arrive in the lymph nodes bear high levels of antigen, and the available evidence indicates that they are derived from epidermal Langerhans' cells (LC). Although freshly isolated LC are relatively inefficient antigen-presenting cells, the antigen-bearing DC which are found within draining nodes following skin sensitization are highly immunostimulatory. Recent investigations indicate that the functional maturation of LC as they migrate from the skin is reflected by an enhanced capacity to form stable clusters with lymphocytes, and is associated with an increased expression of membrane major histocompatibility complex (MHC) class II (Ia) antigen. By analogy with in vitro studies of LC maturation, it is possible that such changes are effected by granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-1 (IL-1), both of which are products of epidermal cells. The question remains as to the nature of the stimulus that initiates LC migration. In the present study we have examined in mice the effects of intradermal injection of tumour necrosis factor-alpha (TNF-alpha), another epidermal cytokine, on the accumulation of DC in lymph nodes. Murine recombinant TNF-alpha was found to cause a concentration- and time-dependent increase in the number of DC within draining nodes. Under the same conditions of exposure murine recombinant GM-CSF was without effect. Heat treatment of mouse TNF-alpha resulted in an equivalent inhibition of both DC accumulation and cytotoxic activity measured by in vitro bioassay. An interesting observation was that equal concentrations of human TNF-alpha, of equivalent specific activity, failed to influence the frequency of lymph node DC. These data demonstrate that TNF-alpha induces DC accumulation in draining lymph nodes, and we propose that this cytokine may provide one stimulus for LC migration during cutaneous immune responses.

Animals↗

PubMed1991

Anamnestic responses to contact allergens: application in the murine local lymph node assay.

The murine local lymph node assay, an alternative predictive test for the identification of contact sensitizing chemicals, is based upon the fact that skin allergens induce proliferation in lymph nodes draining the site of application. In the present study we have examined whether pre-exposure to the test chemical at a distant site enhances subsequent draining lymph node cell proliferation and, thereby, the sensitivity of the assay. Experiments were performed using both in vitro and in situ measurement of induced lymph node cell proliferation. It was found that, with the exception of potent skin sensitizers such as picryl chloride and oxazolone, which impair subsequent proliferative activity as a consequence of induced immunoregulatory processes, pre-treatment with the test allergen resulted in enhanced proliferation. Evidence is presented that the local lymph node assay response to a variety of skin allergens (including eugenol, isoeugenol, dihydrocoumarin, 4-vinylpyridine, cinnamic aldehyde and 2,4,5-trichlorophenol) was augmented when mice received a single exposure to the same chemical 5 days earlier. It is concluded that the use of a modified protocol, incorporating pre-exposure to the test material, can enhance local lymph node assay responses to all but the most potent skin allergens, and may be of particular value when increased sensitivity is required.

Allergens↗

PubMed1991

Serum histamine and the elicitation of murine contact sensitivity.

We report that challenge of previously contact-sensitized mice results in a significant increase in the concentration of serum histamine. In an attempt to determine whether this phenomenon might form the basis of an alternative method for the evaluation of elicitation reactions in experimental contact sensitivity, we have compared challenge-induced increases in ear thickness with elevations in serum histamine. Challenge of sensitized mice revealed that both ear thickness changes and increases in the serum level of histamine were dependent upon the concentration of oxazolone used for sensitization. The kinetics of changes in serum histamine concentration were found to be biphasic, with a small increase measurable 2 h following challenge and the maximal response at 24 or 48 h. In contrast, increases in ear thickness were monophasic, although maximum responses were also observed at 24 h. It is concluded that, although they do not exactly parallel increases in ear thickness, changes in histamine concentration may provide a useful serological correlate of the challenge reaction in contact sensitivity.

Animals↗

PubMed1991

Investigation of lymph node cell proliferation as a possible immunological correlate of contact sensitizing potential.

In an attempt to define an immunological correlate of contact allergic potential it was investigated whether the magnitude of the lymphocyte proliferative response provoked following primary exposure to skin allergens influences the degree to which sensitization is induced. Previous studies have provided circumstantial evidence that there is a causal relationship between proliferation and sensitization. Thus, inhibition of the primary proliferative response to a sensitizing chemical, induced by prior exposure to an unrelated allergen, is associated with a significant depression of contact hypersensitivity. The results of comparative studies performed using a series of antigenically cross-reactive dinitrobenzene derivatives, 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene and 2,4-dinitrothiocyanobenzene are now reported. Evidence is presented that there is a direct correlation between cumulative proliferative activity in the draining lymph nodes and the severity of elicitation reactions. The tentative conclusion which can be drawn is that measurement of lymphocyte proliferative activity may form the basis of a method for comparative evaluation of the contact allergic potential of chemicals.

Animals↗

PubMed1991

Draining lymph node cell activation in guinea pigs: comparisons with the murine local lymph node assay.

The local lymph node assay in the mouse is a novel predictive test for the identification of contact sensitizing chemicals. The purpose of the studies described was to determine whether a similar local lymph node assay could be performed successfully in guinea pigs; currently the species of choice for assessment of sensitizing potential for regulatory purposes. Ten sensitizing chemicals (oxazolone, picryl chloride, 2,4-dinitrofluorobenzene, benzocaine, cinnamic aldehyde, 2,4,-dinitrothiocyanobenzene, p-nitrosodimethylaniline, formaldehyde, p-phenylenediamine and cyanuric chloride) and equal concentrations of sodium lauryl sulphate were examined in a guinea pig local lymph node assay. Animals received three consecutive daily applications of various concentrations of the test chemical on the dorsum of both ears. Control animals were untreated. Five days following the initiation of exposure, draining auricular lymph nodes were excised and weighed. Suspensions of lymph node cells (LNC) were prepared and cultured for 24 or 48 h and proliferation measured by incorporation of [3H]thymidine. Exposure to at least one concentration of all sensitizing chemicals, other than benzocaine, induced proliferation by draining LNC. Responses were higher at 24 h rather than 48 h. Evidence is presented that guinea pig LNC proliferation may be enhanced or maintained by addition to culture of an exogenous source of the T cell growth factor interleukin 2 (IL-2). Draining lymph node weight was increased following exposure to some sensitizing chemicals but, compared with LNC proliferation, provided a less sensitive correlate of lymph node activation. Exposure to sodium lauryl sulphate failed to induce changes in either lymph node weight of LNC proliferation. Data are compared with three-day murine local lymph node assays performed concurrently. The available information indicates that the local lymph node assay may be performed in guinea pigs.

Allergens↗

PubMed1991

The murine local lymph node assay: results of an inter-laboratory trial.

The local lymph node assay is a novel predictive test for the identification of contact allergens. The collaborative study reported here was performed to evaluate the reliability of the method when performed in independent laboratories. Eight chemicals were examined in each of 4 participating laboratories and results compared with predictions of skin-sensitizing activity made from concurrent Magnusson and Kligman guinea-pig maximization tests performed in a single laboratory. The local lymph node assay has as its theoretical basis the fact that contact allergens induce T-lymphocyte proliferative responses. In practice, predictions of contact-sensitizing potential are made following measurement of proliferation in lymph nodes draining the site of exposure to chemical, and derivation of a stimulation index using control values as the comparator. Although in the present study there was some variation between laboratories with respect to the absolute stimulation indices recorded, it was found that with all chemicals each laboratory made the same predictions of sensitizing activity. Six chemicals (2,4-dinitrochlorobenzene, formalin, eugenol, isoeugenol, p-phenylenediamine and potassium dichromate) yielded positive responses, and two (methyl salicylate and benzocaine) were negative, in each laboratory. Furthermore, with 7 of the 8 chemicals tested there was no significant difference between laboratories in terms of the characteristics of the dose-response relationships recorded. With the exception of one chemical (benzocaine), predictions made with the local lymph node assay were in accord with those derived from guinea-pig maximization tests. These inter-laboratory comparisons demonstrate that the local lymph node assay is a robust and reliable method for the identification of at least moderate and strong contact allergens.

Allergens↗

PubMed1991

Lymphocyte transformation and thiuram sensitization.

The use of a lymphocyte transformation test (LTT) to confirm allergic contact dermatitis from thiurams has been investigated. The responses of peripheral blood mononuclear cells (PBMC) from thiuram-sensitive and non-sensitive individuals following culture with dimethylcarbamoyl-protein (human serum albumin; HSA) and dimethylthiocarbamoyl-HSA conjugates has been compared. Only PBMC from those patients who were patch-test-positive with thiuram-mix and sensitized to tetramethylthiuram monosulphide (TMTM) or TMTM and tetramethylthiuram disulphide (TMTD) exhibited significant proliferative responses to these conjugates. Thiuram-patch-test-negative patients and control donors with no history of allergic contact dermatitis failed to mount a significant response to any concentration of either conjugate. Two of the thiuram-sensitive patients were also nickel-patch-test-positive, and PBMC isolated from these donors, but not from nickel-patch-test-negative patients, proved positive in a nickel LTT. The data reveal that relevant hapten-protein conjugates are capable of provoking specific human lymphocyte proliferative responses in vitro, and that, using this technique, the LTT can, in principle, be used for the investigation and/or diagnosis of skin sensitization to lipophilic contact allergens.

Cell Division↗

PubMed1991

Selective impairment of T lymphocyte activation following contact sensitization with oxazolone.

We have previously reported that topical exposure of mice to oxazolone results in the appearance of regulatory mechanisms which markedly depress lymph node cell (LNC) proliferative responses to subsequent challenge with the same chemical. In the present study, we have sought to identify the cellular targets for such immunoregulation. Autoradiographic analyses revealed that although pre-exposure to oxazolone caused a substantial reduction of paracortical hyperplasia following challenge, the frequency of proliferating cells in lymphoid follicles was slightly increased. That B lymphocyte responses are unaffected by oxazolone-induced immunoregulation was confirmed by investigation of anti-hapten antibody formation by draining LNC. Challenge with oxazolone resulted in an accelerated antibody response in mice previously exposed to the same chemical. These data reveal that the active immunoregulation induced following sensitization with oxazolone is selective for T lymphocytes. Evidence is presented that CD4+ and CD8+ T lymphocytes possess equivalent sensitivity to these mechanisms.

Administration, Topical↗

PubMed1991

Inhalation exposure of mice to trimellitic anhydride induces both IgG and IgE anti-hapten antibody.

The development of antibody responses resulting from inhalation exposure to chemical allergens has been studied in mice. Inhalation exposure of BALB/c mice to atmospheres containing approximately 5 mg/m3 of the respiratory allergen trimellitic anhydride (TMA) resulted in the appearance of both serum IgG and IgE anti-hapten antibody. IgE anti-TMA was first detectable 2-3 weeks following the initiation of exposure and was still present at 6 weeks. Under the same conditions of exposure, 2,4-dinitrochlorobenzene (DNCB), a contact allergen which apparently lacks the capacity for respiratory sensitization, failed to elicit detectable amounts of anti-dinitrophenol (DNP) antibody. Exposure to increased concentrations of atmospheric DNCB (15 mg/m3) did, however, result in an IgG anti-DNP response but not in IgE antibody. These data demonstrate firstly, that atmospheres containing low molecular weight respiratory allergens can initiate specific IgE responses in mice, and secondly, that inhaled chemicals may differ in their ability to induce IgE antibody.

Administration, Inhalation↗

PubMed1991

Toxicology and the immune system: a perspective.

The relationship of immunology to toxicology has not always been an easy one, and the product of this association, immunotoxicology, has not infrequently been viewed with a certain scepticism by some of those who consider themselves 'classical' toxicologists. A recent meeting of the British Toxicology Society ('Toxicology and the Immune System', New College Oxford, March 21-22, 1991) provided an opportunity for some remedial work toward a wider appreciation of the issues which exercise immunotoxicologists, and the ways in which they are being addressed. It is not the purpose of this short article to provide a comprehensive account of the scientific presentations, but rather to give a perspective, necessarily a personal one, of immunotoxicology in the context of the meeting.

Humans↗

PubMed1991

MHC class II expression by Langerhans' cells and lymph node dendritic cells: possible evidence for maturation of Langerhans' cells following contact sensitization.

Following exposure of mice to contact sensitizing chemicals, dendritic cells (DC) rapidly accumulate in the draining lymph nodes. A proportion, at least, of the DC which arrive in the nodes bear significant amounts of antigen and are derived from epidermal Langerhans' cells (LC). It is of interest that although LC are relatively inefficient antigen-presenting cells, the antigen-bearing DC found within draining nodes are potent accessory cells and induce immune responses both in vitro and in vivo. Previous in vitro studies have shown that during culture in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF), LC are subject to a functional and phenotypic maturation characterized by the development of effective accessory cell function and elevated membrane Ia antigen expression. We have hypothesized previously that LC may undergo a similar maturation in vivo as they move to the draining lymph nodes following receipt of the stimulus to migrate. As maturation in vitro is accompanied by increased Ia, we have examined the expression of this molecule on epidermal LC and lymph node DC during the induction phase of contact sensitization. The data reported provide evidence that peripheral lymph node DC, irrespective of whether they are derived from draining or resting nodes, and irrespective of whether or not they bear antigen, express comparable high levels of Ia antigen. In contrast, compared with DC, freshly isolated LC have considerably less (on average five times less) Ia antigen. These results indicate that during migration from the skin to lymphoid tissue LC are subject to a phenotypic maturation, comparable with that observed in vitro, and consistent with the acquisition of active antigen-presenting cell function.

Animals↗

PubMed1991

Antigen-specific and non-specific depression of proliferative responses induced during contact sensitivity in mice.

Exposure of the flank of mice to either oxazolone or trinitrochlorobenzene (TNCB) 5 days prior to the application of oxazolone on the ear resulted in a reduced capacity of oxazolone-induced draining lymph node cells to express IL-2 receptors, produce IL-2, protein, RNA and DNA. However, histological examination of the draining lymph node suggest that antigen-specific and antigen-non-specific influences differ with respect to the frequency of pyroninophilic cells. Pre-exposure to oxazolone suppressed the number of oxazolone-induced pyroninophilic T cell blasts, whereas draining lymph nodes from TNCB-pretreated mice contained significantly more pyroninophilic cells than from oxazolone-pretreated mice. However, the majority of these cells were incorporating little or no thymidine. Thus exposure to certain contact sensitizers induces at least two systemic control mechanisms which serve to regulate subsequent lymphoproliferative responses. These mechanisms appear to exert their influences at different stages of in-vivo T cell activation.

Animals↗