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Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 127 records · Page 7Linked to original sources
PubMed1997

Alpha 6 integrins are required for Langerhans cell migration from the epidermis.

Topical exposure of mice to chemical allergens results in the migration of epidermal Langerhans cells (LCs) from the skin and their accumulation as immunostimulatory dendritic cells (DCs) in draining lymph nodes. Epidermal cell-derived cytokines have been implicated in the maturation and migration of LCs, but the adhesion molecules that regulate LC migration have not been studied. We hypothesized that integrin-mediated interactions with extracellular matrix components of the skin and lymph node may regulate LC/DC migration. We found that alpha 6 integrins and alpha 4 integrins were differentially expressed by epidermal LCs and lymph node DCs. A majority of LCs (70%) expressed the alpha 6 integrin subunit, whereas DCs did not express alpha 6 integrins. In contrast, the alpha 4 integrin subunit was expressed at high levels on DCs but at much lower levels on LCs. The anti-alpha 6 integrin antibody, GoH3, which blocks binding to laminin, completely prevented the spontaneous migration of LCs from skin explants in vitro and the rapid migration of LCs from mouse ear skin induced after intradermal administration of TNF-alpha in vivo. GoH3 also reduced the accumulation of DCs in draining lymph nodes by a maximum of 70% after topical administration of the chemical allergen oxazolone. LCs remaining in the epidermis in the presence of GoH3 adopted a rounded morphology, rather than the interdigitating appearance typical of LCs in naive skin, suggesting that the cells had detached from neighboring keratinocytes and withdrawn cellular processes in preparation for migration, but were unable to leave the epidermis. The anti-alpha 4 integrin antibody PS/2, which blocks binding to fibronectin, had no effect on LC migration from the epidermis either in vitro or in vivo, or on the accumulation of DCs in draining lymph nodes after oxazolone application. RGD-containing peptides were also without effect on LC migration from skin explants. These results identify an important role for alpha 6 integrins in the migration of LC from the epidermis to the draining lymph node by regulating access across the epidermal basement membrane. In contrast, alpha 4 integrins, or other integrin-dependent interactions with fibronectin that are mediated by the RGD recognition sequence, did not influence LC migration from the epidermis. In addition, alpha 4 integrins did not affect the accumulation of LCs as DCs in draining lymph nodes.

Animals↗
PubMed1997

Modulation of T-helper cell populations: potential mechanisms of respiratory hypersensitivity and immune suppression.

Information presented at this symposium indicates that modulation of Th cell responses is one means by which xenobiotics may cause immunotoxicity. A shift from Th1 to Th2 responses can enhance both infectious and allergic disease. Hence, in some cases, a common mechanism may be responsible for effects that are generally considered to be very different. Because cytokines produced in the inflammatory process play a role in modulation of Th cell responses, there is a mechanism by which agents that appear to have only local effects at the portal of entry may, in fact, affect immune responses systemically. An understanding of conditions which trigger certain cytokine responses may be useful not only in understanding inflammation but also in predicting certain kinds of immunosuppressive and allergic responses. Future studies in this area are likely to provide insights into many areas of immunotoxicology.

Air Pollutants↗
PubMed1997

Interleukin 1 beta and the stimulation of Langerhans cell migration: comparisons with tumour necrosis factor alpha.

Epidermal Langerhans cells (LC) and the cells into which they mature are believed to play a pivotal role in cutaneous immune function. The induction phase of contact sensitization is associated with the migration of LC from the skin and their accumulation as dendritic cells (DC) in lymph nodes draining the site of exposure. We have demonstrated previously that tumour necrosis factor alpha (TNF-alpha), an epidermal cytokine produced by keratinocytes, provides one signal for LC migration. We describe here experiments designed to evaluate the influence of interleukin 1 beta (IL-1 beta), a product exclusively of LC in murine epidermis, on LC migration, LC morphology and DC accumulation, and to compare the effects of this cytokine with those of TNF-alpha. Both cytokines induced a significant reduction in the frequency of epidermal LC and the arrival of DC in draining lymph nodes. Changes in both parameters were induced more rapidly following intradermal administration of TNF-alpha than were observed after treatment with IL-1 beta. However, the reduction in LC frequency was more persistent with IL-1 beta. Both cytokines caused the activation of LC, characterized by the acquisition of a more dendritic morphology and the increased expression of Ia molecules. These results demonstrate that IL-1 beta and TNF-alpha can each stimulate the migration of epidermal LC, but that the changes induced by these cytokines are not identical.

Animals↗
PubMed1997

A re-appraisal of the skin-sensitizing activity of 2,4-dinitrothiocyanobenzene.

A debate continues regarding the immunological properties of 2,4-dinitrothiocyanobenzene (DNTB). In some investigations this chemical was shown not to cause skin sensitization when applied topically but to induce instead hyporesponsiveness or immunological tolerance. In other studies DNTB was found to cause skin sensitization, but not tolerance. However, this chemical continues to be used to discriminate between the properties of skin sensitizing and non-sensitizing chemicals. This study demonstrates that topical exposure of mice to DNTB induces skin sensitization in mice and that this is associated with the accumulation of dendritic cells in draining lymph nodes and the stimulation of lymph node cell proliferation; the latter responses being of equivalent magnitude to those stimulated by 2,4-dinitrochlorobenzene (DNCB), a chemical known to cause contact sensitization. Moreover, exposure of mice to DNTB, as with exposure to DNCB, resulted in the development of a cytokine secretion pattern by draining lymph node cells (LNC) characteristic of contact allergens. Thus, DNTB and DNCB each induced the production by LNC of high levels of interferon-gamma, but little or no interleukin 4 or interleukin 10. Finally, DNTB was shown in the guinea pig maximization test to behave as an extreme skin sensitizer. These results confirm that DNTB should not be regarded as a universal tolerogen and that it possesses a significant potential to induce contact sensitization. The use of this chemical as a presumptive non-sensitizer and/or tolerogen for the evaluation of the selectivity of new predictive test methods for the identification of contact allergens is therefore considered to be inappropriate.

Administration, Topical↗
PubMed1997

Characteristics of antibody responses induced in mice by protein allergens.

Whereas many foreign proteins are immunogenic, only a proportion is also allergenic, having the capacity to induce the quality of immune response necessary to support the production of IgE antibody. We have demonstrated previously that intraperitoneal administration to mice of proteins such as ovalbumin (OVA) or the industrial enzyme A. oryzae lipase, which possess significant allergenic potential, stimulates the production of both IgG and IgE antibody. Identical exposure to bovine serum albumin (BSA), a protein with limited potential to cause immediate respiratory or gastrointestinal hypersensitivity reactions, induced IgG responses only. In the current investigations, the quality of immune responses induced following exposure to these proteins via mucosal tissue (intranasal) has been compared with those provoked following administration via a non-mucosal (intraperitoneal) route of exposure. Intranasal or intraperitoneal administration of BSA, OVA or A. oryzae lipase elicited in each case vigorous IgG and IgG1 antibody responses. For all three proteins, at every concentration tested, and via both routes of exposure, IgG1 antibody titres paralleled closely IgG titres. However, the three materials displayed a differential potential to provoke IgE responses and this correlated with their known allergenic potential in humans. Thus, OVA and A. oryzae lipase stimulated strong IgE antibody responses, whereas BSA provoked low titre IgE only at the highest concentration tested (5% administered intraperitoneally). The quality of induced responses was not affected by the route of exposure. It would appear, therefore, that the stimulation of IgG and IgG1 antibody responses is a reflection of protein immunogenicity whereas protein allergenicity is associated with the induction of strong IgE responses.

Administration, Intranasal↗
PubMed1997

Langerhans cells require signals from both tumour necrosis factor-alpha and interleukin-1 beta for migration.

The induction phase of contact sensitization is associated with the movement of epidermal Langerhans cells (LC) from the skin and their migration, via afferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendritic cells (DC). It has been demonstrated previously that tumour necrosis factor-alpha (TNF-alpha) provides an important signal for LC migration and that in the absence of this cytokine, movement of LC from the epidermis to regional lymph nodes is inhibited. Recent evidence indicates that interleukin-1 beta (IL-1 beta), a cytokine produced in murine epidermis exclusively by LC, may also play a role in LC migration. The purpose of the investigations described here was to clarify, using relevant neutralizing anti-cytokine antibodies, the contributions made by TNF-alpha and IL-1 beta to the migration of LC from the epidermis. It was found that like anti-TNF-alpha, anti-IL-1 beta administered systemically to mice (by intraperitoneal injection), prior to skin sensitization with the contact allergen oxazolone, resulted in a marked inhibition of DC accumulation in draining lymph nodes. It was shown also that anti-IL-1 beta inhibited TNF-alpha-induced LC migration and DC accumulation and that; in similar fashion, the stimulation of LC migration and DC accumulation induced by IL-1 beta was compromised by prior treatment with anti-TNF-alpha. Based upon these data it is proposed that the stimulation of LC migration in response to skin sensitization requires the receipt by LC of two independent signals, one provided by TNF-alpha and the other by IL-1 beta. Morphological analyses of LC in epidermal sheets prepared from animals exposed to these cytokines with or without prior systemic treatment with anti-cytokine antibody suggested that the changes induced in LC by TNF-alpha and IL-1 beta may include the altered expression of adhesion molecules and acquisition of the ability to interact with and pass through the basement membrane.

Animals↗
PubMed1997

Dinitrohalobenzenes: evaluation of relative skin sensitization potential using the local lymph node assay.

The dinitrohalobenzenes are known to cause skin sensitization and have been used in many seminal investigations of the relationships between physicochemical characteristics and sensitizing potential. The electrophilic theory of skin sensitization implies that contact allergic potential should correlate positively with ability of chemicals to react with proteins to form immunogenic hapten-protein conjugates. It is intriguing, therefore, that previous studies in guinea pigs and mice have suggested that such correlations do not apply to dinitrohalobenzenes. To address this, we have examined, using the murine local lymph node assay (LLNA), the sensitizing activity of 2,4-dinitrofluorobenzene (DNFB), 2,4-dinitrochlorobenzene (DNCB), 2,4-dinitrobromo-benzene (DNBB) and 2,4-dinitroiodobenzene (DNIB). In contrast to previous investigations, it was found that the ability of these chemicals to provoke responses in the LLNA correlated closely with their reported protein reactivity. On the basis of these data, it is proposed that dinitrohalobenzenes conform to the electrophilic theory of skin sensitization and that they should be regarded as direct acting haptens.

Allergens↗
PubMed1997

Differential induction of cutaneous TNF-alpha and IL-6 by topically applied chemicals.

BACKGROUND: Increasing evidence shows that contact allergens and skin irritants can induce or upregulate the cutaneous expression of cytokines, including those that are required for the initiation of immune responses and which participate in inflammatory reactions. OBJECTIVE: The present investigation compared the ability of the skin allergens oxazolone and 2,4-dinitrochlorobenzene (DNCB) and the skin irritant benzalkonium chloride (BZC) to stimulate the cutaneous expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in mice. RESULTS: Each chemical tested induced the dose-dependent production of IL-6 with similar kinetic profiles. BZC was less effective at provoking increases in this cytokine; concentrations (1%) that caused marked edema failed to stimulate significant changes in IL-6 expression. Under conditions of topical exposure in which each of these chemicals caused a vigorous inflammatory response in the skin, as measured by induced edema and the increased production of IL-6, only oxazolone and DNCB stimulated expression of TNF-alpha. The failure of BZC to initiate TNF-alpha production in the skin was not attributable to inhibition of the bioassay used to measure this cytokine and was apparently independent of the stimulation by this chemical of TNF-alpha inhibitory factors. CONCLUSION: These data indicate that not all chemicals that have the ability to cause skin irritation and cutaneous inflammation will elicit detectable TNF-alpha responses and that characterization of cutaneous irritants and allergens on the basis of induced cytokine expression patterns in the skin must be approached with caution.

Adjuvants, Immunologic↗
PubMed1996

Selectivity of IgE responses, mast cell sensitization, and cytokine expression in the immune response of Brown Norway rats to chemical allergens.

Sensitizing chemicals can induce various types of allergic disease, including contact dermatitis and occupational asthma. In the present study we have examined the nature of the immune response induced in Brown Norway (BN) rats by oxazolone (OX), a potent contact allergen, and by trimellitic anhydride (TMA), a chemical known to cause sensitization of the respiratory tract and occupational asthma. BN rats were exposed topically to either OX or TMA at doses selected to achieve similar levels of proliferative activity by draining LNC. Both chemicals stimulated hapten-specific IgG antibody responses, but only TMA induced specific IgE antibody, an increase in total serum IgE and active sensitization of mast cells. Draining LNC from OX-treated rats expressed elevated IFN-gamma mRNA, whereas those from TMA-treated rats expressed elevated IL-5 mRNA compared to controls. Furthermore, Con A-activated draining LNC from rats exposed to TMA, but not OX, released significantly increased concentrations of IL-4. In conclusion, different chemical allergens can induce in the BN rat divergent patterns of IgE response and cytokine expression.

Allergens↗
PubMed1996

Sensitization to 2,4-dinitrochlorobenzene: influence of vehicle on absorption and lymph node activation.

Effective skin sensitization is dependent upon immune activation of lymph nodes draining the site of exposure. The influence of vehicle formulation on the vigour of lymph node cell proliferative responses to 2,4-dinitrochlorobenzene (DNCB) has been examined. Mice (BALB/c strain) were exposed topically to 0.5% DNCB dissolved in either acetone or propylene glycol (PG). A significantly greater lymph node cell proliferative response was induced by DNCB in acetone. The observed differences were not attributable to variations in the numbers of immunostimulatory dendritic cells accumulating in the draining nodes following sensitization. In parallel studies, the absorption and cutaneous disposition of DNCB dissolved in acetone or PG were measured in vitro using static diffusion cells and full thickness mouse skin. Although flux of DNCB through the skin was comparable with both vehicles over 24 h, the absorption of the allergen during the first 4 h of exposure was significantly faster when acetone was used as the vehicle. Localization of DNCB demonstrated that much less of the chemical allergen was present in the skin at 4 h when applied in PG vehicle. However, there were no measurable vehicle effects on skin disposition of DNCB at 24 h. These data indicate that the sensitization potential of DNCB is influenced significantly by the nature of the vehicle used, possibly due to consequential effects on chemical absorption and disposition. The studies described in this paper reveal that the application vehicle may have a significant influence on the ability of DNCB to induce immune activation of draining lymph nodes and hence skin sensitization and that this may in turn be associated with important changes in the absorption and/or disposition of the chemical within the skin.

Acetone↗
PubMed1996

Further evaluation of the local lymph node assay in the final phase of an international collaborative trial.

The local lymph node assay (LLNA) is a method used for the prospective identification in mice of chemicals that have the potential to cause skin sensitization. We report here the results of the second and final phase of an international trial in which the performance of the assay has been evaluated using seven test materials in five independent laboratories. The additional chemicals examined here included compounds which are considered less potent allergens than some of those tested in the first phase of the investigation, and includes hexylcinnamic aldehyde (HCA), a chemical recommended by the Organization for Economic Cooperation and Development (OECD) as a positive control for skin sensitization studies. In each laboratory all skin sensitizing chemicals examined (2,4-dinitrochlorobenzene {DNCB}, HCA, oxazolone, isoeugenal and eugenol) elicited positive responses of comparable magnitude as judged by the derived lowest concentration of test chemical required to elicit a 3-fold or greater increase in the proliferative activity of draining lymph node cells compared with vehicle-treated controls. We observed that sodium lauryl sulphate, considered to be a non-sensitizing skin irritant, also induced a positive response in the assay. Para-aminobenzoic acid (pABA), a nonsensitizing chemical, was negative at all test concentrations in each laboratory. Some laboratories incorporated minor modifications into the standard assay procedure, including the evaluation of lymph nodes pooled from individual mice rather than treatment groups and the use of statistical analyses. The use of statistics did not markedly change the determination of the lowest concentration yielding a positive response. These data confirm that the local lymph node assay is robust and yields equivalent results when performed independently.

Animals↗