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Biomedical subjects

I Kimber

Publications and source records attributed to I Kimber.

At least 163 records · Page 9Linked to original sources
PubMed1996

Exposure of UVB-sensitive mice to immunosuppressive doses of UVB in vivo fails to affect the accessory function or the phenotype of draining lymph node dendritic cells.

Following the application of sensitizing chemicals to the skin, hapten-bearing Langerhans cells (LC) and possibly other cutaneous dendritic cells (DC) migrate to the draining lymph nodes (DLN) of mice and induce the proliferation of antigen specific effector T cells. This migration of DC to the DLN is required for the induction of primary immune responses. In certain strains of mice, irradiation with ultraviolet-B light (UVB) before sensitization results in the suppression of contact hypersensitivity responses. In vitro investigations have suggested that one influence of UVB is to modify the ability of Langerhans cells (LC) to present antigen. In the present investigation, putative UVB-induced alterations in lymph node DC in vivo were examined. Lymph node DC were analysed following exposure of C3H/HeN mice to an immunosuppressive dose of UVB (1440 J/m2) 48 and 24 h prior to skin painting with the sensitizers fluorescein isothiocyanate or oxazolone. In functional studies, DC prepared from the DLN of contact sensitized mice were examined for their ability to induce hapten-specific secondary T-lymphocyte proliferative responses or mixed lymphocyte reactions in vitro. In neither case was the activity of DC influenced by local exposure to an immunosuppressive dose of UVB. The migration of LC from the epidermis to the draining lymph node in response to contact sensitization is associated with increased expression of several membrane determinants necessary for effective antigen presentation, including intercellular adhesion molecule-1 (ICAM-1; CD54), B7-2 (CD86) and Ia antigen. The expression of these molecules was identical on DC isolated from the DLN of UVB-irradiated and from control, unirradiated mice. Thus, the immunosuppressive effect of UVB on the cutaneous immune system may not necessarily reflect changes in the antigen-presenting DC that accumulate in the DLN following skin sensitization.

Adjuvants, Immunologic↗
PubMed1995

Structure activity relationships in skin sensitization using the murine local lymph node assay.

Murine local lymph assay node data for 106 chemicals are listed. Among these, 73 are active in the assay indicating their potential as skin sensitizing agents. Broad structure activity relationships (SAR) are suggested based on the electrophilic theory of skin sensitization suggested by Landsteiner and Jacobs in 1936, and elaborated by Dupuis and Benezra in 1982. Eight classes of agent are discerned; electrophiles, potential electrophiles after metabolism, Michael-reactive agents, benzoylating agents, ionic chemicals and miscellaneous agents. The electrophilic theory cannot at present fully explain the activity of agents in the last two classes. That fact will hopefully focus research into their mode of action. Some chemicals fit equally into more than one class, and such agents are entered into the several classes in order not to bias the analysis. Attention is given to why not all chemicals of a class are active in the assay. It is concluded that a combination of inappropriate lipophilicity, molecular size and metabolic detoxification are responsible for these inactivities. Given a sufficient number of analogues tested within each class it should be possible eventually to predict with accuracy the skin sensitizing potential of new members of the class. However, the present analysis is qualitative, not quantitative. Finally, the parallelism between sensitizing potential and mutagenic potential for chemicals is explored further.

Allergens↗
PubMed1995

An international evaluation of the murine local lymph node assay and comparison of modified procedures.

The murine local lymph node assay is a predictive test for the identification of skin-sensitizing chemicals. The method has been the subject both of national inter-laboratory studies and of extensive comparisons with guinea pig tests. In the investigations reported here, the local lymph node assay has been evaluated further in the context of an international study comprising five independent laboratories. In addition, the influence of minor modifications to the standard assay procedure on the performance of the test has been examined. The modified procedures investigated were exposure of mice for 4 rather than 3 consecutive days, excision of lymph nodes 4 rather than 5 days after the initiation of exposure and the use of an alternative isotope. All five laboratories, irrespective of whether the standard or a modified protocol was used, were able to identify accurately, and with comparable sensitivity, potassium dichromate and 2,4-dinitrochlorobenzene as skin sensitizers. Using standard criteria, none of the laboratories recorded positive responses with methyl salicylate, a non-sensitizer. In the standard protocol, lymph nodes are pooled for each experimental group and the vigor of responses measured as a stimulation index relative to vehicle controls. A stimulation index of 3 or greater is considered to indicate skin-sensitizing potential. One further modification adopted by three of the laboratories was to analyze nodes from individual animals and, thereby, permit statistical evaluation. This allowed a direct comparison of statistical significance with the conventional stimulation index as criteria for a positive response. The data indicate that, while statistical evaluation may provide, in some instances, for small increases in sensitivity, this may be at the expense of some loss of selectivity. There are, however, insufficient data presently to draw firm conclusions regarding the relative value of statistical analysis. These studies demonstrate that the local lymph node assay is sufficiently robust to accommodate minor procedural and technical modifications without material changes in test performance.

Analysis of Variance↗
PubMed1995

Pathology considerations for, and subsequent risk assessment of, chemicals identified as immunosuppressive in routine toxicology.

Several proposals have been made with the aim of assisting in the early identification of chemicals with immunotoxic potential. The Organisation for Economic Cooperation and Development is now likely to incorporate enhanced immunopathology into the test guideline for the 28-day rat study, which may be regarded as a Tier I investigation. However, no guidelines have yet been proposed either for how the new data generated will be evaluated, or for how a subsequent risk assessment will be made. In this paper, considerations for the immunopathological assessment of the thymus, spleen, lymph nodes and bone marrow are described, together with comments on haematological and organ weight changes that may be associated with immunotoxicity. Their interpretation will depend on the doses at which changes are manifest, the quantity and quality of the effects observed and the presence and severity of other forms of toxicity. Lastly, risk assessment and the approach to Tier II testing in immunotoxicity is discussed. It is concluded that much of this work must be on a case-by-case basis, but should not in principle differ from the approach adopted for any other type of toxicity identified ina 28-day study.

Animals↗
PubMed1995

Cytokine regulation of chemical sensitization.

The skin is an immunologically active tissue. Epidermal cells, both keratinocytes and Langerhans cells (LC), produce constitutively or can be stimulated to produce a variety of cytokines, many of which play important roles in the induction and regulation of allergic responses to sensitizing chemicals. Tumor necrosis factor alpha (TNF-alpha) provides the signal for LC migration from the skin and granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin 1 (IL-1) and other cytokines effect the functional maturation of LC and their acquisition of immunostimulatory potential. The initial stimulus for induced or increased epidermal cytokine production derives from chemical exposure, or some other form of skin trauma. However, some epidermal cytokines are regulated in paracrine or autocrine fashion by other cytokines produced locally. The availability of epidermal cytokines has a major impact on the induction of sensitization and on the characteristics of immune responses to chemical allergens.

Animals↗
PubMed1995

Retrospective appraisal of the relationship between skin irritancy and contact sensitization potential.

A retrospective analysis of the association between skin irritancy and the potential to cause contact sensitization has been performed employing a historical database for 50 chemicals and formulations. Correlations between the results of Draize skin irritation tests and skin sensitizing activity measured with the occluded patch test of Buehler have been examined. Weak, but nevertheless statistically significant, associations between contact sensitization and skin irritancy have been demonstrated. It is proposed that such correlations are consistent with the irritant properties of a material exerting an important influence on the extent to which contact sensitization is induced.

Animals↗
PubMed1995

Streptozotocin: inherent but not expressed skin sensitizing activity.

We have shown previously that the alkylating agent streptozotocin (STZ) fails to induce responses in the murine local lymph node assay, a predictive test for contact sensitizing potential. In the present study, we demonstrate that this same compound when injected intradermally into the ears of mice provokes a dose-dependent induction of draining lymph node cell proliferation. These data indicate that the intrinsic immunogenicity of STZ is not displayed in the local lymph node assay under conditions of conventional topical exposure, secondary to a failure to cross the lipophilic stratum corneum in sufficient quantities. This finding has implications for the discernment of structure-activity relationships in contact sensitization.

Animals↗
PubMed1995

Tumour necrosis factor-alpha is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization.

Following skin sensitization epidermal Langerhans' cells (LC), many of which bear antigen, are stimulated to migrate from the skin and traffic via afferent lymphatics to lymph nodes draining the site of exposure. It has been proposed previously that tumour necrosis factor-alpha (TNF-alpha), a keratinocyte-derived epidermal cytokine (the expression of which is augmented following cutaneous sensitization), provides one signal for LC migration. In the experiments described here the influence of systemically administered neutralizing anti-TNF-alpha antibody on dendritic cell (DC) accumulation in draining lymph nodes has been investigated. Treatment with anti-TNF-alpha inhibited markedly the frequency of DC in draining nodes measured 18 hr following exposure to the skin allergens oxazolone and fluorescein isothiocyanate or to the non-sensitizing skin irritant sodium lauryl sulphate. Similar treatment with anti-TNF-alpha 2 hr prior to primary exposure to oxazolone impaired significantly the efficiency of skin sensitization measured 5 days later as a function of challenge-induced increases in ear thickness. The same antibody administered 18 hr following initial exposure to oxazolone was without effect on skin sensitization. These data confirm the importance of TNF-alpha for the migration of LC from the skin to draining lymph nodes and demonstrate that this cytokine is required for optimal contact sensitization.

Animals↗
PubMed1995

Identification of dendritic cells as a major source of interleukin-6 in draining lymph nodes following skin sensitization of mice.

Skin sensitization with chemical allergens is associated with the activation and proliferation of T lymphocytes within lymph nodes draining the site of exposure. These events are accompanied by the secretion of interleukin-6 (IL-6) by lymph node cells (LNC). We have investigated the cellular source of IL-6 seventy-two hours following primary exposure of mice to the contact allergen oxazolone. Immunocytochemical analyses of sections of activated lymph nodes have revealed that cells expressing IL-6 are located within the T-dependent lymph node paracortex, with none present in lymphoid follicles. Cells which expressed IL-6 cofractionated exclusively with LNC of low buoyant density, the majority of which also expressed membrane Ia and had a dendritic morphology. Depletion of dendritic cells from LNC culture was associated with a significant decrease in the secretion of IL-6 by the residual population. These data demonstrate that dendritic cells are a major source of IL-6 within lymph nodes during primary immune responses to cutaneous antigens.

Animals↗