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Biomedical subjects

M Cumberbatch

Publications and source records attributed to M Cumberbatch.

At least 55 records · Page 3Linked to original sources
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↗
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↗
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

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↗
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

Antagonism of synaptic potentials in ventral horn neurones by 6-cyano-7-nitroquinoxaline-2,3-dione: a study in the rat spinal cord in vitro.

1. The rat spinal cord in vitro has been used to assess the effect of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on the dorsal root evoked extracellular ventral root reflex (DR-VRR) and the intracellular excitatory postsynaptic potential (e.p.s.p.) in ventral horn neurones and motoneurones. 2. CNQX (1-5 microM) produces a selective and dose-dependent reduction in the amplitude of the monosynaptic component of the DR-VRR recorded from lumbar spinal segments. 3. With low intensity dorsal root stimulation CNQX selectively attenuates the amplitude of the short latency intracellular e.p.s.p. (70% reduction, P < 0.005) and its rise-time (75%, P < 0.01) without affecting the half-time to decay. 4. When high intensity stimulation is used CNQX significantly attenuates the amplitude of the e.p.s.p. (56%, P < 0.005), rise-time (76%, P < 0.01) and abolishes the short latency spike. In addition longer latency synaptic components are attenuated and the half-time to decay significantly reduced (47%, P < 0.005). 5. The results with CNQX are compared to D-aminophosphonovalerate and discussed in relation to the recruitment of low versus high threshold afferents. The data supports an involvement of non-NMDA receptors in transmission through both mono- and polysynaptic pathways in the ventral horn.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
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

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

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

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

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

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-bearing dendritic cells in the draining lymph nodes of contact sensitized mice: cluster formation with lymphocytes.

Following topical exposure to skin-sensitizing chemicals, Langerhans' cells, a significant proportion of which bear antigen, are induced to migrate from the epidermis to the regional lymph node. There is evidence that the antigen-bearing cells which arrive in the draining lymph nodes have the functional characteristics of mature dendritic cells (DC) and efficiently induce T-lymphocyte activation in vitro and contact sensitization in vivo. In contrast, freshly isolated Langerhans' cells are known to be relatively inefficient antigen-presenting cells. Evidence exists that during culture in the presence of granulocyte/macrophage colony-stimulating factor, Langerhans' cells undergo a functional maturation and assume the characteristics of dendritic cells. We have speculated that, in response to chemical exposure and the stimulus to migrate. Langerhans' cells undergo a similar maturation in vivo. To investigate this we have examined the capacity of draining lymph node DC to form antigen-independent clusters with T lymphocytes. Previous studies have confirmed that freshly isolated Langerhans' cells are unable to form such clusters. We report, however, that the antigen-bearing DC which arrive in the draining lymph nodes following skin sensitization, and which are recently derived from epidermal Langerhans' cells, efficiently form clusters with lymphocytes. Thus, antigen-bearing DC were found to have formed clusters with lymphocytes in situ in the draining lymph node, and to readily form clusters with lymphocytes in vitro. In both cases a higher proportion of lymphocytes associated with DC in clusters were T cells. An interesting observation was that DC within draining nodes appeared more efficient at cluster formation than DC in resting nodes, and that within draining nodes antigen-bearing DC formed clusters with greater affinity and/or greater stability than DC which lacked antigen. Taken together these data demonstrate that Langerhans' cell-derived antigen-bearing cells which accumulate in the draining lymph nodes following skin sensitization form clusters with lymphocytes in the manner of mature DC. This is compatible with the hypothesis that, while in transit from the skin, Langerhans' cells are subject to a functional maturation comparable to that witnessed in vitro.

Animals↗
PubMed1990

Contact hypersensitivity induces plasma interleukin 6.

Previous studies in this laboratory have revealed that elicitation reactions in contact-sensitized mice correlate closely with elevations in the serum concentration of acute-phase proteins. Regulation of the hepatic synthesis of acute-phase proteins is one of the many biological functions ascribed to interleukin 6 (IL-6). We now provide evidence that contact reactions are also associated with a rapid and substantial increase in the plasma concentration of IL-6. Quantitative assessment of plasma IL-6 may provide a useful serological method for the evaluation of experimental allergic contact dermatitis in mice, and possibly in other species.

Animals↗
PubMed1990

Requirements for antigenic competition in contact sensitivity.

The requirements for the induction of antigenic competition in murine contact sensitivity have been examined. Experiments with a variety of skin-sensitizing chemicals revealed a correlation between immunogenicity and the ability to inhibit subsequent responses to an unrelated contact allergen, oxazolone. Previous studies have suggested that, in contact sensitivity at least, antigenic competition is the consequence of a reduced lymphocyte proliferative response to the second antigen. We investigated whether the regulatory events which impair proliferation following exposure to the second antigen are induced as the result of a strong proliferative response to the first (competitor) antigen. It was found, however, that significant inhibition of the primary proliferative response to picryl chloride, by pretreatment of mice with either picryl sulphonic acid or 2,4-dinitrochlorobenzene, failed to prevent picryl chloride inducing antigenic competition for oxazolone. Our studies suggest that following topical exposure to potent skin allergens events other than proliferation in draining lymph nodes induce active immunoregulatory processes, one consequence of which is the appearance of antigenic competition.

Animals↗
PubMed1990

Phenotypic characteristics of antigen-bearing cells in the draining lymph nodes of contact sensitized mice.

Following contact sensitization of mice there is a rapid accumulation of dendritic cells (DC) within lymph nodes draining the site of exposure. Previous studies have revealed that cells bearing high levels of contact allergen can also be identified within the low buoyant density fraction of draining lymph node cells, and it has been assumed that the majority of these are DC. The purpose of the present study was to establish the phenotypic characteristics of the antigen-bearing cells which appear in lymph nodes within hours of skin painting with contact allergens, including the contact sensitizing fluorochromes fluorescein isothiocyanate (FITC) and rhodamine B isothiocyanate (RITC). Indirect immunofluorescence and two-colour immunofluorescence analyses revealed that initially all antigen-bearing cells which arrive in the draining lymph nodes express class II MHC antigens and exhibit a dendritic morphology. Phagocytic cells, cells reactive with F4/80 and anti-Mac-1 antibodies and lymphoblasts are not associated with detectable levels of antigen. In addition, although Thy-1+ cells co-fractionate with lymph node DC they are not dendritic in nature and are not associated with antigen. These data are compatible with the hypothesis that following skin sensitization epidermal Langerhans' cells bind antigen and transport it to the regional lymph nodes. In addition, it is clear that the recently described population of Thy-1+, Ia- dendritic cells within the murine epidermis do not perform a similar function.

Adenosine Triphosphatases↗