Effect of local ultraviolet irradiation on infections of mice with Candida albicans, Mycobacterium bovis BCG, and Schistosoma mansoni.

In this study, we investigated whether mice given ultraviolet (UV)-B (280-320 nm) radiation in doses sufficient to alter cutaneous immune cells and impair the induction of contact hypersensitivity would also have impaired resistance to infectious agents administered at the site of UV irradiation. C3H mice were exposed to 400 J/m2 UVR from FS40 sunlamps on four consecutive days. Immediately after the last UV treatment, groups of mice were injected subcutaneously with Candida albicans, injected intradermally (ID) with Mycobacterium bovis bacillus Calmette-Guerin (BCG), or infected percutaneously with Schistosoma mansoni in UV-irradiated skin. The induction of the delayed hypersensitivity response to C. albicans and BCG, as assessed by footpad swelling, was unaffected by UV irradiation. However, the number of viable mycobacteria recovered from the lymphoid organs of BCG-infected mice was increased significantly in the UV-irradiated animals for a period of more than 2 months. Low-dose UV irradiation of the skin at the site of infection did not influence the number of S. mansoni parasites recoverable from the internal organs of mice that had been infected with cercariae percutaneously 6 weeks earlier. We conclude that the ability of UV radiation to impair the development of cell-mediated immunity to antigens introduced in a UV-irradiated site is not universal and depends on the particular antigen administered. We hypothesize that the involvement of epidermal Langerhans cells as the primary antigen-presenting cells in the induction of cell-mediated immunity may be the critical factor in determining whether a particular immune response will be affected by local UV irradiation.     

Immunosuppression by factors released from UV-irradiated epidermal cells: selective effects on the generation of contact and delayed hypersensitivity after exposure to UVA or UVB radiation

Exposure of murine epidermal cells to UV radiation in vitro causes the release of immunoregulatory factors that mimic some of the immunosuppressive effects of in vivo UV irradiation. The purpose of this study was to investigate the spectrum of immune responses affected following i.v. injection of supernatants obtained from cultures of epidermal cells exposed in vitro to UV radiation. Treatment of primary epidermal cell cultures or transformed keratinocytes (Pam 212 cells) with UVB (280-320 nm) radiation caused the release of factors that suppressed the induction of delayed hypersensitivity to alloantigen and trinitrophenyl-modified self-antigens in syngeneic and allogeneic mice. Contrary to expectations, however, the injection of supernatants from UVB-irradiated epidermal cells had no effect on the induction of contact hypersensitivity to trinitrochlorobenzene. On the other hand, treatment of the keratinocytes with UVA radiation (320-400 nm, filtered to remove wavelengths in the UVB region) resulted in the release of a factor that suppressed contact but not delayed hypersensitivity. Neither the UVA-induced nor the UVB-induced suppressive factor inhibited the generation of an antibody response to sheep erythrocytes, indicating that, like the suppression that occurs after in vivo exposure to UV radiation, the suppression induced by factors from UV-irradiated keratinocytes is selective in nature. These data support the hypothesis that soluble keratinocyte-derived suppressive factors are involved in the induction of systemic immune suppression by UV radiation. In addition, they suggest that multiple suppressive factors, having different immunosuppressive properties, are produced by different wavelengths of UV radiation.     

Rôle of DNA damage in local suppression of contact hypersensitivity in mice by UV radiation

Abstract Exposure of mice to UVB radiation down-regulates the induction of contact hypersensitivity (CHS) responses to haptens applied to the site of irradiation. Concomittantly, the activity of antigen-presenting cells (APC) in the draining lymph nodes is decreased, and T lymphocytes that suppress the induction of CHS are induced. We assessed the röle of DNA damage in modulation of the CHS response by UV irradiation by applying liposomes containing T4 endonuclease V (T4N5) to the UV-irradiated skin. Liposomal T4N5. which increases the rate of repair of cyclobutyl pyrimidine dimers (CPD) in DNA. prevented the reduction in the CHS response, the impairment in APC function, and the induction of transferrable immune suppression. Liposomes containing heat-inactivated T4N5 did not restore immune responsiveness. In this model, hapten-bearing APC from unirradiated mice also fail to induce CHS upon injection into UV-irradiated recipients. This systemic effect of UV irradiation on APC function was also prevented by application of liposomes containing active, but not inactive, T4N5. These studies support the hypothesis that DNA damage is an essential initiator of one or more steps leading to impaired immune responsiveness after UV irradiation. They further imply that the release of cytokines that modulate APC function after UV irradiation is triggered by DNA damage.     

Topical imiquimod treatment prevents UV-light induced loss of contact hypersensitivity and immune tolerance

Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV irradiation, imiquimod alone or the combination of UV irradiation and imiquimod indicated the same in vivo synergy between imiquimod irradiation and UV irradiation in enhancing IL-12p70 production. These data suggest that topical imiquimod applications may play a role in preventing UV-induced impairment of the skin immune system, which is thought to be one of the critical events that allow the development of UV-induced skin cancers.     

Association between melanoma and dermal mast cell prevalence in sun-unexposed skin

BACKGROUND: Both exposure to intermittent intense sunlight during childhood and ultraviolet (UV) radiation-induced immunomodulation have been directly associated with melanoma development. In mice, the prevalence of dermal mast cells determines susceptibility to UVB-induced systemic suppression of contact hypersensitivity responses and thus may affect immunological responses to melanoma antigens. OBJECTIVES: To determine the relevance of murine studies of dermal mast cell prevalence to human melanoma pathogenesis. METHODS: The prevalence of mast cells was examined in sun-unexposed buttock skin of 45 melanoma patients and 68 control volunteers who had no history of skin cancer development. Buttock skin was studied because mast cell prevalence is stable with ageing and the confounding effects of environmental UV exposure are minimized. RESULTS: Using tissue immunostaining, the buttock skin from melanoma patients had a significantly higher dermal mast cell prevalence (mean +/- SEM 38 +/- 2 mast cells mm(-2)) than controls (32 +/- 2 mast cells mm(-2)) (P = 0.02). Analysis by binary logistic regression showed that the association between mast cell prevalence and melanoma outcome was not significantly altered by skin phototype. CONCLUSIONS: The immunomodulatory effects of mast cell products in UV-irradiated skin may contribute significantly to the initiation and development of human cutaneous malignant melanoma.     

UVB irradiation decreases the magnitude of the Th1 response to hapten but does not increase the Th2 response

Exposure of murine skin to low doses of ultraviolet-B (UVB) radiation before sensitization with hapten reduces the ability of antigen presenting cells (APC) in the draining lymph nodes to initiate contact hypersensitivity responses in vivo and results in the induction of hapten-specific suppressor T cells. In the present study, we tested the hypothesis that exposure of skin to UVB radiation suppresses T cell responses to hapten in vivo by altering the functions of APC, resulting in decreased stimulation of Th1 lymphocytes, which mediate contact hypersensitivity responses, and preferential activation of Th2 cells. C3H/HeN mice were exposed to either a single 2 kJ/m² dose of UVB or to 400 J/m² of UVB daily from FS40 sunlamps for four consecutive days and sensitized with fluorescein isothiocyanate on UV-irradiated skin. Draining lymph node cells were collected 18 h after sensitization and co-cultured with nylon wool-purified T cells from naive or fluorescein-immunized mice. Unseparated lymph node cells or sorter-purified fluorescein-bearing APC from UV-irradiated mice induced less T cell proliferation than APC from non-UV-exposed mice. Lymph node cells produced less Th1 and Th2-associated cytokines, interferon-gamma and interleukin-4, respectively, in response to APC from UV-irradiated animals compared with APC from unirradiated, fluorescein-sensitized mice. Thus, low doses of UV radiation do not result in preferential stimulation of Th2 response in lymph nodes, and results from cloned cell lines may incompletely reflect T cell responses in vivo.     

Antigen-presenting cells in the induction of contact hypersensitivity in mice: evidence that Langerhans cells are sufficient but not required

One explanation for the fact that certain genetically defined strains of mice prove to be resistant to effects of low dose ultraviolet B radiation on the induction of contact hypersensitivity is that ultraviolet B resistant mice possess a second pathway for antigen presentation through the skin--a pathway that is independent of epidermal Langerhans cells and beyond the reach of the damaging effects of ultraviolet B light. As a corollary, ultraviolet-B susceptible mice would be expected to be deficient in this pathway. Several experimental strategies were employed to determine whether Langerhans cells are required for the induction of contact hypersensitivity by epicutaneously applied hapten. The results reveal that tape-stripped skin supports the induction of contact hypersensitivity, whereas surgical excision of hapten-painted skin within 1 h of application fails to permit the development of contact hypersensitivity. Because the former selectively eliminates epidermal Langerhans cells while the latter deletes both Langerhans cells and dermal antigen-presenting cells, we conclude that either Langerhans cells or dermal cells are sufficient to provide antigen presentation in the induction of contact hypersensitivity. When large amounts of hapten are painted epicutaneously, or when hapten is injected subcutaneously or painted on sub-dermal tissues, contact hypersensitivity also results, indicating that induction of contact hypersensitivity does not require that antigen processing and presentation be provided by cutaneous cells. Reasons are presented for concluding that under physiologic circumstances induction of contact hypersensitivity by epicutaneous hapten application relies primarily upon the antigen-presenting capabilities of epidermal (Langerhans cells) and dermal cells.     

Squalene peroxides may contribute to ultraviolet light-induced immunological effects.

Ultraviolet (UV) irradiation is capable of producing a dose-dependent decomposition of skin surface lipids and particularly of squalene, with the concomitant generation of active lipoperoxides. The biological effects of UV-peroxidated squalene were tested, compared with those produced by synthetic lipoperoxides (cumene hydroperoxide), on some immunological parameters in vivo modified by UVB irradiation. Application of UV-peroxidated squalene as well as cumene hydroperoxide significantly inhibited the induction of contact hypersensitivity to dinitrofluorobenzene in mice, which was associated with a decrease in the number of ATPase positive cells. The effect was dose-dependent (over 40 micrograms for peroxidated squalene and over 20 micrograms for cumene) and relevant after 2 d of treatment. Down-regulation towards the applied hapten was demonstrated. The results indicate that UV-induced lipoperoxides of squalene are capable of inhibiting the induction of contact hypersensitivity in mice and suggest that, among the other photoproducts generated in humans, squalene peroxides may play a role as biochemical messengers of the biological effects of UV irradiation of the skin.     

Inhibition of the induction of contact hypersensitivity by a UV-mediated epidermal cytokine

UVB exposure (290-320 nm) of mice has been shown to cause systemic suppression of contact hypersensitivity (CHS). Because UVB radiation hardly penetrates the epidermis, epidermal cells have been anticipated to be the site of the initiation of immunosuppression. Supernatants derived from UV-irradiated BALB/c epidermal cell cultures and a keratinocyte cell line (Pam 212) were evaluated for the ability to induce suppression of CHS after i.v. injection to BALB/c mice. Injection of supernatants derived from UV-treated epidermal cells and Pam 212 cells significantly blocked induction but not elicitation of CHS. In contrast, i.v. application of supernatants derived from unirradiated cells did not inhibit CHS. Using high-performance liquid chromatography gel filtration this mediator was shown to be a low-molecular-weight protein (15-50 kD). Moreover UV-mediated inhibitor production seems to be confined to epidermal cells since neither P 388 macrophages nor L 929 fibroblasts released this inhibitory cytokine. Therefore UV radiation may induce epidermal cells to produce an inhibitor of CHS which is distinct from prostaglandins and leukotrienes and may participate in the regulation of UV-mediated local as well as systemic immunosuppression.     

Preservation of the delayed-type hypersensitivity response to alloantigen by xyloglucans or oligogalacturonide does not correlate with the capacity to reject ultraviolet-induced skin tumors in mice

Chronic exposure to ultraviolet radiation suppresses T cell-mediated immune responses and induces the formation of suppressor T lymphocytes that prevent the rejection of highly antigenic ultraviolet-induced skin cancers in mice. Tamarind seed xyloglucans and pectinic oligogalacturonides prevent suppression of delayed-type hypersensitivity immune responses in mice to Candida albicans and alloantigen caused by a single exposure of ultraviolet radiation. We therefore investigated the ability of these poly/oligosaccharides to prevent suppression of T cell-mediated immune responses and suppressor cell induction during chronic ultraviolet irradiation and to preserve the capacity of ultraviolet-irradiated mice to reject a transplanted, highly antigenic, ultraviolet-induced tumor. C3H/HeN mice were treated 3x per week for 12 wk with 15 kJ per m2 ultraviolet B radiation followed by application of the polysaccharides/ oligosaccharides. The delayed-type hypersensitivity responses to C. albicans and alloantigen were measured after 1, 6, and 12 wk of treatment. Following the 12th wk of treatment the remaining mice were injected with the highly antigenic ultraviolet-induced, syngeneic tumor cell line UV5497-5. The polysaccharides/oligosaccharides protected delayed-type hypersensitivity responses to C. albicans but not contact hypersensitivity responses to dinitrofluorobenzene for up to 6 wk of ultraviolet radiation after which protection declined and suppressor cells were observed. In contrast, the delayed-type hypersensitivity response to alloantigen was preserved for the entire 12 wk of ultraviolet irradiation. Despite protection of immunity to alloantigen, the transplanted tumor cells grew equally well in all ultraviolet-irradiated animals. These results indicate that delayed-type hypersensitivity responses are heterogeneous and that delayed-type hypersensitivity to alloantigen is not a surrogate marker for rejection of ultraviolet-induced skin tumors.     

Effects of ultraviolet irradiation on surface marker expression by epidermal immunocompetent cells and contact sensitization to dinitrofluorobenzene in mice

We studied the effects of ultraviolet (UV) irradiation on murine epidermal Ia-positive Langerhans cells (Ia + LC) and Thy-I-positive dendritic epidermal cells (Thy-I + dEC). We also studied contact hypersensitivity to dinitrofluorobenzene (DNFB) introduced through UV-treated epidermis. C3H/HeN mice were exposed to UVB or 8-methoxypsoralen plus UVA (PUVA). UVB and PUVA treatment led to a dramatic reduction in surface marker expression of both Ia + LC and Thy-I + dEC. High-dose UVB irradiation (360 J/m2) interfered with contact hypersensitivity to DNFB; the density of Ia + LC may thus be related to the sensitizing potential. In contrast, low-dose UVB (120 J/m2) and PUVA treatment had little effect on contact hypersensitivity despite a marked reduction in Ia + LC. The density of Thy-I + dEC appeared not to be associated with contact hypersensitivity. These results suggest that there may be a Langerhans cell density-independent mechanism for the induction of contact hypersensitivity.     

Two phenotypically distinct T cells are involved in ultraviolet-irradiated urocanic acid-induced suppression of the efferent delayed-type hypersensitivity response to herpes simplex virus, type 1 in vivo

When UVB-irradiated urocanic acid, the putative photoreceptor/mediator for UVB suppression, is administered to mice it induces a dose-dependent suppression of the delayed-type hypersensitivity response to herpes simplex virus, type 1 (HSV-1), of similar magnitude to that induced by UV irradiation of mice. In this study, the efferent suppression of delayed-type hypersensitivity by UV-irradiated urocanic acid is demonstrated to be due to 2 phenotypically distinct T cells, (Thy1+, L3T4-, Ly2+) and (Thy1+, L3T4+, Ly2-). The suppression is specific for HSV-1. This situation parallels the generation of 2 distinct T-suppressor cells for HSV-1 by UV irradiation of mice and provides further evidence for the involvement of urocanic acid in the generation of UVB suppression.     

Ultraviolet A irradiation of the eye induces immunomodulation of skin and intestine in mice via hypothalomo–pituitary–adrenal pathways

Irradiation by ultraviolet A (UVA) initiates the suppression of skin contact hypersensitivity. However, the change in the whole body immunity by UVA irradiation of the eye is still unknown. The mice used in this study were separated into four groups namely: a control, UVA irradiation of the eye, UVA irradiation of the ear, UVA irradiation of the eye + a glucocorticoid receptor antagonist (RU-486) administrated, UVA irradiation of the eye with an adrenalectomy and non-irradiation + cortisol administrated groups. The eye or ear was locally exposed to UVA after covering the remaining body surface with aluminum foil at a dose of 110 kJ/m² using a FL20SBLB-A lamp. Plasma adrenocorticotropic hormone, cortisol, and interleukin-10 (IL-10) content increased by UVA irradiation of the eye. In addition, UVA irradiation of the eye induced down-regulation of the epidermal Langerhans cells in the ear and the up-regulation of the mucosal immunoglobulin A (IgA) in the intestine. However, the changes in the epidermal Langerhans cells and mucosal IgA of UVA irradiation of the eye are not induced either by the RU-486 treatment or an adrenalectomy. These results clearly indicate that the signal evoked by UVA irradiation of the eye, through the hypothalamo–pituitary–adrenal pathway, up-regulated the production of glucocorticosterone. This hormone controls immunity, and the possibility that it performed a living body defense for UVA exposure was thus suggested.     

Ratio of Langerhans cells to Thy-1+ dendritic epidermal cells in murine epidermis influences the intensity of contact hypersensitivity

We have initiated a series of studies in vivo to investigate the physiologic role of Langerhans cells and Thy-1+ dendritic epidermal cells in the development and regulation of contact hypersensitivity. The density of I-A+ Langerhans cells and Thy-1+ dendritic epidermal cells in ammonium thiocyanate-separated epidermal sheets was determined in ten strains of inbred mice using immunofluorescence microscopy with monoclonal anti-I-A and anti-Thy-1 antibodies. Mice of different inbred strains were sensitized by painting the left ear with varying doses of either oxazolone or trinitrochlorobenzene. From five to 20 days after sensitization, groups of mice were challenged with the relevant antigen and the intensity of contact hypersensitivity, as measured by ear swelling, was determined. We then determined whether the intensity and/or duration of contact hypersensitivity in different strains of mice was influenced by the density of Thy-1+ dendritic epidermal cells or the ratio of I-A+ Langerhans cells to Thy-1+ dendritic epidermal cells. We found that there was marked variability in the density of Thy-1+ dendritic epidermal cells and I-A+ Langerhans cells in the ten strains of mice studied. The ratio of I-A+ Langerhans cells to Thy-1+ dendritic epidermal cells ranged from 0.5 in C57BL/10J mice to greater than 22 in A/J and BALB/cByJ mice. When small amounts of contact sensitizers were used to induce contact hypersensitivity (e.g., 20 micrograms of oxazolone or trinitrochlorobenzene), there was consistent strain variability in the intensity of ear swelling. There was a significant correlation between the ratio of I-A+ Langerhans cells to Thy-1+ dendritic epidermal cells and the intensity of contact hypersensitivity (Pearson's correlation coefficient 0.85, p = 0.002). Strains with the highest ratios of I-A+ Langerhans cells to Thy-1+ dendritic epidermal cells had the most ear swelling. There were no consistent differences in the duration of contact hypersensitivity observed among the ten different strains. Our results indicate that Thy-1+ dendritic epidermal cells may play a physiologic role in down-regulating contact hypersensitivity in vivo.     

Nerve growth factor, neuropeptides, and mast cells in ultraviolet-B-induced systemic suppression of contact hypersensitivity responses in mice

The induction of systemic immunosuppression following ultraviolet B radiation exposure has been linked with the release of inflammatory and immunomodulatory mediators by cells of the epidermis and dermis. Nerve growth factor has not previously been linked with ultraviolet-B-induced immunosuppressive effects. Nerve growth factor antibodies abrogated ultraviolet-B-induced systemic suppression of contact hypersensitivity responses in BALB/C mice. Subcutaneous injection of nerve growth factor (20 microg per mouse) into dorsal skin 5 d before hapten sensitization on ventral skin suppressed contact hypersensitivity responses in mast-cell-replete but not Wf/Wf mast-cell-depleted mice. Nerve growth factor injected 24 h prior to challenge was not able to suppress the efferent phase of the contact hypersensitivity response. Subcutaneous injection of nerve growth factor (20 microg per mouse) did not suppress contact hypersensitivity responses in capsaicin-pretreated (neuropeptide-depleted) BALB/c mice, and thus sensory c-fibers are necessary for nerve-growth-factor-mediated systemic suppression of contact hypersensitivity responses. Increased concentrations of nerve growth factor within epidermal keratinocytes 8 h after ultraviolet B irradiation were confirmed immunohistochemically. These findings support a role for keratinocyte-derived nerve growth factor via its action on sensory c-fibers, and subsequent release of neuropeptides to mediate mast cell degranulation in systemic suppression of contact hypersensitivity responses in mice following ultraviolet B exposure.     

Tumor antigen presentation by dermal antigen-presenting cells

Several phenotypes of antigen-presenting cells are present in the dermis, where they presumably function to present encountered antigens for immune responses. This study examined the ability of dermal antigen-presenting cells to present tumor-associated antigens for the induction of in vivo antitumor immunity. Total murine dermal cells were exposed either to medium alone or to medium containing tumor-associated antigens from S1509a tumor cells. Subsequently, dermal cells were injected subcutaneously at weekly intervals into na?ve mice for a total of three immunizations. One week following the final immunization, mice were challenged with living tumor cells. In these experiments, dermal cells pulsed with tumor-associated antigens induced protective immunity to tumor growth. Dermal cells exposed to tumor-associated antigens were also able to elicit delayed-type hypersensitivity after footpad injection into mice previously immunized against S1509a tumor cells. The ability to present tumor-associated antigens for both induction of antitumor immunity and elicitation of delayed-type hypersensitivity was dependent on I-A+ cells and was genetically restricted. Finally, dermal cells tended towards eliciting a greater antitumor delayed-type hypersensitivity response than epidermal cells. These results show that the murine dermis contains antigen-presenting cells capable of processing S1509a tumor antigens for the generation of protective antitumor immunity in vivo.     

Glucocorticoid effects on contact hypersensitivity and on the cutaneous response to ultraviolet light in the mouse

A single exposure to 254 nm ultraviolet irradiation (UV) can systemically suppress experimental sensitization to the simple allergen 2,4-dinitro, 1-chlorobenzene (DNCB) in the mouse. We show here that topical application at the site of irradiation of the 21-oic acid methyl ester derivative of the synthetic glucocorticoid triamcinolone acetonide (TAme) prevents UV suppression of sensitization. That is, mice painted with TAme at the site of UV exposure developed normal contact hypersensitivity (CH); mice exposed to UV only, like mice treated with the parent compound triamcinolone acetonide (TA), failed to be sensitized by DNCB applied to a distal site. TAme is inactivated rapidly by plasma esterases, so its effect is thought to be confined to the skin. Apparently, TAme blocked the cutaneous signal(s) for systemic suppression of CH. Histologically, irradiated skin exhibited mild inflammation and hyperproliferation, but these effects were greatly exaggerated and prolonged in the UV + TAme-treated skin, independent of sensitization at the distal site. The infiltrate consisted mostly of neutrophils and lacked the round cells characteristic of cell-mediated immunity. Apparently, normal immune suppression by UV prevented this vigorous reaction to irradiated skin. Applied together with DNCB. TAme blocked sensitization. It also prevented response to challenge by DNCB in previously sensitized animals. However, unlike the parent compound triamcinolone acetonide (TA), Budesonide or Beclomethasone diproprionate, each of which can penetrate the epidermis in active form, TAme had no effect on sensitization when applied at a distal site. Likewise, TAme did not affect plasma B (17-desoxycortisol) levels, whereas the other three compounds reduced plasma B tenfold, as expected of compounds causing adrenal-pituitary suppression. The results as a whole show that glucocorticoids can specifically inhibit cutaneous steps in induction of cell-mediated immunity or its suppression, and can, at the site of challenge, prevent its expression in CH.     

Effects of whole-body UVB irradiation on cytokine production by peripheral blood mononuclear cells from stage I melanoma patients

Abstract  Ultraviolet (UV) radiation causes significant impairment of immunological function in human skin. The immunosuppressive effects of UV radiation are thought to be due to local release of cytokines by human keratinocytes, leading to impaired function of epidermal antigen-presenting cells (APC) and failure to induce cutaneous delayed-type hypersensitivity (DTH) reactions. Recent studies have shown that individuals susceptible to UV-induced suppression of DTH may be more prone to develop skin cancer including malignant melanoma (MM). Since the causal relationship between UV radiation and the induction of MM still seems obscure, we investigated the immunological reactions of peripheral blood mononuclear cells (PBMC) to whole-body irradiation with UVB in 15 stage I melanoma patients as compared to PBMC from normal volunteers matched for age, gender and skin type. Whole-body irradiation was performed with 0.8 minimal erythema dosages on five consecutive days. Peripheral blood was obtained before and after the procedure. Overall, there were no major effects of UVB irradiation on peripheral lymphocyte subsets and proliferation of PBMC from patients or normal controls, but UVB irradiation led to a significant increase in PWM-stimulated production of IL-6, IL-2R and TNF by PBMC. These changes were independent of the individual UVB dosages administered and appeared in both groups similarly. UVB irradiation did not lead to significant changes on IL-1 and IL-2 expression by PBMC. Our results suggest that PBMC participate in the cytokine response to UV, even in the absence of inflammatory reactions, but that this participation is not specific to MM patients. Received: 4 November 1999 / Revised: 15 March 2000 / Accepted: 17 March 2000     

The skin as an immunologic organ. A tribute to Marion B. Sulzberger

The early experiments of Marion B. Sulzberger suggested that the skin played a vital role in the generation of allergic contact dermatitis and other delayed type hypersensitivity reactions. This lecture is presented in the historical context of Dr. Sulzberger's lifework and interest in mechanisms involved in delayed type hypersensitivity. I review recent studies indicating that epidermal Langerhans cells are critical for many immune responses involving the skin and that keratinocytes may also play a role in epidermal immunologic functions in that they secrete factors that may modulate various types of skin reactions. The interaction between these cells and factors and lymphoid cells indicates, as Dr. Sulzberger implied, that the skin should be viewed as an organ of immunity.     

Inhibition of irritation and contact hypersensitivity by phenoxyacetic acid methyl ester in mice

New anti-irritant treatments are required to prevent irritation and sensitization reactions to consumer medicines and dermatological drugs. We report here that phenoxyacetic acid methyl ester (PAME) is an effective agent to prevent and treat irritant and allergic contact dermatitis. Balb/c mice skin-treated with 1% PAME do not lose weight relative to vehicle-treated mice, nor is it irritating to mouse skin. Topical PAME prevents skin irritation to a wide variety of irritants including: arachidonic acid, capsaicin, sodium lauryl sulfate (SLS), disodium laureth sulfosuccinate and tetradecanoylphorbol-13-acetate. Histological studies showed that 1% PAME greatly diminished dermal neutrophilic infiltration and dermal capillary vessel dilation, and prevented epidermal hyperproliferation and hyperkeratosis that accompanies detergent (SLS)-induced skin irritation. Topical PAME inhibited ear swelling following ear challenge during the elicitation phase of contact hypersensitivity in mice sensitized with 1-chloro-2, 4-dinitrochlorobenzene (DNCB), oxazolone and the hair coloring dye rho-phenylenediamine (PPD). Finally, topical administration of 1% PAME prior to PPD or DNCB sensitization prevented the induction phase of contact hypersensitivity. These results indicate that PAME represents a potential new category of potent topical anti-inflammatory agents.