Inelastic scattering of quasifree electrons on O7+ projectiles.
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Journal Article↗
Biomedical subjects
S Grabbe
Publications and source records attributed to S Grabbe.
Interleukin-12 prevents ultraviolet B-induced local immunosuppression and overcomes UVB-induced tolerance.
Ultraviolet (UV) light abrogates contact hypersensitivity (CHS) responses and induces hapten-specific tolerance. Because Th-1 cells are critically involved in CHS and are induced to develop by the cytokine interleukin (IL)-12, we asked whether IL-12 might overcome UV-induced local immunosuppression. C3H/HeN mice exposed to low doses of UV light over 4 d and hapten sensitized through the irradiated skin area with dinitrofluorobenzene showed profound inhibition of the CHS response, which was completely prevented upon intraperitoneal injection of murine recombinant IL-12 (rIL-12) after the last UV exposure. UV-treated mice resensitized 14 d after the first challenge displayed hapten-specific tolerance, whereas UV-exposed mice injected with rIL-12 before the first sensitization exhibited a vigorous CHS response. Furthermore, mice that were initially sensitized through UV-exposed skin also produced a significant CHS reaction when they received rIL-12 before resensitization. Adoptive transfer of spleen and lymph node cells from UV-irradiated mice treated with rIL-12 had no effect on the CHS response in recipient mice, whereas transfer of cells from UV-treated mice inhibited the immune response. These findings demonstrate that rIL-12 can prevent UV-induced local immunosuppression and overcome UV-induced hapten-specific tolerance.
Animals↗
Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity.
At first sight, the pathophysiology of contact hypersensitivity (CHS) seems to be well understood. Whereas this may apply to some extent to the sensitization phase of CHS, very little is actually known about the elicitation phase of this response. Although the mechanisms of T-cell priming (sensitization) may be more interesting for immunologists, those involved in the elicitation of T cell-mediated secondary responses are more relevant for clinical management because clinically manifest allergic contact dermatitis always reflects the effector phase of CHS. This review summarizes the role of different cellular components and soluble mediators on the elicitation of CHS. In addition, recent studies revealed that, besides selective activation of antigen-specific T cells, epicutaneous application of haptens has a number of direct effects on the cutaneous immune system. The most relevant of these are induction of cytokine and chemokine secretion and endothelial activation. In an attempt to integrate data on this issue, it is proposed that the capacity of contact allergens to directly induce proinflammatory signals in the skin is of relevance and perhaps essential for elicitation of clinically manifest CHS responses. Moreover, the proinflammatory effect of allergens themselves may explain the strict dose dependency of CHS responses and the relatively high concentrations of allergens needed for elicitation of CHS because allergens evoke nonspecific irritation only when applied in relatively concentrated form.
Allergens↗
Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity.
Whereas epidermal Langerhans cells (LC) are thought to be the principal APCs for initiation of contact hypersensitivity (CHS) responses, their role as APC in the effector phase of CHS is still unclear. It is currently thought that LC elicit the CHS response by presenting Ag to trafficking Ag-specific T cells within the skin. To test this hypothesis, we removed the majority of resident LC at the site of CHS challenge by topical application of various steroid creams to one ear in BALB/c mice (> 85% LC depletion). Either 2 days before or 4 days after steroid treatment of the ear, mice were sensitized on the abdomen with the hapten trinitrophenyl and challenged 10 days later at the steroid-pretreated ear. At that time point, direct anti-inflammatory effects of the steroid were no longer present. Surprisingly, CHS responses were markedly stronger at the sites of prior steroid application when compared with vehicle-treated controls, indicating that depletion of most of the resident LC not only fails to impair, but enhances, the expression of CHS significantly. UV irradiation or application of croton oil at the challenge site, as well as systemic steroid application, all of which are alternative methods of diminishing the number of epidermal LC, also significantly up-regulated CHS. In contrast, irritant dermatitis and sensitization or elicitation of CHS in steroid-treated mice at distant sites, as well as delayed-type hypersensitivity responses against the same hapten, were unaffected by topical steroid pretreatment. In conclusion, our data suggest that resident LC are not the relevant APC in the effector phase of CHS and that they may even provide down-regulatory, rather than stimulatory, signals during elicitation of CHS.
Administration, Topical↗
IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells.
IL-10 inhibits Langerhans cell (LC) Ag presentation to Th1 clones. As LC are capable of presenting tumor-associated Ags (TAA) for primary and secondary tumor immune responses, we examined the effect of IL-10 on LC Ag presentation in a model of immunity to the S1509a spindle cell tumor (H-2a). Because induction of immunity to S1509a requires exposure of LC to granulocyte-macrophage (GM)-CSF, this system also allowed us to study the regulatory interactions of GM-CSF and IL-10 on LC. Naive CAF1 (H-2a/d) mice could be immunized against S1509a by injection with GM-CSF-exposed and TAA-pulsed epidermal cells (EC) as assessed by inhibition of the growth of inoculated tumor cells. Incubation of EC in IL-10 before GM-CSF exposure completely inhibited Ag presentation in this system. Significantly, neither co-incubation of EC in IL-10 and GM-CSF (without preincubation in IL-10) nor IL-10 treatment after GM-CSF incubation was able to exert a down-regulatory effect. The ability of IL-10 to modulate EC presentation of TAA for a secondary immune response was also examined. EC were pulsed with TAA in vitro and then injected into a hind footpad of tumor-immune mice with 24 h swelling assessed as a measure of delayed-type hypersensitivity. Preincubation in IL-10 before TAA exposure significantly inhibited elicitation of delayed-type hypersensitivity with or without subsequent exposure to GM-CSF. Co-incubation of EC in IL-10 and GM-CSF or exposure to IL-10 after GM-CSF led to a normal response. These data indicate that IL-10 may serve as an important regulator of LC Ag-presenting function for tumor immune responses. IL-10 appears to specifically prevent the GM-CSF-induced maturation of LC Ag-presenting function when treatment with IL-10 occurs before exposure to GM-CSF but does not reverse the established mature state.
Animals↗
Dendritic cells as initiators of tumor immune responses: a possible strategy for tumor immunotherapy?
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Animals↗
Modulation of Langerhans cell function by epidermal nerves.
Many if not most epidermal Langerhans cells appeared to be closely associated anatomically with calcitonin gene-related peptide (CGRP)-containing nerves as determined by confocal laser scanning microscopy. Furthermore, a small proportion of Langerhans cells had immunoreactive CGRP at or near their cell surfaces, suggesting that nerves are capable of depositing CGRP at or near Langerhans cells. CGRP inhibited Langerhans cell antigen-presenting capability for elicitation of delayed-type hypersensitivity in immunized mice to present alloantigens in the mixed epidermal cell-lymphocyte reaction and to present a protein antigen to a responsive hybridoma. As a whole, these data suggest the possibility that products of nerves within the epidermis might serve to regulate Langerhans cell function. The apparent apposition of epidermal nerves with Langerhans cells suggests a possible locus of interaction between the nervous system and the immune system within the skin.
Animals↗
Coexisting lichen planus and subacute cutaneous lupus erythematosus.
We report a patient who presented with annular erythematous skin lesions and generalized lichenoid papules. The clinical picture as well as histopathology, immunofluorescence and laboratory findings indicated coexistence of subacute cutaneous lupus erythematosus (SCLE) and extensive generalized lichen planus (LP). Clinically and histologically, SCLE-like lesions appeared to progress into LP-like lesions, supporting the concept of a common autoimmune pathophysiology in these disorders. Treatment with cyclosporin A (2.5 mg/kg body weight) resulted in a significant remission of the inflammatory skin lesions.
Aged↗
Epidermal cell presentation of tumor-associated antigens for induction of tolerance.
Intravenous administration of hapten-coupled epidermal cells (EC) induces tolerance in mice. To assess the relevance of this observation to cutaneous tumors, the ability of EC to induce tolerance to the S1509a spindle cell tumor (H-2a) was examined. ECs were prepared from CAF1 (H-2a/d) mice and the supernatant from a freeze-thaw lysate of S1509a cells was used as a source of soluble tumor-associated Ag (TAA). ECs were incubated in TAA or medium alone followed by washing. Two hundred thousand TAA-pulsed ECs, non-TAA-pulsed ECs, or TAA-pulsed ECs killed by freeze-thawing were injected i.v. into groups of CAF1 mice. To determine whether this regimen induced tolerance, a tumor-specific delayed-type hypersensitivity (DTH) response was measured in mice subsequently immunized to the S1509a tumor. To assess the degree of immunity induced in these animals, ECs were prepared and deleted of Thy-1-bearing cells by Ab and complement-mediated lysis. These cells were then pulsed with TAA and 5 x 10(5) were injected into the right hind footpad of each mouse. Footpad swelling was assessed at 24 to 48 h as a measure of the DTH. Mice primed i.v. with viable TAA-pulsed EC but not killed TAA-pulsed EC demonstrated a greatly suppressed DTH response. Other experiments demonstrated that exposure of EC to a dose of ultraviolet radiation (200 J/m2), which inhibits the ability of these cells to induce immunity by subcutaneous injection either before or after TAA pulsing, did not prevent induction of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Interferon-gamma inhibits tumor antigen presentation by epidermal antigen-presenting cells.
Murine I-A+ epidermal antigen-presenting cells (APCs) have been shown to be capable of presenting soluble tumor fragments (TFs), as a source of tumor-associated antigens (TAAs), for primary and secondary tumor immune responses. In this study we investigated whether incubation of epidermal APCs in interferon-gamma (IFN-gamma) modulates their ability to present TAA and whether the effects of IFN-gamma on the presentation of tumor antigen correspond to its effects on alloantigen presentation in both primed and unprimed systems. Our results show that three weekly subcutaneous injections of naive mice with GM-CSF-cultured but not with fresh TAA-pulsed epidermal APCs induce protective tumor immunity in naive mice and that the immunostimulatory effect of GM-CSF in this system is abrogated by coculture of epidermal cells in IFN-gamma. Furthermore, epidermal APCs are able to present TAA to primed, tumor-immune mice, as assessed by the elicitation of tumor-specific delayed-type hypersensitivity after injection of TAA-pulsed epidermal APCs. IFN-gamma was found to inhibit tumor antigen presentation by freshly prepared epidermal APCs in this system. The effects of IFN-gamma on the presentation of tumor antigen correlated well with its effects on the primary and secondary mixed epidermal cell-lymphocyte reaction, indicating that IFN-gamma differentially modulates the function of epidermal APCs with regard to induction versus elicitation of immunity.
Animals↗
A unique non-Langerhans cell histiocytosis with some features of generalized eruptive histiocytoma.
A symmetric eruption of hundreds of coalescent small red macules and a few slightly elevated papules sparing the flexures was observed in a 73-year-old man. Light microscopic examination showed loose aggregates of small and large histiocytic cells. Electron microscopy showed an absence of Langerhans cell granules and lipid droplets. Features shared with generalized eruptive histiocytoma were the symmetry of the eruption sparing the flexures, the blue-red coloration, and the absence of lipid-containing foam cells and multinucleated giant cells. However, the primary occurrence of macules rather than papules or nodules, the tendency of the macules to coalesce, and the dimorphic histiocytoid infiltrate are not found in generalized eruptive histiocytoma. Nevertheless, immunohistochemistry confirmed that this unique condition is a form of MS-1+ cutaneous non-Langerhans cell histiocytosis.
Aged↗
Projectile-charge-state dependence of 0 degrees binary-encounter electron production in 30-MeV Oq++O2 collisions.
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Journal Article↗
Interleukin 1 alpha but not transforming growth factor beta inhibits tumor antigen presentation by epidermal antigen-presenting cells.
Cutaneous I-A+ Langerhans cells are the principal antigen-presenting cells within the epidermis, capable of both initiating and eliciting CD4-dependent immune reactions. We recently demonstrated that epidermal Langerhans cells can present tumor-associated antigens and thus may be important in cutaneous tumor immunity. Despite the ability of Langerhans cells to present tumor antigens, they generally fail to induce protective tumor immunity against growing tumors in situ. We therefore investigated whether locally produced cytokines may be able to down-regulate the presentation of tumor-associated antigens and alloantigen by epidermal antigen-presenting cells in primed as well as in unprimed systems in vivo and in vitro. Naive syngeneic mice could be successfully immunized against the spindle cell tumor S1509a by injecting them with granulocyte-macrophage colony-stimulating factor-exposed and tumor-associated antigen-pulsed epidermal cells three times at weekly intervals. Co-incubation of epidermal cells in granulocyte-macrophage colony-stimulating factor and interleukin-1 alpha inhibited tumor-antigen presentation by epidermal antigen-presenting cells in this system and also inhibited alloantigen presentation in the primary mixed epidermal cell-lymphocyte reaction. Tumor necrosis factor-alpha appeared to be a significant mediator of the inhibitory effect of interleukin-1 alpha on the ability of epidermal antigen-presenting cells to induce protective tumor immunity, because addition of anti-tumor necrosis factor-alpha antibody abrogated the observed effect of interleukin-1 alpha. However, the effects of interleukin-1 alpha and tumor necrosis factor-alpha differed with regard to presentation of tumor-associated antigens by epidermal antigen-presenting cells in a primed system. Whereas incubation of epidermal cells in interleukin-1 alpha before or after tumor antigen pulse inhibited their ability to elicit a delayed-type hypersensitivity response against S1509a tumor-associated antigens in tumor-immune mice, culture in tumor necrosis factor-alpha significantly enhanced delayed-type hypersensitivity. Again, these in vivo data corresponded well to similar results obtained in vitro using the secondary mixed epidermal cell-lymphocyte reaction. Incubation of epidermal cells in transforming growth factor-beta, which has been shown to down-regulate T-cell-mediated immune responses in other systems, did not suppress tumor immunity in our assays. Thus, interleukin-1 alpha may be an important regulator of Langerhans cell antigen-presenting function, having effects that are partially mediated via interleukin-1 alpha-induced up-regulation of tumor necrosis factor-alpha secretion within the skin.
Animals↗
In vivo effects of interleukin-10 on contact hypersensitivity and delayed-type hypersensitivity reactions.
Interleukin (IL) 10 is a recently discovered cytokine, originally isolated from T-helper 2 (Th2) cells, which inhibits cytokine production of T-helper 1 (Th1) cells. Because Th1 cells appear to be of importance during the contact hypersensitivity reaction (CHS) we hypothesized that IL-10 might modulate the outcome of CHS in vivo. Intraperitoneal injection of murine recombinant IL-10 (1000 ng) into naive mice 24, 72, or 120 h before sensitization by epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) did not affect ear swelling when ears were challenged 5 d later. However, intraperitoneal injection of IL-10 into already sensitized mice 24 h before challenge resulted in a significant suppression of the ear swelling response, suggesting that under the conditions employed IL-10 is able to block the effector phase, but not the induction phase of CHS in vivo. The suppression could be reversed by the concurrent injection of an IL-10 antibody. Moreover, heat inactivation of native IL-10 resulted in loss of the inhibitory capacity. When mice were sensitized by subcutaneous injection of trinitrophenyl-coupled spleen cells (DTH) instead of epicutaneous application of the hapten (CHS), intraperitoneally-injected IL-10 suppressed the effector phase, but also the induction phase of DTH. IL-10 did not inhibit the toxic ear-swelling response induced by topical application of two irritants tested (croton oil or benzalkonium chloride). The capacity of IL-10 to suppress the effector phase of CHS and DTH supports an important role for this cytokine in the downregulation of type IV immune reactions in vivo. The finding that IL-10 suppresses the induction of DTH, but not of CHS, further suggests that CHS and DTH are related but distinct immune reactions.
Animals↗
Characterization of cutaneous antigen presentation in partially inbred miniature swine.
MHC class I and II-defined, partially inbred miniature swine have recently become available as a large animal model in transplantation immunology. To investigate cutaneous immunocompetence in this model, cutaneous antigen presenting cell (APC) function was assessed. For morphologic analysis, punch biopsies were examined by electron microscopy. By this technique, epidermal Langerhans cells bearing typical Birbeck granules could be detected. For functional studies, epidermal cell (EC) suspensions were prepared from split thickness skin specimens. Using FACS analysis, freshly prepared epidermal cell suspensions contained 1.8-4.7% MHC class II-positive cells. These EC potently stimulated allogeneic nylon wool-enriched peripheral blood T cells in the primary mixed EC-lymphocyte reaction. For in vivo assessment of cutaneous APC function, EC suspensions enriched for or depleted of class II-positive EC were generated by panning of class II-positive EC using mouse anti-MHC class II antibodies and anti-mouse IgG-coated petri dishes. EC were then coupled to the hapten trinitrophenol (TNP) and injected s.c. into autologous or MHC-mismatched pigs twice at a one week interval. One week later, pigs were challenged by s.c.-injection of 0.5-1 x 10(7) TNP-coupled or uncoupled EC. Autologous unseparated EC as well as EC enriched for MHC class II-positive cells were able to sensitize naive animals against TNP, whereas neither TNP-coupled EC depleted of class II-positive APC, MHC-mismatched EC coupled to TNP, nor uncoupled EC induced immunity to TNP. Our data indicate that inbred miniature swine possess competent cutaneous APC which are able to induce cutaneous APC which are able to induce cutaneous immunity in a matter similar to Langerhans cells in murine or human skin.
Animals↗
Production of interleukin-6 and granulocyte-macrophage colony-stimulating factor by murine iris and ciliary body explants.
PURPOSE: To examine the ability of murine iris-ciliary body explants to produce cytokines with proinflammatory activities. METHODS: Supernatants derived from murine iris-ciliary body (I-CB) tissue explants cultured (four per well in 1 ml medium) in the presence of indomethacin were analyzed for the production of IL-1, IL-2, IL-3, IL-6, tumor necrosis factor-alpha/beta (TNF alpha/beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Analysis was performed by thymocyte costimulation, growth factor-dependent cell proliferation, TGF-beta-sensitive mink lung epithelial cell proliferation, and enzyme-linked immunosorbent assays (ELISA). RESULTS: Supernatants from I-CB explants cultured in vitro for 24 hours contained significant thymocyte costimulatory activity. This activity was fully neutralized by a combination of antisera to IL-1 and IL-6, and ELISA analysis confirmed that IL-6 was a significant component of the supernatant (402.7 pg/ml). TNF alpha/beta were also found in low concentrations (approximately 2.0 U/ml) by ELISA analysis, whereas IL-2 and IL-4 were not detectable. Significant amounts of GM-CSF (15.8 U/ml), but no IL-3, were detected. CONCLUSIONS: These results demonstrate that normal I-CB tissue contains cells capable of producing IL-6, GM-CSF, and IL-1. Because of the proinflammatory nature of IL-6 and IL-1, and the ability of GM-CSF, IL-1, and IL-6 to enhance functional capabilities of antigen presenting cells, regulation of the production of these cytokines may contribute significantly to the maintenance of the immunologic status of this regional site.
Animals↗
Mechanisms of ultraviolet radiation carcinogenesis.
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Animals↗
Deficient antigen presentation by Langerhans cells from athymic (nu/nu) mice. Restoration with thymic transplantation or administration of cytokines.
Epidermal Langerhans cells (LC) are a unique subtype of I-A+ dendritic cells able to present Ag for CD4-dependent immune responses. To investigate whether cutaneous Ag presentation is regulated by thymic elements or soluble factors produced by thymus-derived cells, we compared LC function in athymic nude mice and euthymic normal controls. Examination of the ability of LC to present alloantigens to T cell-enriched responder populations, and insulin to an insulin-specific T cell hybridoma, demonstrated that this function is deficient in LC from inbred and outbred strains of congenitally athymic (nu/nu) mice compared with euthymic litter mates. Adoptive transfer of thymic tissue from euthymic to athymic mice reconstituted the ability of LC derived from athymic mice to present alloantigens. To investigate whether an altered local cytokine microenvironment was responsible for the diminished LC function in athymic mice, various cytokines were administered in vivo and in vitro before determination of alloantigen presentation by epidermal cells from athymic and euthymic mice. Continuous intraperitoneal infusion of granulocyte-macrophage colony stimulating factor (GM-CSF) or TNF-alpha, but not IL-1 alpha or IL-2, restored alloantigen presenting ability in athymic LC. In vitro preincubation of LC in GM-CSF or TNF-alpha but not in other cytokines tested also reconstituted alloantigen presentation by LC from athymic mice in most, but not all, of the experiments performed. Furthermore, analysis of cytokine production by epidermal cells in athymic and euthymic mice revealed that epidermal cells from athymic mice produce less GM-CSF and more TNF-alpha, but normal amounts of various other cytokines. However, reconstitution of athymic mice with thymic tissue did not result in normalization of GM-CSF or TNF-alpha production by epidermal cells. These data suggest that LC Ag presenting ability is regulated by thymic factors and that adequate function of cutaneous APC in situ may require the continuous presence of sufficient amounts of cytokines including GM-CSF and TNF-alpha.
Animals↗