RESUMEN
Nickel is the most common contact allergen in humans. Until recently, many questions concerning tolerance mechanisms to nickel were unresolved. Besides human ex vivo, intervention and observation studies, the establishment of a reproducible mouse model has contributed to the analysis of these mechanisms. A more detailed understanding of the pathogenesis of nickel allergy and tolerance towards nickel by investigations in an animal model and in human studies is a prerequisite for developing specific prevention and therapy of nickel allergy. With this article, we provide a review of the investigations concerning nickel allergy and give perspectives towards oral tolerance induction to nickel in the animal model and in humans.
Asunto(s)
Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/inmunología , Modelos Animales de Enfermedad , Tolerancia Inmunológica/inmunología , Níquel/toxicidad , Piel/efectos de los fármacos , Piel/inmunología , Alérgenos/toxicidad , Animales , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/terapia , Tolerancia a Medicamentos/inmunología , Humanos , RatonesAsunto(s)
Dermatitis Alérgica por Contacto/etiología , Tolerancia a Medicamentos , Hipersensibilidad , Níquel/administración & dosificación , Níquel/efectos adversos , Administración Oral , Animales , Dermatitis Alérgica por Contacto/epidemiología , Dermatitis Alérgica por Contacto/inmunología , Humanos , Hombres , Ratones , Níquel/inmunología , Linfocitos T/inmunología , MujeresRESUMEN
We adapted our mouse model of allergic contact hypersensitivity to nickel for the study of tolerance. Sensitization in this model is achieved by the administration of nickel ions with H(2)O(2); nickel ions alone are unable to prime naive T cells, but can restimulate primed ones. A 4-wk course of oral or i.p. administration of 10 mM NiCl(2) to naive mice induced tolerance, preventing the induction of hypersensitivity for at least 20 wk; long term desensitization of nickel-sensitized mice, however, required continuous NiCl(2) administration. When splenic T cells of orally tolerized donors, even after a treatment-free interval of 20 wk, were transferred to naive recipients, as with lymph node cells (LNC), they specifically prevented sensitization of the recipients. The LNC of such donors were anergic, because upon in vivo sensitization with NiCl(2) in H(2)O(2) and in vitro restimulation with NiCl(2), they failed to show the enhanced proliferation and IL-2 production as seen with LNC of mice not tolerized before sensitization. As few as 10(2) bulk T cells, consisting of both CD4(+) and CD8(+) cells, were able to specifically transfer tolerance to nickel. A hypothesis is provided to account for this extraordinarily high frequency of nickel-reactive, suppressive T cells; it takes into account that nickel ions fail to act as classical haptens, but form versatile, unstable metal-protein and metal-peptide complexes. Furthermore, a powerful amplification mechanism, such as infectious tolerance, must operate which allows but a few donor T cells to tolerize the recipient.
Asunto(s)
Anergia Clonal , Dermatitis Alérgica por Contacto/inmunología , Níquel/farmacología , Linfocitos T Reguladores/inmunología , Adyuvantes Inmunológicos/farmacología , Administración Oral , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Células Cultivadas , Dermatitis Alérgica por Contacto/tratamiento farmacológico , Dermatitis Alérgica por Contacto/metabolismo , Femenino , Peróxido de Hidrógeno/farmacología , Inyecciones Intraperitoneales , Interleucina-2/biosíntesis , Cinética , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Níquel/administración & dosificación , Níquel/farmacocinética , Bazo/inmunología , Linfocitos T Reguladores/trasplanteRESUMEN
The most basic arylamine, aniline, belongs to a class of compounds notorious for inducing allergic and autoimmune reactions. In 1981 in Spain, many people succumbed to toxic oil syndrome (TOS), a disease caused by ingestion of cooking oil contaminated with aniline. Indirect evidence points toward an immune pathogenesis of TOS driven by T lymphocytes, but it is unclear to which antigens these cells could react. Here, using the popliteal lymph node (PLN) assay in mice, we analyzed the sensitizing potential of aniline, its metabolites, and some of the aniline-coupled lipids detected in the contaminated cooking oil. Whereas aniline itself and its non-protein-reactive metabolites nitrobenzene, p-aminophenol and N-acetyl-p-aminophenol, failed to elicit PLN responses, its reactive metabolites nitrosobenzene and N-hydroxylaniline did. The aniline-coupled lipids, namely, linoleic anilide and linolenic anilide, and a mixture of fatty acid esters of 3-(N-phenylamino)-1,2-propanediol, all implicated in TOS, induced significant PLN responses, whereas the respective aniline-free lipids, linoleic acid, linolenic acid, and triolein, did not. Hence, the aniline moiety plays a crucial role in the immunogenicity of the aniline-coupled lipids of TOS. PLN responses to the reactive aniline metabolites and the one aniline-coupled lipid that was tested, linolenic anilide, were T-cell-dependent. Secondary PLN responses to nitrosobenzene were detectable not only after priming with nitrosobenzene but, in some experiments, also after priming with linolenic anilide. This suggests that the aniline moiety was cleaved from the aniline-coupled lipid and metabolized to the intermediate nitrosobenzene that generated the prospective neoantigens. Consistent with this, in lymphocyte proliferation tests in vitro, T cells primed to nitrosobenzene reacted in anamnestic fashion to white bone marrow cells (WBMCs) pulsed with aniline. Hence, we propose that aniline is a prohapten that can be metabolized by WBMCs, which form neoantigens that are recognized by T cells. The possible significance of these findings for the pathogenesis of TOS is discussed.
Asunto(s)
Compuestos de Anilina/efectos adversos , Haptenos/inmunología , Aceites/efectos adversos , Fagocitos/inmunología , Linfocitos T/efectos de los fármacos , Compuestos de Anilina/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Células Cultivadas , Femenino , Humanos , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Linfocitos T/inmunologíaRESUMEN
A 32-year-old patient developed an anaphylactic reaction minutes after oral intake of acetaminophen-containing tablets (Doregrippin)). Scratch testing of the whole preparation was positive in contrast with the negative results obtained with pure acetaminophen. Therefore, scratch tests with the remaining drug components were performed and showed polyvinylpyrrolidone (PVP) to be the aetiological agent. Furthermore, specific IgE antibodies against PVP were demonstrated using a dot blot technique, thus ruling out a pseudo-allergic reaction. This case underlines the necessity to consider not only the active ingredient, but also additives as the causative agent.
Asunto(s)
Anafilaxia/inducido químicamente , Excipientes Farmacéuticos/efectos adversos , Povidona/efectos adversos , Acetaminofén , Adulto , Analgésicos no Narcóticos , Humanos , Inmunoglobulina E/sangre , Masculino , Pruebas CutáneasRESUMEN
The arylhydrocarbon receptor (AhR), a ligand-activated transcription factor, is differentially distributed in tissues and abundant in the thymus epithelium. The activated AhR can induce the transcription of an array of genes, including genes of cell growth and differentiation. Neither the physiological function of the AhR nor its putative natural ligand is known. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a xenobiotic high-affinity activator of the AhR, and appears to be essential for most of the multifold toxic effects of TCDD. Activation of the AhR by even low doses of TCDD results in general immunosuppression and thymus hypoplasia. TCDD exposure interferes with thymocyte development; for instance, it reduces the proliferation rate of the very immature (CD4- CD8- and CD4- CD8+ HSA+) thymocytes, leads to preferential emigration of very immature cells, and drastically skews the differentiation of thymocyte subpopulations towards mature CD4- CD8+ alphabeta TCRhigh thymocytes. As shown here, in fetal thymi of AhR-deficient mice, thymocyte differentiation kinetics as defined by CD4 and CD8 surface markers, was comparable to AhR+/+ C57BL/6 mice. Also, the cell emigration characteristics were similar to AhR+/+ mice. These parameters were refractory to TCDD exposure in the AhR-/- mice, but not in the C57BL/6 mice. However, in AhR deficient mice at gestation day 15 more CD4- CD8- immature cells bore high amounts of the (alphabeta-T-cell receptor. Also, fetal thymocyte numbers were significantly lower, as compared to strain C57BL/6. Thus, the AhR is the mediator of thymotoxic effects of TCDD.
Asunto(s)
Inmunosupresores/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/fisiología , Subgrupos de Linfocitos T/efectos de los fármacos , Timo/patología , Animales , Atrofia , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Receptores de Hialuranos/análisis , Síndromes de Inmunodeficiencia/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Timo/efectos de los fármacos , Xenobióticos/farmacocinética , Xenobióticos/toxicidadRESUMEN
The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val-allele (OR = 2.59) when compared to controls (n = 184). However, no significant differences in allele frequencies for MspI in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.
Asunto(s)
Arilamina N-Acetiltransferasa/genética , Citocromo P-450 CYP1A1/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Esclerodermia Sistémica/genética , Alelos , Arilamina N-Acetiltransferasa/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Frecuencia de los Genes , Genotipo , Humanos , Lupus Eritematoso Sistémico/enzimología , Fenotipo , Esclerodermia Sistémica/enzimología , Xenobióticos/metabolismoRESUMEN
Using the popliteal lymph node (PLN) assay in mice, we studied the sensitizing potential of benzene and its metabolites. Whereas benzene and phenol failed to induce a PLN reaction, catechol and hydroquinone induced a moderate, and p-benzoquinone a vigorous response. Following a single injection of the reactive metabolite p-benzoquinone (100 nmol/mouse), cellularity in the draining PLN was increased > 15-fold, and reverted back to normal only after approximately 100 days. Although the PLN response was T cell-dependent, flow cytometric analysis revealed that the increased cellularity in the PLN after a single injection of p-benzoquinone was mainly due to an increase in B cells. Mice primed to p-benzoquinone and challenged with a small dose of p-benzoquinone (0.1 nmol/mouse) mounted a secondary PLN reaction, indicating hapten specificity of the reaction; this was confirmed by results obtained in the adoptive transfer PLN assay. An unexpected finding was the secondary PLN response to benzene (1 nmol/mouse) observed in mice primed to p-benzoquinone. This finding suggests that some of the benzene (at least 10%) was locally converted into p-benzoquinone, which then elicited the secondary response observed. In conclusion, the reactive intermediate metabolites hydroquinone and p-benzoquinone can act as haptens and sensitize; their precursors, benzene and phenol, may be considered as prohaptens.
Asunto(s)
Benceno/metabolismo , Benceno/toxicidad , Hipersensibilidad a las Drogas/inmunología , Ganglios Linfáticos/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos/inmunología , Benzoquinonas/toxicidad , Catecoles/toxicidad , Femenino , Citometría de Flujo , Hidroquinonas/toxicidad , Ganglios Linfáticos/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fenol/toxicidad , Organismos Libres de Patógenos Específicos , Bazo/citología , Factores de TiempoRESUMEN
Attempts to induce contact hypersensitivity to nickel in mice using, e.g., Ni(II)Cl2 often failed. Here, we report that sensitization was achieved by injecting Ni(II)Cl2 in combination with either CFA or an irritant, such as SDS and PMA, or IL-12, or by administering nickel at higher oxidation states, i.e., Ni(III) and Ni(IV). Although Ni(II), given alone, was ineffective in T cell priming, it sufficed for eliciting recall responses in vivo and in vitro, suggesting that Ni(II) is able to provide an effective signal 1 for T cell activation, but is unable to provide an adequate signal 2 for priming. Immunization of mice with nickel-binding proteins pretreated with Ni(IV), but not with Ni(II), allowed them to generate nickel-specific CD4+ T cell hybridomas. Ni(II) sufficed for restimulation of T cell hybridomas; in this and other aspects as well, the hybridomas resembled the nickel-specific human T cell clones reported in the literature. Interestingly, restimulation of hybridomas did not require the original Ni(IV)-protein complex used for priming, suggesting either that the nickel ions underwent ligand exchange toward unknown self proteins or peptides or that nickel recognition by the TCR is carrier-independent. In conclusion, we found that Ni(III) and Ni(IV), but not Ni(II) alone, were able to sensitize naive T cells. Since both Ni(III) and Ni(IV) can be generated from Ni(II) by reactive oxygen species, released during inflammation, our findings might explain why in humans nickel contact dermatitis develops much more readily in irritated than in normal skin.
Asunto(s)
Dermatitis Alérgica por Contacto/inmunología , Inmunización , Níquel/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Dermatitis Alérgica por Contacto/metabolismo , Relación Dosis-Respuesta a Droga , Oído Externo , Epítopos de Linfocito T/inmunología , Femenino , Hibridomas/inmunología , Inmunización Secundaria , Inyecciones Intradérmicas , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Activación de Linfocitos , Complejo Mayor de Histocompatibilidad/inmunología , Metales/inmunología , Ratones , Ratones Endogámicos C57BL , Níquel/administración & dosificación , Níquel/metabolismo , Oxidación-Reducción , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Pruebas CutáneasRESUMEN
Procainamide (PA) may cause drug-induced lupus, and its reactive metabolites, hydroxylamine-PA (HAPA) and nitroso-PA, are held responsible for this. Here, we show that N-oxidation of PA to these metabolites can take place in macrophages and lead to formation of neoantigens that sensitize T cells. Murine peritoneal macrophages (PMvarphi), exposed to PA in vitro, generated neoantigens related to HAPA as indicated by (1) their capacity to elicit a specific recall response of HAPA-primed T cells in the adoptive transfer popliteal lymph node (PLN) assay and (2) the appearance of metabolite-bound protein in PA-pulsed PMvarphi, as determined by Western blot. Analysis of five phase I enzymes that might be responsible for HAPA formation by PMvarphi pointed to prostaglandin H synthase-2 (PGHS-2) as a likely candidate. Experimental evidence that PA can be oxidized to HAPA by PGHS was obtained by exposing PA to PGHS in vitro. The resulting metabolites were identified by mass spectral analysis and covalent protein binding in ELISA. In vitro, PA exposure of PMvarphi of slow acetylator A/J and fast acetylator C57BL/6 mice failed to show significant strain differences in enzyme mRNA expression, enzyme activities, or formation of HAPA-related neoantigens. By contrast, after long-term PA treatment in vivo only in slow acetylators the PMvarphi harbored HAPA-related neoantigens and T cells were sensitized to them. PMvarphi of fast acetylator C57BL/6 mice only contained HAPA-related neoantigens, and their T cells were only sensitized to them if, in addition to long-term PA treatment, their donors had received injections of phorbol myristate acetate (PMA), a known enhancer of oxidative enzymes in phagocytes. In conclusion, PA treatment leads to N-oxidation of PA by enzymes, in particular PGHS-2, present in antigen-presenting cells (APC) and, hence, to generation of neoantigens which sensitize T cells. The enhanced neoantigen formation and T cell sensitization seen in slow acetylators might be explained by their higher concentration of PA substrate that is available for extrahepatic N-oxidation in APC.
Asunto(s)
Isoenzimas/biosíntesis , Macrófagos Peritoneales/efectos de los fármacos , Procainamida/farmacología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Linfocitos T/efectos de los fármacos , Animales , Arilamina N-Acetiltransferasa/metabolismo , Inducción Enzimática , Femenino , Lupus Eritematoso Sistémico/inducido químicamente , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/metabolismo , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Genetic factors that could mediate the pathogenesis of male reproductive disorders are largely unclear. Polymorphisms of cytochrome P4501A1 (CYP1A1), a key enzyme in the extrahepatic metabolism of lipophilic xenobiotics, have been shown to influence susceptibility to xenobiotics. Here, CYP1A1 polymorphisms were investigated in 134 infertile Caucasian men. The frequencies of the Mspl polymorphism in the 3'-flanking region of the CYP1A1 gene and a mutation in exon 7 causing an isoleucine-valine exchange (IVE) in the heme-binding region of the enzyme were increased among infertile men when compared with those of unselected, healthy male controls (odds ratio (OR)) 1.4, Cl95 0.68-2.89 for Mspl polymorphism; OR 2.4, Cl95 0.83-6.95 for IVE). Patients with normozoospermia revealed the highest frequencies for both polymorphisms (n = 8; OR 4.5, Cl95 0.97-20.91 for Mspl polymorphism; OR 13.7, Cl95 2.53-74.13 for IVE). ORs for the IVE exceeded the values calculated for the Mspl polymorphism. These preliminary results suggest that genetic variation in the metabolism of xenobiotics may codetermine individual susceptibility to infertility.
Asunto(s)
Citocromo P-450 CYP1A1/genética , Infertilidad Masculina/enzimología , Infertilidad Masculina/genética , Polimorfismo de Longitud del Fragmento de Restricción , Desoxirribonucleasa HpaII , Genotipo , Humanos , Infertilidad Masculina/fisiopatología , Masculino , Oligospermia/genética , Reacción en Cadena de la Polimerasa , Recuento de Espermatozoides , Motilidad Espermática , Población BlancaRESUMEN
Induction of allergic and autoimmune reactions by drugs and other chemicals constitutes a major public health problem. Elucidation of the underlying mechanisms might help improve diagnostic tools and therapeutic approaches. Here, Peter Griem and colleagues focus on several aspects of neoantigen formation by xenobiotics: metabolism of xenobiotics into reactive, haptenic metabolites; polymorphisms of metabolizing enzymes; induction of costimulatory signals; and sensitization of T cells.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Hipersensibilidad a las Drogas/inmunología , Xenobióticos/inmunología , Animales , Exposición a Riesgos Ambientales , Humanos , Modelos Inmunológicos , Salud PúblicaAsunto(s)
Adyuvantes Inmunológicos/fisiología , Dermatitis Alérgica por Contacto/inmunología , Tolerancia Inmunológica , Metales Pesados/inmunología , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/farmacología , Animales , Dermatitis Alérgica por Contacto/etiología , Modelos Animales de Enfermedad , Compuestos de Oro/efectos adversos , Compuestos de Oro/farmacología , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/fisiopatología , Tolerancia Inmunológica/efectos de los fármacos , Mercurio/efectos adversos , Mercurio/farmacología , Metales Pesados/efectos adversos , Metales Pesados/farmacología , Ratones , Paladio/efectos adversos , Paladio/farmacología , Platino (Metal)/efectos adversos , Platino (Metal)/farmacología , Ratas , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Previous work has shown that the Au(I) moiety of the antirheumatic drug disodium aurothiomalate (Au(I)TM) can selectively inhibit the response of murine CD4+ T-cell hybridomas to antigenic peptides containing two or more cysteine (Cys) residues. Here, we investigated the mechanism that underlies the inhibitory effect of Au(I)TM on T-cell recognition of bovine insulin (BI). We found that low concentrations of Au(I)TM (10 microM) inhibited the BI-induced proliferation of bulk T-cells from BI-immunized BALB/c mice as well as the IL-2 release of Ab- and Ad-restricted T-cell hybridoma clones. Au(I)TM was found to inhibit binding of the immunodominant BI peptide A1-14 to isolated MHC class II molecules. We suggest that Au(I) forms stable chelate complexes with thiol groups of two Cys residues in the BI A1-14 peptide. Conceivably, formation of these metal-peptide complexes keeps the peptide in a sterical conformation that cannot undergo binding to MHC class II molecules, resulting in an inhibition of T-cell activation due to insufficient peptide presentation.
Asunto(s)
Antirreumáticos/farmacología , Tiomalato Sódico de Oro/farmacología , Antígenos de Histocompatibilidad/metabolismo , Insulina/metabolismo , Linfocitos T/efectos de los fármacos , Animales , Presentación de Antígeno/efectos de los fármacos , Células Clonales , Femenino , Antígenos H-2/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Complejo Mayor de Histocompatibilidad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fragmentos de Péptidos/metabolismo , Unión Proteica/efectos de los fármacos , Linfocitos T/citologíaRESUMEN
Upon treatment with HgCl2, H-2s mice, such as B10.S, develop an activation of B lymphocytes that depends, at least partially, on activation of T helper type 2 (Th2) cells and results in increased serum levels of IgG1 and IgE, appearance of IgG autoantibodies, and development of immune glomerulonephritis and vasculitis. Results of previous studies and of experiments presented here indicate that the B cell activation and systemic autoimmune disease fail to develop in MHC-congenic B10.D2 (H-2d) and B10.BR (H-2k) mice treated with HgCl2, although B10.D2 T cells showed signs of activation by and specificity for HgCl2 comparable to those seen in strain B10.S. Here, we report that following HgCl2 injections the antibody response to sheep erythrocytes is normal in B10.S, but suppressed in B10.D2 mice. This suppression was prevented by MoAb to mouse IFN-gamma. Conversely, treatment of B10.D2 mice with murine recombinant IFN-gamma (rIFN-gamma) was able to reproduce the immunosuppression seen after HgCl2 treatment. In B10.S mice, it took administration of both rIFN-gamma and HgCl2 to suppress the anti-sheep erythrocyte response. Although rIFN-gamma diminished the increase in IgE serum levels of HgCl2-treated B10.S mice, it failed to prevent their autoantibody production and immune glomerulonephritis. These findings further strengthen the concept that B10.S mice react to HgCl2 by preferential activation of their Th2 cells producing IL-4, whereas B10.D2 mice react to HgCl2 by preferential activation of their Th1 cells, which produce IFN-gamma and thus suppress antibody responses.
Asunto(s)
Terapia de Inmunosupresión , Interferón gamma/genética , Interferón gamma/inmunología , Cloruro de Mercurio/inmunología , Animales , Anticuerpos Antinucleares , Anticuerpos Bloqueadores/inmunología , Formación de Anticuerpos , Autoanticuerpos/metabolismo , Eritrocitos/inmunología , Femenino , Glomerulonefritis/inmunología , Inmunoglobulina E/análisis , Inmunoglobulina E/sangre , Inmunoglobulina E/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Riñón/inmunología , Ratones , Ratones Endogámicos , Ratones Mutantes , Proteínas Recombinantes/inmunología , Ovinos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Ciprofloxacin (CPFX) is a widely used fluoroquinolone antibiotic, inducing cutaneous adverse drug reactions in about 1 to 2% of the treated patients. Conclusive diagnosis of drug allergy, however, still remains a major problem in daily clinical practice. Here, we present 2 patients with drug allergy to CPFX. In both cases the clinical suspicion for CPFX as the causative agent was confirmed in vitro by means of the lymphocyte transformation test, whereas epicutaneous patch tests remained negative. In vivo, a small percentage of the drug is biotransformed to the three major metabolites desethylene-, sulfo- and oxociprofloxacin. Though structurally closely related to their mother compound, these metabolites failed to induce in vitro lymphocyte proliferation in both patients. On the other hand, in vitro crossreactivity to ofloxacin, another fluorinated quinolone, could be demonstrated, which to our knowledge has not previously been reported.
Asunto(s)
Antiinfecciosos/efectos adversos , Ciprofloxacina/efectos adversos , Erupciones por Medicamentos/diagnóstico , Activación de Linfocitos/efectos de los fármacos , Ofloxacino/efectos adversos , Anciano , Ciprofloxacina/farmacocinética , Reacciones Cruzadas , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/inmunología , Hipersensibilidad a las Drogas , Femenino , Humanos , Persona de Mediana Edad , Ofloxacino/farmacocinética , Pruebas del ParcheRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds and activates the aryl hydrocarbon receptor (Ah-R), an endogenous transcription factor that is expressed in the thymus. TCDD exposure leads, among other effects, to thymus atrophy and immunosuppression. We previously analyzed the interference of TCDD with differentiation processes in fetal thymus organ cultures and found that in the presence of TCDD, the proliferation rate of immature (CD4- CD8- and CD4- CD8+ HSA+) thymocytes is inhibited, whereas the maturation along the CD4/CD8 path is accelerated. Moreover, the differentiation of thymocytes is skewed by TCDD at < or = 40% (compared with approximately 15% without TCDD) of the CD8 single-positive subset of future cytotoxic T cells, and apparently more cells audition for and pass positive selection. The fetal murine thymus expresses functional Ah-R mRNA, as shown by reverse transcription-polymerase chain reaction and TCDD-inducible CYP1A1 and CYP1B1 expression. Because the differentiation of thymocytes is to a considerable extent controlled by cytokines and many cytokine genes are potential targets of the Ah-R due to Ah-R-binding elements (xenobiotic response elements) in their promoters, we analyzed the cytokine expression in fetal thymus organ culture exposed to TCDD. Fetal thymi were cultured from gestation day 15 for < or = 8 days, thus covering ex vivo the period after population of the thymus anlage until birth. We show with semiquantitative reverse transcription-polymerase chain reaction that more interleukin (IL)-1beta, IL-2, IL-6, tumor growth factor (TGF)-beta3, and tumor necrosis factor-alpha are produced in TCDD-exposed thymi, whereas other cytokines (e.g., TGF-beta1, PAI-2, or IL-4) are only slightly up- and down-modulated during the culture period or not modulated at all (e.g., IL-1beta, IL-7, interferon-gamma, and TGF-beta2).
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Citocinas/genética , Proteínas de Unión al ADN , Feto/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Timo/efectos de los fármacos , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo , Southern Blotting , Citocromo P-450 CYP1A1/efectos de los fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1 , Femenino , Feto/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Reacción en Cadena de la Polimerasa , Receptores de Hidrocarburo de Aril/genética , Timo/metabolismo , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genéticaRESUMEN
Tissue concentrations of mercury were determined by cold vapor atomic absorption spectrometry in different inbred mouse strains after continuous treatment with HgCl2 (3 weekly sc injections of 0.5 mg/kg bw) for up to 12 weeks. Except for the thymus, in which steadily increasing mercury concentrations were found, in steady state levels of mercury were reached in blood and liver after 4 weeks and in spleen and kidney after 8 weeks. In the closely related strains C57BL/6, B10.D2, and B10.S, which differ only or primarily at the major histocompatibility complex, mercury concentrations in blood and liver were about twofold lower and renal concentrations were about three- to fivefold lower than those detected in strains A.SW and DBA/2. Another strain difference was observed in the spleen: after 8 and 12 weeks of continuous HgCl2 treatment, mercury concentrations in the spleen of strains A.SW, C57BL/6, and B10.S were significantly higher than those in strains DBA/2 and B10.D2. The strain difference in the spleen, an organ of the immune system, correlates with the susceptibility to the HgCl2-induced systemic autoimmune syndrome in mice in that the strains showing a higher mercury accumulation in the spleen are susceptible to this form of chemically induced autoimmunity, whereas the strains with lower mercury concentrations in the spleen are resistant.
Asunto(s)
Cloruro de Mercurio/administración & dosificación , Mercurio/farmacocinética , Animales , Riñón/química , Hígado/química , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Especificidad de la Especie , Bazo/química , Timo/química , Distribución TisularRESUMEN
The novel antiepileptic drug lamotrigine (LTG) is effective as an adjunctive medication in partial seizures. The main adverse effects of LTG are skin eruptions, occurring in 3-10% of the treated patients, but these are rarely severe. The risk of cutaneous side effects is increased in patients receiving sodium valproate comedication, probably by doubling the plasma half-life of LTG due to competition with hepatic glucuronidation. Conversely, the risk can be reduced by adding LTG in a lower dose. Here, we report a patient who developed Stevens-Johnson syndrome (SJS) 5 weeks after adding low-dose LTG comedication to sodium valproate. An LTG-induced pathogenesis of the SJS was considered likely by a positive lymphocyte transformation test to the drug. The patient showed maximal peripheral blood lymphocyte reactivity to 50 micrograms LTG/ml with a stimulation index of 4.7 but not to nontoxic concentrations of sodium valproate. Lymphocytes from untreated controls neither reacted to LTG nor to sodium valproate.
Asunto(s)
Anticonvulsivantes/efectos adversos , Erupciones por Medicamentos/etiología , Linfocitos/efectos de los fármacos , Síndrome de Stevens-Johnson/inducido químicamente , Triazinas/efectos adversos , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Concanavalina A/farmacología , Erupciones por Medicamentos/patología , Quimioterapia Combinada , Semivida , Humanos , Lamotrigina , Hígado/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Factores de Riesgo , Síndrome de Stevens-Johnson/patología , Triazinas/administración & dosificación , Triazinas/sangre , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversosRESUMEN
Complex platinum (Pt) compounds are known as occupational respiratory sensitizers whereas their role in skin exposure is unclear. In this study, both skin irritation and induction of contact hypersensitivity by halide Pt salts were characterized in mice. Repeated application of Na2[PtCl6] (5% in acetone) to both ears of naive BALB/c mice induced activation of the draining auricular lymph nodes. Flow cytometric analysis revealed a striking increase in the number of lymph node cells expressing proliferating cell nuclear antigen. In separate experiments, Na2[PtCl6] or acetone were applied only to the right ear of mice on 4-8 consecutive days and the animals were challenged on the left ear 6 days later. Ear thickness was determined before and 0.5, 24, 48, and 72 h after challenge with 0.5 or 2% Na2[PtCl6] or acetone. Maximal swelling of the left ear was recorded at 48 h in Pt-sensitized mice challenged with 2% Na2[PtCl6]. Furthermore, the concentration of Na2[PtCl6] required for sensitization caused an irritant reaction as demonstrated by significant swelling of the right ear. These data support the concept that both irritant and allergic contact dermatitis to halide Pt salts may occur in humans. Concerning skin exposure to halide Pt salts, Pt-induced irritant reactions resulting from an intrinsic adjuvant's activity of the compound could be a prerequisite for sensitization.