Search

Oral administration of nickel or chromium to naive guinea pigs results in immune unresponsiveness to subsequent induction of allergic contact hypersensitivity. Such "oral tolerance" depends on the oral dose, is antigen specific, T-suppressor-cell mediated, and very persistent. In contrast, oral antigen administration to sensitized animals results at best in transient desensitization. Here we report that even non-sensitizing epicutaneous skin contacts prevented the subsequent induction of oral tolerance. These data support the view that primed T cells are less sensitive to suppressor T-cell function than naive T cells. [ABSTRACT FROM AUTHOR]

Antigen contact via the alimentary tract prior to sensitization may result in systemic immunologic unresponsiveness ("oral tolerance"). The induction of oral tolerance seems an attractive strategy to combat undesired immune responses, such as allograft rejection and autoimmune and allergic diseases. We describe clear and reproducible sensitization to nickel in mice reared under nickel-free conditions. Hypersensitivity was induced by injecting nickel sulfate intradermally into the flank skin and elicited by injecting the metal salt into the pinnae of the cars. The effectiveness of orally induced hyporesponsiveness could be inferred from a low degree of hypersensitivity obtained with mice raised and maintained in cages with nickel-releasing covers and water nipples. This mouse model for the assay of nickel hypersensitivity was used for oral tolerance studies by administrating non-toxic doses of nickel sulfate in drinking water or intragastrically prior to sensitization. In these animals, the development of delayed-type hypersensitivity was suppressed in a dose-dependent way and the hyporesponsiveness could be transferred by CD8 cells. The antigen specificity of this oral tolerance could be demonstrated by the concomitant use of sensitization and challenge procedures for nickel and chromium. The hyper sensitivity assay described provides a versatile, highly reproducible experimental model to study immunoregulation of oral tolerance to clinically relevant metal allergens. [ABSTRACT FROM AUTHOR]

Oral administration of allergens, foreign proteins, or cell- bound antigens may induce systemic suppression of subsequent humoral and cell-mediated immune responses ("oral tolerance") The induction of specific immune tolerance provides a potential strategy for treatment of T-celldependent immune diseases. Therefore, in depth studies into reconditions for optimal and persistent tolerance induction are mandatory. Here we report on such studies in a guinea pig model using the non-cross-reactive contact allergens nickel and chromium. Feeding per os of nickel sulfate or potassium. dichromate did not trigger systemic TDTH-effector functions. Instead, short feeding periods led to a close-dependent, and metal-specific, suppression of subsequently induced allergic contact hypersensitivity. Administration of the allergens onto the oral mucosa was most effective in the induction of immune tolerance. When first sensitizing attempts were delayed until 1 year after feeding, the degree of unresponsiveness was reduced. In contrast, with cutaneous contacts starting Shortly after the feeding period, tolerance was fully stable and undiminished for at least 2 years. Thus, in orally treated guinea pigs cutaneous contacts provide boosting tolerogenic signals, supporting the view that oral tolerance does not result from clonal deletion but from active antigen-specific immunosuppression. Indeed, unresponsiveness to cutaneous immunization could be transferred by lymphoid cells from fed guinea pigs in a metal-specific way. [ABSTRACT FROM AUTHOR]

Aim: The role of metal exposure in the development of autoimmune disease (AID) is still controversial. Here, we studied the relationship between oral metal exposure, metal allergy and autoimmunity.Methods: A mixed population (n = 78) of non-allergic volunteers, metal-allergic patients and patients with oral problems putatively due to metal alloys was evaluated for oral Ni, Pd, Au and Hg exposure and skin hypersensitivity. Clinical autoimmune parameters were based on medical histories; additionally, serum levels of the four most common autoantibodies were measured.Results: Skin hypersensitivity, as seen mainly for Ni and/or Pd, was not positively associated with autoimmune parameters. In contrast, metal hypersensitive individuals showed an extremely low frequency of thyroid autoantibodies (3% vs 20% in non-hypersensitive controls). Next, the relation between metal exposure and autoimmunity was evaluated in individuals >35 years (n = 58), since from that age on metal exposure had plateaued and was not correlated with age. In this subgroup, oral Ni exposure was associated (p < 0.01) with self-reported AID, irrespective of autoantibody levels. These unexpected findings warrant further confirmation in a larger test group. Of note, oral Pd, Au or Hg contacts were not associated with any of the clinical or serological autoimmune phenomena tested.Conclusion: The results of this study support the view that development of metal contact allergies may prevent autoimmune activation, and, second, that oral exposure to Pd, Au or Hg does not facilitate the development of AID. [ABSTRACT FROM PUBLISHER]

Background Palladium (Pd) and gold (Au) based dental alloys have been associated with oral disease. Objectives This study was designed to explore possible associations between the presence of Au-based and Pd-based dental alloys, and oral lesions, systemic complaints, and specific in vivo and in vitro immune responses. Methods The investigated population consisted of three groups: 26 non-metal-allergic volunteers, 25 metal-allergic patients, and 20 oral disease patients. Medical histories were taken, oral examinations were carried out, and compositions of all dental alloys were determined. Then, Au and Pd patch tests and in vitro assays were performed, revealing cytokine production by peripheral blood mononuclear cells [T helper ( Th)1, interferon-γ; Th2, interleukin ( IL)-5 and IL-13] and lymphocyte proliferation ( LTT-MELISA®). Results Non-plaque-related gingivitis was associated with the presence of Pd-based dental alloys, and Pd-positive patch tests and in vitro assays. Collectively, participants with Pd-based dental alloys showed increased Pd patch test reactivity ( p < 0.05) and lymphoproliferation ( p < 0.05). In contrast, oral lichenoid lesions were associated with Au-based alloys ( p < 0.05), but this was not reflected by Au-specific immunoreactivity. Conclusions Oral lesions and Pd-induced immune responses are associated with the presence of dental alloys. However, most oral disease patients did not show positive patch test results or in vitro signs of specific immunoreactivity, suggesting local toxic reactions or the involvement of innate immune responses. [ABSTRACT FROM AUTHOR]

Background & Aims: In most cases celiac disease (CD) is successfully treated with a gluten-free diet (GFD). However, some patients become refractory to the GFD. Refractory CD (RCD) patients have an increased risk for developing enteropathy associated T-cell lymphoma and early diagnosis is therefore of importance. Currently, RCD diagnosis relies on endoscopy and adequate serological markers are lacking. Antibodies against glycoprotein-2 (GP2A) were described in Crohn's disease (CrD) and active CD but not in ulcerative colitis (UC), suggesting this is a specific marker for small intestinal lesions. Methods: Sera obtained from patients visiting our outpatient clinic for routine serological tests for diagnosis and/or follow-up of inflammatory bowel disease (n=78), active CD (n=45), GFD (n=34) and RCD (n=15) were analysed for GP2A titres. Results: Increased GP2A-IgA levels in CrD and active CD as compared to controls (p<0.001) and lack thereof in UC was confirmed. However, we could not confirm the association with small bowel localization within the CrD patient group. Within CD patients, we demonstrated a significant decrease of GP2A-IgA titres upon a GFD and increased levels in RCD patients as compared to patients on a GFD. Although GP2A-IgA was not associated with the degree of villous atrophy, GP2A-IgA levels were able to distinguish RCD patients from GFD patients (ROC AUC=0.79, p=0.002). Conclusion: Follow-up of GP2A-IgA titres in CD patients on a GFD may help to identify patients at risk for developing RCD. [ABSTRACT FROM AUTHOR]

Background Nickel was recently identified as a potent activator of dendritic cells through ligating with human Toll-like receptor (TLR)-4. Objectives Here, we studied an extended panel of transition metals neighbouring nickel in the periodic table of elements, for their capacity to activate human monocyte-derived dendritic cells (MoDCs). Methods The panel included chromium, cobalt, and palladium, all of which are known to be frequent clinical sensitizers. MoDC activation was monitored by assessment of release of the pro-inflammatory mediator interleukin (IL)-8, a major downstream result of TLR ligation. Results The data obtained in the present study show that cobalt and palladium also have potent MoDC-activating capacities, whereas copper and zinc, but not iron and chromium, have low but distinct MoDC-activating potential. Involvement of endotoxin contamination in MoDC activation was excluded by Limulus assays and consistent stimulation in the presence of polymyxin B. The critical role of TLR4 in nickel-induced, cobalt-induced and palladium-induced activation was confirmed by essentially similar stimulatory patterns obtained in an HEK293 TLR4/MD2 transfectant cell line. Conclusions Given the adjuvant role of costimulatory danger signals, the development of contact allergies to the stimulatory metals may be facilitated by signals from direct TLR4 ligation, whereas other metal sensitizers, such as chromium, may rather depend on microbial or tissue-derived cofactors to induce clinical sensitization. [ABSTRACT FROM AUTHOR]

Background. Exposure to palladium (Pd) may lead to clinical allergic reactions. With frequent nickel (Ni) exposure and cross-reactivity between Ni and Pd at the T cell recognition level, positive Pd reactions on patch testing are surprisingly uncommon. PdCl2 is often used for epicutaneous patch testing. Objectives. To compare the sensitivity and specificity of sodium tetrachloropalladate (Na2PdCl4) and PdCl2 for Pd patch testing in metal-allergic patients and non-allergic controls. Methods. Twenty-six metal-allergic patients and 26 non-allergic controls were selected on the basis of detailed medical histories. Patch test results were used to determine the diagnostic performance of the two Pd salts as compared with NiSO4. Results. With three outliers in both groups, the sensitivity/specificity were calculated to be 42%/96% for PdCl2, 65%/92% for Na2PdCl4, and 77%/92% for NiSO4. Furthermore, of all (n = 19) Na2PdCl4 reactors, 17 (89%) also showed positive reactions to NiSO4. Conversely, of all (n = 22) NiSO4 reactors, 17 (77%) showed concomitant positive reactions to Na2PdCl4. Conclusions. Positive test reactions to Na2PdCl4 are confirmed by large-scale concordant reactions to PdCl2 and NiSO4. Although statistical significance was not reached, the increased sensitivity has important clinical relevance, as false-positive results are rare. Incorporation of Na2PdCl4 into standard and/or dental screening patch test series is suggested. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to use of serum intestinal-fatty acid binding protein as a biomarker in the previous issue.