Activation of T cells by dendritic cells exposed to a reference sensitizer: Towards a promising model to assess the allergenic potential of chemicals.

BACKGROUND: Low molecular weight chemicals constitute one of the major causes of occupational allergies. European legislation on chemicals recommends limiting the use of in vivo models for assessing the sensitizing potential of chemicals, and encourages the development of integrated alternative methods. An in vitro mouse model of bone marrow-derived dendritic cells (BMDCs) that showed good accuracy (75%) and sensitivity (69%) has previously been developed to assess the sensitizing potential of chemicals. OBJECTIVE: To assess the ability of BMDCs to activate T cells (TCs) in vitro. METHODS: BMDCs pre-exposed to the reference sensitizer ammonium hexachloroplatinate (AHCP) were co-cultured with different subpopulations of TCs. TC activation was assessed by surface marker expression, proliferation, and cytokine release. RESULTS: The results showed significant activation of TCs co-cultured with dendritic cells pre-exposed to AHCP as evaluated by CD124 expression, proliferation, and cytokine secretion. Moreover, the response of TCs appeared to be Th2-oriented. Naive TCs were shown to be involved in this response, and the removal of regulatory TCs did not improve the cell response. CONCLUSIONS: The BMDCs used in this previously developed model appear to have the ability to activate TCs, confirming that the BMDC model represents a reliable assay for assessing the sensitizing potential of chemicals.

Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service.

WHAT IS KNOWN AND OBJECTIVE: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma. METHODS: A single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified. RESULTS: The hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients. WHAT IS NEW AND CONCLUSION: Skin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.

Platinum Chemotherapy Hypersensitivity: Prevalence and Management.

Hypersensitivity reactions to platinum agents are common. For carboplatin and cisplatin, the first hypersensitivity reaction typically occurs around the second and third re-exposure during the second line of therapy (eighth and ninth courses overall). For oxaliplatin, the first hypersensitivity reaction can occur throughout the treatment course. Skin testing helps risk stratify patients to appropriate desensitization protocols and assess risk for breakthrough HSRs during desensitization. A risk-stratification protocol using 3 serial skin tests and desensitization protocols enables patients with platinum agent hypersensitivity to receive first-line chemotherapy treatment safely.

Basophil Activation Test is a Relevant Biomarker of the Outcome of Rapid Desensitization in Platinum Compounds-Allergy.

BACKGROUND: Rapid drug desensitization (RDD) has become a cornerstone in the management of immediate drug hypersensitivity reactions (DHRs) to chemotherapeutic agents. Because of the inherent risk of anaphylaxis during RDD, biomarkers to predict patients at risk of developing such severe reactions are needed. The basophil activation test (BAT) has been used in DHRs as a diagnostic tool. OBJECTIVE: We evaluated basophil CD63 and CD203c expression (BAT) as a biomarker to assess the safety and effectiveness of RDD in platinum compounds-allergic patients. METHODS: Patients allergic to platinum compounds (n = 15) undergoing RDD were assessed through clinical history, skin testing, serum tryptase levels, and BAT. BAT was performed immediately before RDD, assessing CD203c and CD63 expression on basophils. BAT was also performed in 6 patients tolerant to platinum compounds and in 6 healthy volunteers. RESULTS: BAT was positive to CD203c or CD63 in 11 out of 15 patients allergic to platinum compounds (73%), with increased expression of CD203c and CD63 in 11 (73%) and 6 (40%) patients, respectively. Increased CD63 expression tended to be associated with more severe initial reactions. All controls had negative test results. Reactions during RDD were associated with BAT positivity and increased tryptase levels. Only 1 of 4 patients with negative BAT had a mild reaction during RDD. BAT remained positive in multiple sequential RDD. CONCLUSIONS: BAT identified patients allergic to platinum compounds with an increased risk of reactions during desensitization and higher CD63 expression was observed in severe reactions. Multiple RDDs to platinum compounds did not induce persistent hyporesponsiveness on basophils. BAT is a potential biomarker for RDD.

Diagnostic tools for hypersensitivity to platinum drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators.

Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum-reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available.

Platinum group elements enhance the allergic immune response by acting on dendritic cells.

BACKGROUND: Atmospheric pollution may play a role in the immune response to allergens either directly or by entering the food chain. While particulate platinum group elements (PLGE) emitted by catalytic converters can be considered biologically inert, approximately 10% of these species accumulate in the environment as bioavailable soluble forms. METHODS: We challenged in vitro human immature and mature monocyte-derived dendritic cells with subtoxic concentrations of soluble species of PLGE. Dendritic cells were studied both at baseline and following treatment with Na(2)PtCl(6), Na(2)PdCl(6) or Na(3)RhCl(6). (NH(4))(6)Mo(7)O(24) was included as control. The following end-points were considered: expression of differentiation markers, effectiveness of allergen presentation and Th2 cytokine production by cocultured T lymphocytes, expression of IgE-type I receptor and efficiency of IgE-dependent endocytosis. RESULTS: We found that treatment with PLGE (but not with the control metal) increased costimulatory molecule expression and antigen presentation, amplified IL-5 production by cocultured T lymphocytes, upregulated IgE-type I receptor membrane expression, and augmented IgE-type I receptor-mediated endocytosis. CONCLUSIONS: We conclude that PLGE have an adjuvant-like effect on dendritic cells that can favor and amplify the immune response to allergens.

Exposure-effect relationship of platinum salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study.

BACKGROUND: There is a high incidence of occupational asthma and rhinitis caused by platinum (Pt) salts in precious-metal refineries. OBJECTIVE: We sought to assess exposure to Pt salts and the incidence of Pt salt allergy in a catalyst production plant. METHODS: A 5-year prospective cohort study was performed in 159 catalyst production workers (94.6% of recruited), 50 craftsmen (92. 6% of recruited), and 66 control subjects (76.7% of recruited) at yearly intervals. Subjects were assigned to exposure categories of high levels of Pt (n = 115), persistently low levels of Pt (n = 51), intermittently low levels of Pt (n = 61), or no Pt (n = 48) after the initial survey according to job title and job location. Skin prick test conversion from a negative response to a 4 mm or larger wheal response with a 10(-2) mol/L hexachloroplatinic acid solution was chosen as the outcome variable. RESULTS: Exposure assessment of airborne Pt and Pt in the serum of workers demonstrated clear differences between exposure categories. The threshold limit value of 2 microg/m(3) for soluble Pt was exceeded in 3 (4%) of 78 measurements. Thirteen subjects assigned to high exposure showed skin test conversion, and new allergic symptoms were associated with exposure. Among the high-exposure category, the incidence rate of skin prick test conversion was 5.9 per 100 person-years for newly employed subjects (n = 79) and 2.1 per 100 person-years for those who had already been employed at the time of the initial survey (n = 36). A predicting factor for skin test conversion in highly exposed subjects was smoking status (relative risk, 3.9; 95% confidence interval, 1.6-9.7) but not atopy or bronchial hyperresponsiveness. CONCLUSION: Sensitization to Pt salts may develop in workers of catalyst production plants. Both the exposure to Pt salts and the incidence of Pt salt allergy were lower compared with reported data from precious-metal refineries.

20 years of medical surveillance on exposure to allergenic and non-allergenic platinum compounds: the importance of chemical speciation.

OBJECTIVES: Chloroplatinates are potent allergens but other soluble platinum compounds such as tetraammine platinum dichloride (TPC) do not provoke reactions in subjects who are sensitive to chloroplatinates. TPC has been used in the manufacture of autocatalysts for 20 years. This study analyses 20 year data on exposure to soluble platinum compounds and medical surveillance to confirm that TPC is not allergenic. METHODS: Workers in three distinct operations were exposed to soluble platinum compounds as chloroplatinates, chloroplatinates with TPC, or to TPC alone. Results of personal air sampling for soluble platinum compounds were compared together with the results of medical surveillance. RESULTS: The levels of exposure to soluble platinum compounds in each operation were comparable but the incidence of allergy was significantly different. In a subgroup of workers consistently exposed to chemical processes in each operation, the cumulative chance of being sensitised after 5 years of exposure was estimated as 51% for chloroplatinate exposure, 33% for mixed exposure, and 0% for TPC alone. The differences in sensitisation rates could not be explained by age, sex, and atopy. Nor could they be explained by the increased frequency of smoking in the workers with chloroplatinate exposure, despite the markedly higher risk of sensitisation in smokers. The differences could only be explained by the chemical stability of TPC. CONCLUSIONS: This study shows that the soluble platinum compound TPC is not allergenic under normal industrial conditions. Characterisation of the chemical compound (speciation) is essential to prevent stringent exposure limits being imposed for all soluble compounds on a generic basis.

Interaction of HLA phenotype and exposure intensity in sensitization to complex platinum salts.

The development of sensitization to inhaled allergens is determined by the interaction of multiple genetic and environmental influences. Occupational sensitization to low-molecular-weight chemicals allows a specific immunological response to an inhaled hapten to be studied in a well-defined population with characterized exposure. We investigated the workforce of a large platinum refinery exposed to ammonium hexachloroplatinate (ACP) to test the hypothesis that the development of IgE-associated sensitization to ACP was influenced by human leukocyte-associated antigen (HLA) phenotype, especially in those with lower ACP exposure. We performed HLA typing in 44 cases with a positive skin prick test to ACP, and 57 nonsensitized referents matched on age, race, duration of employment, and category of ACP exposure. An HLA-DR3 phenotype was more common among cases (odds ratio [OR] 2.3), and more so in those with low (OR infinite) than with high exposure (OR 1.6); HLA-DR6 was less common among the cases (OR 0.4), an association also stronger in the low-exposure group (OR 0.1 versus 0.5). These results provide evidence that HLA phenotype is a significant determinant of sensitization to complex platinum salts and for the first time show that the strength of this association varies with intensity of exposure to the sensitizing agent. They imply that as exposure-control measures are taken to prevent occupational sensitization and, by analogy, sensitization to allergens outside the workplace, disease incidence will increasingly be determined by genetic susceptibility.

Allergy to complex salts of platinum in refinery workers: prospective evaluations of IgE and Phadiatop status.

BACKGROUND: Experience has shown some variation in the associations between IgE, atopy, and sensitization to platinum salts. Clarification of these associations, and the value of the parameters in predicting and diagnosing sensitization of workers at risk, required prospective investigation. OBJECTIVES: Evaluation of total IgE and Phadiatop(R) status to establish baseline values, and changes during employment, predictive or associated with subsequent platinum salt sensitization. METHODS: A 24-month prospective study, in a South African primary platinum refinery, of a cohort of 78 healthy recruits without evidence of atopy (tested negative to skin prick test with common allergens). Subsequently they were categorized as 22 sensitized (positive skin prick test to platinum salts), 46 not sensitized (negative skin prick test and symptom free), and 10 symptomatic subjects not included in either category. RESULTS: (1) Pre-employment: four (18%) of the subsequently sensitized subjects and eight (17%) not sensitized were Phadiatop(R) positive. Levels of total IgE > 100 kU/L, present in 16 subjects were associated with positive Phadiatop(R) status and race. (2) During employment: Phadiatop(R) status converted from negative to positive in more sensitized (12/18) than unsensitized (6/38) subjects (P

Immunostimulatory effects of platinum compounds: correlation between sensitizing properties in vivo and modulation of receptor-mediated endocytosis in vitro.

The sensitizing properties of different complex salts of platinum were defined in vivo by means of the popliteal lymph node (PLN) assay in mice. Hexa- and tetrachloroplatinates were confirmed to be highly immunogenic, inducing vigorous primary immune responses in the draining PLN following single subcutaneous injections. Flow-cytometric analysis revealed a dramatic increase in the total number of cells expressing proliferating cell nuclear antigen. The majority of these cells were of the T helper phenotype (CD4+) reflecting the T-cell dependence of the PLN response induced by Pt salts such as Na2[PtCl6] or Na2[PtCl4]. In contrast, [Pt(NH3)4]Cl2 failed to elicit a significant increase in PLN cell proliferation when compared with saline-treated controls. The differential immunogenicity of the Pt compounds found in vivo directly correlated with their capacity to modulate mechanisms of receptor-mediated endocytosis in murine Langerhans cells in vitro. The reactivity of Na2[PtCl6] or Na2[PtCl4] resembled that of potent contact sensitizers in this endocytosis assay whereas [Pt(NH3)4]Cl2 proved to be mert. These results suggest that [Pt(NH3)4]Cl2 might be less harmful to humans than hexa- or tetrachloroplatinates. As demonstrated with Pt compounds, monitoring of direct effects of low-molecular-weight chemicals on antigen-presenting dendritic cells in vitro is able to predict their sensitizing potential in vivo.