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Non-Immediate Reaction to Iodine Contrast Media
Abstracts S247
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Monitoring the T Cell Response in a Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) to Phenytoin in both Peripheral Blood and Skin J. A. Cornejo-Garcia1, E. Martin2, T. D. Fernandez1, C. Mayorga1, S. Lopez1, R. R-Pena1, I. Doña2, J. L. Rodriguez-Bada1, M. Blanca2; 1Research Laboratory, Carlos Haya Hospital, Malaga, SPAIN, 2Allergy Service, Carlos Haya Hospital, Malaga, SPAIN. RATIONALE: DRESS is a rare syndrome, most frequently caused by aromatic antiepileptic agents, such as phenytoin. Although T lymphocytes have been shown to be involved, the immunological mechanisms are not well understood. We monitored a 30-year-old woman who had DRESS to phenytoin. METHODS: Sequential samples from peripheral blood and skin from the onset of the reaction (acute phase) until it subsided were studied. Peripheral blood mononuclear cells were analyzed by flow cytometry and skin biopsies by immunohistochemistry techniques. The clinical diagnosis was made by patch testing with different anticonvulsants, hematological measurements, and serological analyses for viral infections. RESULTS: The flow cytometry results showed an increase in activated CD4 lymphocytes expressing the skin homing receptor (CLA), with a maximum level 12 days after onset of the reaction, and an increase in perforin in CD8 lymphocytes, in parallel with the clinical symptoms. The skin biopsies showed several foci of vacuolar alterations in the epidermis, with a perivascular dermal infiltrate, composed mainly of activated CD4 lymphocytes expressing CLA and macrophages. These findings were reproduced in the skin biopsy from the positive intradermal test to phenytoin. CONCLUSIONS: Monitoring this patient with DRESS to phenytoin showed involvement of an immunological mechanism mediated by the two T lymphocyte subsets (CD4 and CD8), in both peripheral blood and skin biopsies, which paralleled the clinical symptoms. The involvement of phenytoin as the drug causing the reaction was demonstrated by a positive patch test which reproduced the same immunological response. Funding: FIS and Junta de Andalucia
956
957
Non-Immediate Reaction to Iodine Contrast Media
E. Martin1, J. A. Cornejo-Garcia2, R. R-Pena2, T. D. Fernandez2, S. Lopez2, C. Mayorga2, M. J. Torres1, C. Antunez2, M. Valenzuela1, M. Blanca1; 1Allergy Service, Carlos Haya Hospital, Malaga, SPAIN, 2Research Laboratory, Carlos Haya Hospital, Malaga, SPAIN. RATIONALE: Non-immediate reactions to iodine contrast media (ICM) affect 2-5% of patients with adverse reactions to ICM, although this may be an underestimation. Associating the adverse reaction with ICM administration is not easy. We studied the immunological mechanisms involved in a patient with exanthema after administration of Iomeprol. METHODS: The study was performed in sequential blood samples taken from the onset of the reaction (acute phase) until it subsided, using flow cytometry in peripheral blood mononuclear cells (PBMCs) and immunohistochemistry techniques with the skin biopsy. Diagnosis was confirmed by skin testing and the lymphocyte transformation test (LTT) with different ICM. RESULTS: Flow cytometry showed an increase in the different activation markers (CD69, CD25 and HLA-DR) and the skin homing receptor (CLA), mainly in CD4 lymphocytes, whereas perforin was higher in the CD8 subpopulation. In the skin biopsy, at the acute phase, there was a perivascular mononuclear infiltrate composed of CD4 lymphocytes, expressing CD25, HLA-DR and CLA, with a high presence of eosinophils. Intradermal skin tests were positive to iomeprol, iodixanol, iopramide, iobitridol, ioversol and sodium meglumine ioxaglate. The LTT showed lymphocyte proliferation with the six ICM analyzed in the patient, with negative results in all five healthy controls. CONCLUSIONS: We can confirm a specific immunological mechanism implicated in this non-immediate adverse reaction to ICM. Moreover, the positive results in skin tests and lymphocyte proliferation tests to several ICM indicate cross-reactivity. Funding: FIS and Junta de Andalucia Tolerance Induction Via the Nasal Route is Associated with Downregulation of Lung Cytokine Production, Including Il-10, in a Mouse Model of Asthma C. Longaretti, C. Boudousquié, F. Spertini; Laboratoire d’Immunologie et Allergie, CHUV, Lausanne, SWITZERLAND. RATIONALE: We have recently shown that therapeutic induction of tolerance via the nasal route in ovalbumin (OVA) allergic mice limited eosinophil recruitment, IgE production and airway hyperreactivity. Implication of IL-10 in tolerance induction has been demonstrated in several allergy models. METHODS: OVA-sensitized asthmatic mice were treated intranasally with 1.5 mg OVA for 3 days. Mice were challenged by OVA aerosols 10 days later. IL-5, IL-4, IL-10, IL-13 and IFN were measured in bronchoalveolar lavage fluid (BALF), lung tissue and supernatants of OVA-stimulated cultures of bronchial lymph node (BLN) and lung cells. RESULTS: Upon OVA aerosol challenge, intranasal OVA treatment (INT) drastically reduced cytokine levels in BALF, in total lung extract as well as secretion by BLN and lung T cells in response to OVA, as compared to control animals. Before challenge in contrast, 7 days after INT, production of all measured cytokines was markedly exacerbated. The frequency of IL-10+CD4+ T cells followed the same pattern. CONCLUSIONS: INT with OVA was able to markedly downregulate both Th1 and Th2 cytokine production upon allergen challenge. Exacerbation of cytokine secretion after INT suggests a transient proinflammatory T cell activation prior to tolerance induction. The respective role of IL-10 as a proinflammatory Th2 cytokine or its contribution to tolerance via inducible IL-10+CD4+ T cells will have to be defined. Funding: Swiss National Science Foundation
958
MONDAY
Expression of Polarized T-Cell Surface Markers in Respiratory Allergy U. De Fanis, F. Mori, S. L. Limb, R. G. Hamilton, N. F. Adkinson, Jr., V. Casolaro; Johns Hopkins University, Baltimore, MD. RATIONALE: An imbalance of T cell subsets in asthma and other atopic diseases, with a predominance of Th2 cells, has been postulated. In the present study, the expression of CC chemokine receptor 5 (CCR5), a Th1 marker, and of chemoattractant receptor-homolog expressed on Th2 cells (CRTH2) was investigated to assess the validity of these indexes as predictors of Th-cell bias in respiratory allergy. METHODS: Expression of T-cell lineage markers, including CCR5 and CRTH2, was studied by multi-color flow cytometry of peripheral blood samples from 8 atopic asthmatics, 11 atopic non-asthmatics, and 17 sexand age-matched healthy control subjects. Established protocols were used for quantitation of total IgE and eosinophil numbers in all subjects. RESULTS: The frequency of CD4-CCR5+ cells within the CD3+CD45RO+ subset (memory T cells) was significantly lower in asthmatics than controls (29.0±2.1% vs. 38.2±1.3%, respectively; p=0.0005). Whereas the frequency of CD3+CRTH2+ cells was higher in asthmatics than controls (3.7±0.6% vs. 2.8±0.2%), this difference did not reach statistical significance (p=0.1). The frequency of CD3+CD45RO+CCR5+ cells in all subjects was in versely correlated with eosinophil numbers (r=-0.53, p=0.004); an inverse correlation with IgE levels was also observed, which, however, only approximated statistical significance (r=-0.32; p=0.07). CONCLUSIONS: The reduced frequency of CD8+CCR5+ T cells in asthmatic subjects and its inverse relationship to the eosinophil number, an established index of atopic conditions, strengthen the recent notion that type 1 cytotoxic T cells (Tc1) play a critical role in the control, or lack thereof, of immune and inflammatory processes that lead to the onset of asthma.
955
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Monitoring the T Cell Response in a Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) to Phenytoin in both Peripheral Blood and Skin J. A. Cornejo-Garcia1, E. Martin2, T. D. Fernandez1, C. Mayorga1, S. Lopez1, R. R-Pena1, I. Doña2, J. L. Rodriguez-Bada1, M. Blanca2; 1Research Laboratory, Carlos Haya Hospital, Malaga, SPAIN, 2Allergy Service, Carlos Haya Hospital, Malaga, SPAIN. RATIONALE: DRESS is a rare syndrome, most frequently caused by aromatic antiepileptic agents, such as phenytoin. Although T lymphocytes have been shown to be involved, the immunological mechanisms are not well understood. We monitored a 30-year-old woman who had DRESS to phenytoin. METHODS: Sequential samples from peripheral blood and skin from the onset of the reaction (acute phase) until it subsided were studied. Peripheral blood mononuclear cells were analyzed by flow cytometry and skin biopsies by immunohistochemistry techniques. The clinical diagnosis was made by patch testing with different anticonvulsants, hematological measurements, and serological analyses for viral infections. RESULTS: The flow cytometry results showed an increase in activated CD4 lymphocytes expressing the skin homing receptor (CLA), with a maximum level 12 days after onset of the reaction, and an increase in perforin in CD8 lymphocytes, in parallel with the clinical symptoms. The skin biopsies showed several foci of vacuolar alterations in the epidermis, with a perivascular dermal infiltrate, composed mainly of activated CD4 lymphocytes expressing CLA and macrophages. These findings were reproduced in the skin biopsy from the positive intradermal test to phenytoin. CONCLUSIONS: Monitoring this patient with DRESS to phenytoin showed involvement of an immunological mechanism mediated by the two T lymphocyte subsets (CD4 and CD8), in both peripheral blood and skin biopsies, which paralleled the clinical symptoms. The involvement of phenytoin as the drug causing the reaction was demonstrated by a positive patch test which reproduced the same immunological response. Funding: FIS and Junta de Andalucia
956
957
Non-Immediate Reaction to Iodine Contrast Media
E. Martin1, J. A. Cornejo-Garcia2, R. R-Pena2, T. D. Fernandez2, S. Lopez2, C. Mayorga2, M. J. Torres1, C. Antunez2, M. Valenzuela1, M. Blanca1; 1Allergy Service, Carlos Haya Hospital, Malaga, SPAIN, 2Research Laboratory, Carlos Haya Hospital, Malaga, SPAIN. RATIONALE: Non-immediate reactions to iodine contrast media (ICM) affect 2-5% of patients with adverse reactions to ICM, although this may be an underestimation. Associating the adverse reaction with ICM administration is not easy. We studied the immunological mechanisms involved in a patient with exanthema after administration of Iomeprol. METHODS: The study was performed in sequential blood samples taken from the onset of the reaction (acute phase) until it subsided, using flow cytometry in peripheral blood mononuclear cells (PBMCs) and immunohistochemistry techniques with the skin biopsy. Diagnosis was confirmed by skin testing and the lymphocyte transformation test (LTT) with different ICM. RESULTS: Flow cytometry showed an increase in the different activation markers (CD69, CD25 and HLA-DR) and the skin homing receptor (CLA), mainly in CD4 lymphocytes, whereas perforin was higher in the CD8 subpopulation. In the skin biopsy, at the acute phase, there was a perivascular mononuclear infiltrate composed of CD4 lymphocytes, expressing CD25, HLA-DR and CLA, with a high presence of eosinophils. Intradermal skin tests were positive to iomeprol, iodixanol, iopramide, iobitridol, ioversol and sodium meglumine ioxaglate. The LTT showed lymphocyte proliferation with the six ICM analyzed in the patient, with negative results in all five healthy controls. CONCLUSIONS: We can confirm a specific immunological mechanism implicated in this non-immediate adverse reaction to ICM. Moreover, the positive results in skin tests and lymphocyte proliferation tests to several ICM indicate cross-reactivity. Funding: FIS and Junta de Andalucia Tolerance Induction Via the Nasal Route is Associated with Downregulation of Lung Cytokine Production, Including Il-10, in a Mouse Model of Asthma C. Longaretti, C. Boudousquié, F. Spertini; Laboratoire d’Immunologie et Allergie, CHUV, Lausanne, SWITZERLAND. RATIONALE: We have recently shown that therapeutic induction of tolerance via the nasal route in ovalbumin (OVA) allergic mice limited eosinophil recruitment, IgE production and airway hyperreactivity. Implication of IL-10 in tolerance induction has been demonstrated in several allergy models. METHODS: OVA-sensitized asthmatic mice were treated intranasally with 1.5 mg OVA for 3 days. Mice were challenged by OVA aerosols 10 days later. IL-5, IL-4, IL-10, IL-13 and IFN were measured in bronchoalveolar lavage fluid (BALF), lung tissue and supernatants of OVA-stimulated cultures of bronchial lymph node (BLN) and lung cells. RESULTS: Upon OVA aerosol challenge, intranasal OVA treatment (INT) drastically reduced cytokine levels in BALF, in total lung extract as well as secretion by BLN and lung T cells in response to OVA, as compared to control animals. Before challenge in contrast, 7 days after INT, production of all measured cytokines was markedly exacerbated. The frequency of IL-10+CD4+ T cells followed the same pattern. CONCLUSIONS: INT with OVA was able to markedly downregulate both Th1 and Th2 cytokine production upon allergen challenge. Exacerbation of cytokine secretion after INT suggests a transient proinflammatory T cell activation prior to tolerance induction. The respective role of IL-10 as a proinflammatory Th2 cytokine or its contribution to tolerance via inducible IL-10+CD4+ T cells will have to be defined. Funding: Swiss National Science Foundation
958
MONDAY
Expression of Polarized T-Cell Surface Markers in Respiratory Allergy U. De Fanis, F. Mori, S. L. Limb, R. G. Hamilton, N. F. Adkinson, Jr., V. Casolaro; Johns Hopkins University, Baltimore, MD. RATIONALE: An imbalance of T cell subsets in asthma and other atopic diseases, with a predominance of Th2 cells, has been postulated. In the present study, the expression of CC chemokine receptor 5 (CCR5), a Th1 marker, and of chemoattractant receptor-homolog expressed on Th2 cells (CRTH2) was investigated to assess the validity of these indexes as predictors of Th-cell bias in respiratory allergy. METHODS: Expression of T-cell lineage markers, including CCR5 and CRTH2, was studied by multi-color flow cytometry of peripheral blood samples from 8 atopic asthmatics, 11 atopic non-asthmatics, and 17 sexand age-matched healthy control subjects. Established protocols were used for quantitation of total IgE and eosinophil numbers in all subjects. RESULTS: The frequency of CD4-CCR5+ cells within the CD3+CD45RO+ subset (memory T cells) was significantly lower in asthmatics than controls (29.0±2.1% vs. 38.2±1.3%, respectively; p=0.0005). Whereas the frequency of CD3+CRTH2+ cells was higher in asthmatics than controls (3.7±0.6% vs. 2.8±0.2%), this difference did not reach statistical significance (p=0.1). The frequency of CD3+CD45RO+CCR5+ cells in all subjects was in versely correlated with eosinophil numbers (r=-0.53, p=0.004); an inverse correlation with IgE levels was also observed, which, however, only approximated statistical significance (r=-0.32; p=0.07). CONCLUSIONS: The reduced frequency of CD8+CCR5+ T cells in asthmatic subjects and its inverse relationship to the eosinophil number, an established index of atopic conditions, strengthen the recent notion that type 1 cytotoxic T cells (Tc1) play a critical role in the control, or lack thereof, of immune and inflammatory processes that lead to the onset of asthma.
955