drug hypersensitivity; p-i concept; prediction of drug induced side effects; subsets of cytotoxic CD8 cells; primary immune response; Abacavir hypersensitivity
Pichler Werner J., Adam Jacqueline, Watkins Stephen, Wuillemin Natascha, Yun James, Yerly Daniel (2015), Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors, in International Archives of Allergy and Immunology
, 168(1), 13-24.
Jörg-Walther Lukas, Schnyder Benno, Helbling Arthur, Helsing Karin, Schüller Alexandra, Wochner Annette, Pichler Werner (2015), Flare-up reactions in severe drug hypersensitivity: infection or ongoing T-cell hyperresponsiveness, in Clinical Case Reports
, 3(10), 798-801.
Adam Jacqueline, Wuillemin Natascha, Watkins Stephan, Jamin Heidi, Eriksson Klara K., Villiger Peter, Fontana Stefano, Pichler Werner J., Yerly Daniel (2014), Abacavir Induced T Cell Reactivity from Drug Naïve Individuals Shares Features of Allo-Immune Responses, in PLoS ONE
, 9(4), e95339-e95339.
Watkins Stephan Pichler WJ (2013), Activating interactions of sulfanilamides with T cell receptors, in Open Journal of Immunology
, 3(3), 139-157.
Schnyder Benno, Pichler Werner J (2013), Allergy to sulfonamides., in The Journal of allergy and clinical immunology
, 131(1), 256-257.
Schnyder B, Porebski G, Pichler W J (2013), Allergy workup of severe cutaneous adverse drug reactions: a light at the end of the tunnel?, in The British journal of dermatology
, 168(3), 463-4.
Yun James Sip, Mattsson J., Schnyder Karin, Fontana Stefano, Largíadér Carlo Rodolfo, Pichler Werner Joseph, Yerly Daniel (2013), Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response, in Clinical and Experimental Allergy
, 43(11), 1246-1255.
Wuillemin Natascha, Adam Jacqueline, Fontana Stefano, Krähenbühl Stephan, Pichler Werner J, Yerly Daniel (2013), HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin., in Journal of immunology (Baltimore, Md. : 1950)
, 190(10), 4956-64.
Schnyder Benno, Adam Jacqueline, Rauch Andri, Thurnheer Maria C, Pichler Werner J (2013), HLA-B*57:01(+) abacavir-naive individuals have specific T cells but no patch test reactivity., in The Journal of allergy and clinical immunology
, 132(3), 756-8.
Porebski G, Pecaric-Petkovic T, Groux-Keller M, Bosak M, Kawabata TT, Pichler WJ (2013), In vitro drug causality assessment in Stevens-Johnson syndrome – alternatives for lymphocyte transformation test, in Clinical & Experimental Allergy
, 43(9), 1027-1037.
Watkins Stephan, Pichler Werner J. (2013), Sulfamethoxazole Induces a Switch Mechanism in T Cell Receptors Containing TCRV beta 20-1, Altering pHLA Recognition, in PLOS ONE
, 8(10), e76211-e76211.
Adam Jacqueline, Eriksson Klara K, Schnyder Benno, Fontana Stefano, Pichler Werner J, Yerly Daniel (2012), Avidity determines T-cell reactivity in abacavir hypersensitivity., in European journal of immunology
Hausmann O, Schnyder B, Pichler W J (2012), Etiology and pathogenesis of adverse drug reactions., in Chemical immunology and allergy
, 97, 32-46.
Yun J, Adam J, Yerly D, Pichler W J (2012), Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA., in Allergy
, 67(11), 1338-46.
Daubner B, Groux-Keller M, Hausmann O V, Kawabata T, Naisbitt D J, Park B K, Wendland T, Lerch M, Pichler W J (2012), Multiple drug hypersensitivity: normal Treg cell function but enhanced in vivo activation of drug-specific T cells., in Allergy
, 67(1), 58-66.
Schnyder Benno, Pichler Werner J (2012), Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach., in The Journal of allergy and clinical immunology
, 129(4), 1170-1.
Wendland T, Daubner B, Pichler WJ (2011), Ceftobiprole associated agranulocytosis after drug rash with eosinophilia and systemic symptoms induced by vancomycin and rifampicin, in BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
, 71(2), 297-300.
Adam Jacqueline, Pichler Werner J, Yerly Daniel (2011), Delayed drug hypersensitivity: models of T-cell stimulation., in British journal of clinical pharmacology
, 71(5), 701-7.
Pichler WJ, Daubner B, Kawabata T (2011), Drug hypersensitivity: Flare-up reactions, cross-reactivity and multiple drug hypersensitivity, in JOURNAL OF DERMATOLOGY
, 38(3), 216-221.
Elsheikh Ayman, Castrejon Luis, Lavergne Sidonie N, Whitaker Paul, Monshi Manal, Callan Hayley, El-Ghaiesh Sabah, Farrell John, Pichler Werner J, Peckham Daniel, Park B Kevin, Naisbitt Dean J (2011), Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis., in The Journal of allergy and clinical immunology
, 127(6), 1543-1543.
McCormack Mark, Alfirevic Ana, Bourgeois Stephane, Farrell John J, Kasperavičiūtė Dalia, Carrington Mary, Sills Graeme J, Marson Tony, Jia Xiaoming, de Bakker Paul I W, Chinthapalli Krishna, Molokhia Mariam, Johnson Michael R, O'Connor Gerard D, Chaila Elijah, Alhusaini Saud, Shianna Kevin V, Radtke Rodney A, Heinzen Erin L, Walley Nicole, Pandolfo Massimo, Pichler Werner, Park B Kevin, Depondt Chantal, Sisodiya Sanjay M (2011), HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans., in The New England journal of medicine
, 364(12), 1134-43.
Pichler Werner J, Naisbitt Dean J, Park B Kevin (2011), Immune pathomechanism of drug hypersensitivity reactions., in The Journal of allergy and clinical immunology
, 127(3 Suppl), 74-81.
Porebski G, Gschwend-Zawodniak A, Pichler W J (2011), In vitro diagnosis of T cell-mediated drug allergy., in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunolo
, 41(4), 461-70.
Schlapbach C, Zawodniak A, Irla N, Adam J, Hunger R E, Yerly D, Pichler W J, Yawalkar N (2011), NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions., in Allergy
, 66(11), 1469-76.
Elsheikh Ayman, Lavergne Sidonie N, Castrejon J Luis, Farrell John, Wang Haiyi, Sathish Jean, Pichler Werner J, Park B Kevin, Naisbitt Dean J (2010), Drug antigenicity, immunogenicity, and costimulatory signaling: evidence for formation of a functional antigen through immune cell metabolism., in Journal of immunology (Baltimore, Md. : 1950)
, 185(11), 6448-60.
Martin Stefan F, Esser Philipp R, Schmucker Sonja, Dietz Lisa, Naisbitt Dean J, Park B Kevin, Vocanson Marc, Nicolas Jean-Francois, Keller Monika, Pichler Werner J, Peiser Matthias, Luch Andreas, Wanner Reinhard, Maggi Enrico, Cavani Andrea, Rustemeyer Thomas, Richter Anne, Thierse Hermann-Josef, Sallusto Federica (2010), T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays., in Cellular and molecular life sciences : CMLS
, 67(24), 4171-84.
Hausmann Oliver V, Seitz Michael, Villiger Peter M, Pichler Werner J (2010), The complex clinical picture of side effects to biologicals., in The Medical clinics of North America
, 94(4), 791-804.
Hitherto, experiments aimed to understand drug hypersensitivity were based on in vivo primed cells from allergic individuals, and thus investigated the memory immune response. How the drug specific T cells were primed remained enigmatic, as it was difficult to induce a primary, drug specific immune response in humans and no animal experiments existed. The discovery of important risk factors like HLA-B*5701 for severe abacavir (ABC) hypersensitivity opened the possibility to investigate a primary immune response to a drug in drug naïve individuals in vitro: Peripheral blood mononuclear cells (PBMC) of healthy, HIV negative persons with the HLA-B*5701+ phenotype, which were never exposed to ABC, can be stimulated in vitro with ABC, and we recently could even generate ABC specific T cell clones (TCC) from abacavir naïve donors: two patterns of abacavir recognition were seen: some TCC react with abacavir directly (pharmacological interaction (p-i) concept), other TCC react after abacavir uptake and processing by dendritic cells, possibly due to hapten mechanism. In this grant application/period we would like to investigate a) Under which conditions can abacavir stimulate CD8+ T cells directly (p-i mechanism), namely without ABC uptake/processing/metabolism in dendritic cells (DC) or other antigen presenting cells? To this end ABC pulsed DC as well as DC blocked in ABC metabolism will be used to induce a primary immune response to ABC. The development of hapten and p-i stimulated T cell clones under these conditions will be evaluated. Further, the role of DC activation will be tested, e.g, whether ABC, independent of the way T cells react to it, is activating DC and whether HLA-B*5701 positive or negative DC are similarly activated. b) It is at present unclear from which compartment (naïve or memory) the directly (p-i) and indirectly (hapten) stimulated, ABC specific T cells arise: Do such hapten -reactive T cells stem from the antigen-naive T cell pool, while p-i-stimulated TCC derive exclusively from the memory T cell pool, suggesting a prior priming with a peptide antigen? c) The killing mechanism of CD8+ T cell is quite diverse (granzymeB/perforin, granulysin, FasL, TRAIL, TNFa). In view of the importance of killing by granulysin for severe drug allergies like toxic epidermal necrolysis (TEN), we will investigate under which stimulatory conditions granulysin is induced, whether the type of killing is related to the type of drug recognition (p-i or hapten) and to what extent the priming of the reacting cell cultures with a mixture of cytokines can modify the naïve CD8+ T cell response? The study gives the opportunity to investigate the regulation of CD8 subsets in humans, a still rather unknown area of research. Overall, our studies aim to better understand the initiation of an immune reactivity to drugs, which is a clue to prevent or predict such side effects, and may give insights into the regulation of cytotoxicity in CD8+, human T cells.