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Investigating the primary immune response against drugs in humans

English title Investigating the primary immune response against drugs in humans
Applicant Pichler Werner Joseph
Number 129828
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik für Rheumatologie, Immunologie und Allergologie Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Immunology and Immunopathology
Start/End 01.05.2010 - 31.10.2013
Approved amount 484'520.00
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Keywords (6)

drug hypersensitivity; p-i concept; prediction of drug induced side effects; subsets of cytotoxic CD8 cells; primary immune response; Abacavir hypersensitivity

Lay Summary (German)

Lead
Lay summary
Medikamentenallergien betreffend ca. 2 bis 4 % der hospitalisierten Personen und sind auch ein häufiges Problem in der ärztlichen Praxis. Sie können oft harmlos verlaufen , gelegentlich aber lebensgefährliche Systemreaktionen bewirken. Die Allergologie in Bern beschäftigt sich seit vielen Jahren mit dem Wirkmechanismus der medikamentenallergischen Reaktionen im Bestreben, derartige Reaktionen besser vermeiden zu können. Im Nationalfonds-Gesuch 310030_129828/1 von 2010 bis 2013 wird folgende Frage wissenschaftlich untersucht: Wie kommt es zur Entwicklung einer Medikamentenallergie in Personen, die genetisch dafür prädestiniert sind? Hintergrund für diese Fragestellung ist der Befund, dass einige Medikamente (Abacavir, ein Anti-HIV Medikament) nur in Personen mit einem bestimmten HLA-Phänotyp Allergien entwickeln (HLA-B*5701): Man benutzt diese Eigenschaft schon, um z.B. Abacavir - bedingte Nebenwirkungen zu vermeiden, da nur ca. 5% der Bevölkerung diese HLA-Gene haben. Das heisst, zum Vermeiden dieser Nebenwirkung wird bereits "personalisierte Medizin" betrieben, zum Schutze des Patienten. Andererseits kann man Blut von HLA-B*5701 positiven aber gesunden, und nie Abacavir-exponierten Personen nehmen und es in vitro mit Abacavir stimulieren. Dies erlaubt, die Neuentwicklung einer Immunantwort in vitro zu beobachten! Basieren auf Vorstudien haben wir festgestellt, dass Abacavir auch direkt an Immunrezeptoren binden und die Immunzellen stimulieren kann: Dieser Mechanismus wird "pharmacological interaction with immune receptors (pi-mechanism)" genannt, und unterscheidet sich wesentlich von anderen Immunmechanismen. Da für Medikamentenallergien kaum Tiermodelle existieren, ist dieses in vitro Modell eine ideale Möglichkeit, die Entwicklung von Medikamentenallergien zu untersuchen. Ist es nötig, dass dendritische Zellen stimuliert werden von Abacavir, damit sich eine Immunantwort entwickelt? Welche T-Zellen werden zuerst stimuliert (Gedächtnis-T-Zellen oder naive T-Zellen)? Weisen die Abacavir reaktiven Zellen auch eine weitere Spezifität auf? Kann Verhinderung des Abacavir-Metabolismus dazu führen, dass die Primärantwort verhindert wird, oder dass die Abacavir-reaktiven Zellen nur in einer bestimmten Form mit Abacavir reagieren? Diese Untersuchungen sollten beitragen herauszufinden, wie man besser gefährliche Medikamentenallergien vermeiden kann.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors
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.
Flare-up reactions in severe drug hypersensitivity: infection or ongoing T-cell hyperresponsiveness
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.
Abacavir Induced T Cell Reactivity from Drug Naïve Individuals Shares Features of Allo-Immune Responses
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.
Activating interactions of sulfanilamides with T cell receptors
Watkins Stephan Pichler WJ (2013), Activating interactions of sulfanilamides with T cell receptors, in Open Journal of Immunology, 3(3), 139-157.
Allergy to sulfonamides.
Schnyder Benno, Pichler Werner J (2013), Allergy to sulfonamides., in The Journal of allergy and clinical immunology, 131(1), 256-257.
Allergy workup of severe cutaneous adverse drug reactions: a light at the end of the tunnel?
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.
Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response
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.
HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin.
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.
HLA-B*57:01(+) abacavir-naive individuals have specific T cells but no patch test reactivity.
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.
In vitro drug causality assessment in Stevens-Johnson syndrome – alternatives for lymphocyte transformation test
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.
Sulfamethoxazole Induces a Switch Mechanism in T Cell Receptors Containing TCRV beta 20-1, Altering pHLA Recognition
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.
Avidity determines T-cell reactivity in abacavir hypersensitivity.
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, 1-10.
Etiology and pathogenesis of adverse drug reactions.
Hausmann O, Schnyder B, Pichler W J (2012), Etiology and pathogenesis of adverse drug reactions., in Chemical immunology and allergy, 97, 32-46.
Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA.
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.
Multiple drug hypersensitivity: normal Treg cell function but enhanced in vivo activation of drug-specific T cells.
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.
Nonimmediate drug allergy: diagnostic benefit of skin testing and practical approach.
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.
Ceftobiprole associated agranulocytosis after drug rash with eosinophilia and systemic symptoms induced by vancomycin and rifampicin
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.
Delayed drug hypersensitivity: models of T-cell stimulation.
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.
Drug hypersensitivity: Flare-up reactions, cross-reactivity and multiple drug hypersensitivity
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.
Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis.
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.
HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.
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.
Immune pathomechanism of drug hypersensitivity reactions.
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.
In vitro diagnosis of T cell-mediated drug allergy.
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.
NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions.
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.
Drug antigenicity, immunogenicity, and costimulatory signaling: evidence for formation of a functional antigen through immune cell metabolism.
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.
T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays.
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.
The complex clinical picture of side effects to biologicals.
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.

Collaboration

Group / person Country
Types of collaboration
Allergiestifgung Ulrich Mueller-Gierok Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University of Liverpool Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Drug Hypersensitivity Meeting 5 11.04.2012 Munich, Germany

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions update on drug hypersensititivity Western Switzerland German-speaking Switzerland 2016

Awards

Title Year
Klaus Kalveram Preis des Arzteverbandes deutscher Allergologen 2013
Pfizer Forschungspreis (klinische Immunologie) 2013
Paul Ehrlich Award of EAACI (Promotion of Science) 2012

Associated projects

Number Title Start Funding scheme
116113 Drug-TCR interactions, TCR specificity and TCR activation in drug hypersensitivity 01.05.2007 Project funding (Div. I-III)
113744 T cells simultaneously reacting to peptides and drugs 01.10.2006 Project funding (Div. I-III)

Abstract

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.
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