Mechanism of drug-induced anaphylaxis

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely distributed and frequently prescribed as mild analgesics and antipyretics for various types of pain including migraine, acute muscle pain, and algomenorrhea, and for treatment of rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis. Systemic hypersensitivity reactions to NSAIDs represent one type of possible adverse drug reactions, but may have potentially life-threatening consequences. Often sensitive individuals have to be treated by emergency doctors. Notably, the mechanism of hypersensitivity reactions often remains unclear due to the lack of appropriate diagnostic means, and a differentiation between allergic (activation of drug-specific B and T cells) and pseudoallergic (interference with immune effector mechanisms) adverse reaction can not be made unequivocally. We have previously demonstrated that adverse reactions against the NSAID propyphenazone are IgE-mediated (Himly et al., JACI 111: 882, 2003). Here we will investigate the mechanism of systemic hypersensitivity to diclofenac, another representative of NSAIDs. In order to reach this task we will investigate the immune interactions of diclofenac by histamine release and human serology. Negative results of skin tests and the symptomatic of systemic hypersensitivity have pointed at the involvement of metabolic bioactivation in diclofenac allergy. Therefore, five major metabolites will be tested in addition to diclofenac, and four alternative means of conjugating diclofenac to a carrier protein, human serum albumin, will be investigated. We aim to develop an in vitro diagnostic test system and assess its clinical applicability in collaboration with two major allergy centers in Austria. We will evaluate initial steps towards the validation of this test system. As mouse models have repeatedly proven to be versatile instruments in allergy research, we will use immunization protocols capable of inducing an immune response resembling the in vivo situation in humans for the establishment of a mouse model for diclofenac allergy. We will furthermore apply proteomic methods to identify serum proteins being haptenized by diclofenac and study novel immune interactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely distributed and frequently prescribed as mild analgesics and antipyretics for various types of pain including migraine, acute muscle pain, and algomenorrhea, and for treatment of rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis. Systemic hypersensitivity reactions to NSAIDs represent one type of possible adverse drug reactions, but may have potentially life-threatening consequences. Often sensitive individuals have to be treated by emergency doctors. Notably, the mechanism of hypersensitivity reactions often remains unclear due to the lack of appropriate diagnostic means, and a differentiation between allergic (activation of drug-specific B and T cells) and pseudoallergic (interference with immune effector mechanisms) adverse reaction can not be made unequivocally. We have previously demonstrated that adverse reactions against the NSAID propyphenazone are IgE-mediated (Himly et al., JACI 111: 882, 2003). Here we will investigate the mechanism of systemic hypersensitivity to diclofenac, another representative of NSAIDs. In order to reach this task we will investigate the immune interactions of diclofenac by histamine release and human serology. Negative results of skin tests and the symptomatic of systemic hypersensitivity have pointed at the involvement of metabolic bioactivation in diclofenac allergy. Therefore, five major metabolites will be tested in addition to diclofenac, and four alternative means of conjugating diclofenac to a carrier protein, human serum albumin, will be investigated. We aim to develop an in vitro diagnostic test system and assess its clinical applicability in collaboration with two major allergy centers in Austria. We will evaluate initial steps towards the validation of this test system. As mouse models have repeatedly proven to be versatile instruments in allergy research, we will use immunization protocols capable of inducing an immune response resembling the in vivo situation in humans for the establishment of a mouse model for diclofenac allergy. We will furthermore apply proteomic methods to identify serum proteins being haptenized by diclofenac and study novel immune interactions.