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Thesis Abstract Drug hypersensitivity reactions represent a major problem in clinical practice. Their clinical characteristics are very heterogeneous as drugs can elicit all types of immune reactions. The antigenicity of drugs relies on the fact that small molecules can bind covalently to carrier proteins, which become modified and then behave like a foreign antigenic proteins inducing humoral and T cell-mediated reactions, particular if the drug or the metabolite is stimulating the innate immune system as well. In addition, drug can directly interact with immune receptors like the highly polymorphic T cell receptors or MHC molecules (p-i-concept) and thereby initiating a specific T-cell immune response. Drugs can also induce cytotoxic cell responses involving cells of innate (NK cells) and adaptive (CD8 and CD4 T cells) immune system. Drug-specific cytotoxic cells were found in skin lesions in all forms of drug hypersensitivity reactions including maculo-papular, pustular and bullous exanthemas as well as in affected organs of patients with systemic drug hypersensitivity (interstitial nephritis and hepatitis of patients with DRESS). Drug specific T cell clones and lines could be generated from peripheral blood of patients with different forms of drug reactions and different mechanisms of drug-specific killing (granzymeB/perforin-; granulysin-; and FasL/Fas-mediated) could be shown. In the first part of my thesis, I present an introduction into the field with emphasis on cytotoxic mechanism in drug hypersensitivity; In the second part, a review article describes general immunological principles of drug hypersensitivity and summarizes the knowledge about how small molecular substances like drugs can interact and activate the innate and adaptive immune systems, and what are the clinical consequences of these interactions Third part of my thesis contains two publications, one original article and one case report: The first publication addresses the topic whether drug-reacting cytotoxic cells can be detected in the peripheral blood of drug-allergic patients in remission and whether in-vitro detection of these cells might be helpful in drug-allergy diagnosis. In the second publication, we describe a case of fulminate liver failure after vancomycine treatment in 60-year-old patient with sulfasalazine-induced DRESS syndrome. This case report is unique, as we obtained four biopsies, before and after liver transplantation, and we could elute cells from the affected organ. The data underline the important mechanism of cytotoxic T lymphocytes, mediating presumably drug-specific cytotoxicity via granzyme B and FasL as well. In the forth part of my thesis, I present a second review article on current in-vitro techniques used in the diagnosis of drug hypersensitivity reactions, and new promising tools in the diagnosis of T-cell mediated hypersensitivity to drugs.