Download Thesis Abstract Drug hypersensitivity reactions represent a major

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.