Search Results - (Author, Cooperation:M. Britschgi)

2011-09-03

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Aging ; Animals ; Chemokine CCL11/blood/cerebrospinal fluid/metabolism/pharmacology ; Chemokines/*blood/cerebrospinal fluid/*metabolism ; Female ; Learning/drug effects/*physiology ; Learning Disorders/blood/cerebrospinal fluid/physiopathology ; Male ; Memory Disorders/blood/cerebrospinal fluid/physiopathology ; Mice ; Mice, Inbred C57BL ; Neurogenesis/drug effects/*physiology ; Parabiosis ; Plasma/chemistry ; Time Factors

1365-2222

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Background It has been shown that drugs comprise a group of non-peptide antigens that can be recognized by human T cells in the context of HLA class II and that this recognition is involved in allergic reactions. Recent studies have demonstrated a MHC-restricted but processing- and metabolism-independent pathway for the presentation of allergenic drugs such as lidocaine and sulfamethoxazole (SMX) to drug-specific T cells. However, there is little information so far on the precise molecular mechanisms of this non-covalent drug presentation.Objective The aim of this study was to evaluate the requirements for a specific peptide occupying the groove of the MHC class II molecule for the efficient presentation of non-covalently bound drugs to CD4+ T cells.Methods We analysed the effect of coincubation or prepulse of antigen presenting cells (APC) with different peptides on the proliferative responses of SMX-specific CD4+ T cell clones. In a second series of experiments, we eluted HLA-bound peptides from the surface of antigen presenting cells by mild acid treatment. Successful removal of peptides was tested directly using labelled peptides and functionally by monitoring activation and proliferation of peptide-specific T cell clones. Finally, the presentation of SMX to SMX-specific T cell clones before and after elution of MHC class II bound peptides was tested.Results We found that neither peptide coincubation nor peptide prepulse of APC altered the proliferative response of SMX-specific T cells. APC treated with the acid for a short time retained cell viability, MHC class II expression and antigen presenting cell function. However, defined peptides could be eluted from surface MHC class II molecules nearly quantitatively. Nevertheless, the chemically non-reactive drug SMX could still be presented to specific T cells independent of the presence of distinct self-peptides.Conclusion Our data suggest that small molecules like drugs can bind to a multitude of HLA-bound peptides or that, similar to superantigens, they might bind directly to HLA.

Electronic Resource

1398-9995

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Background:  Cytotoxic mechanisms are involved in different forms of drug induced exanthems.Methods:  Here we compare the killing pathways of CD4+, CD8+ and CD4/CD8+ T-cell lines (TCL) and clones derived from patients suffering from maculopapular, bullous and pustular drug eruptions. In vitro, perforin and Fas-mediated killing was analysed in cytotoxicity assays against autologous Epstein–Barr virus (EBV)-transformed B-cell lines, Fas-transfected mouse lymphoblasts and natural killer (NK)-target cells. In addition, affected skin lesions and the TCL and clones were stained for perforin and FasL-expression.Results:  We detected perforin and some FasL-mediated killing in all three types of exanthems. Some of the drug-specific T-cell clones analysed exerted mainly perforin-, other more FasL-mediated killing showing no strict relationship between their perforin- and Fas-mediated cytotoxic capacity. Using a cell culture method focusing on the generation of cytotoxic T cells, we detected drug-specific CD8+, TCRαβ+ T cells, which failed to proliferate to drug presentation by antigen presenting cells but killed in a drug dependent way. Interestingly, these cells had substantial natural killer-like T cell(s) like features as they were CD56+ and CD94+ and had the ability to kill the NK-sensitive cell line K562.Conclusion:  Our data underline the important role of cytotoxic mechanisms in different forms of drug induced exanthems and suggest that even some T cells with NK-like characteristics may be involved in drug hypersensitivity.

Electronic Resource