Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…This in turn might explain why strong associations between expression of specific HLA alleles and SMX reactions have not been identified (Lonjou et al, 2008;Alfirevic et al, 2009). Independent research groups have shown that skin-and blood-derived T cells from all SMX hypersensitive patients are activated by nitroso SMX, which indicates that drug metabolism and the formation of hapten-modified proteins are relevant in the clinical setting (Schnyder et al, 2000;Burkhart et al, 2001;Nassif et al, 2004;Elsheikh et al, 2011 ). Furthermore, recent studies show that nitroso SMX stimulates the majority (~90%) of drug responsive T-cell clones isolated from patients with a history of SMX-induced skin injury (Castrejon et al, 2010a).…”

“…Using a multidisciplinary approach with samples from animal and human experimental systems, we have also been able to characterize SMX metabolismderived protein adducts in immune cells and define the relationship between adduct formation, costimulatory signaling, and stimulation of a T-cell response (Sanderson et al, 2007;Lavergne et al, 2009Lavergne et al, , 2010Elsheikh et al, 2010Elsheikh et al, , 2011. The presence of various pathologic factors [e.g., lipopolysaccharide (LPS), viral proteins, and cytokines] increased the formation of protein adducts in SMX-treated dendritic cells and reduced the time needed to detect adducts.…”

Hepatotoxicity Induced by Trimethoprim-Sulfamethoxazole in a Child with Cystic Fibrosis

“…However, little is known about toxic or adverse effects of TMP-SMX in this patient popuTrimethoprim-Sulfamethoxazole-Induced Hepatotoxicity lation. Elsheikh et al 3 showed that T cells from patients with CF and SMX hypersensitivity are primarily stimulated with oxidative metabolites of SMX, most likely due to recurrent infections that promote SMX metabolism. These T cells were also found to secrete higher levels of proinflammatory cytokines, such as interferon-gamma, than T cells from patients without CF.…”

“…These patients are more susceptible to various adverse drug hypersensitivity reactions secondary to repeated drug exposure, intense systemic inflammation, and elevated concentrations of inflammatory mediators. [1][2][3] Trimethoprim-sulfamethoxazole (TMP-SMX) is regularly prescribed to children with CF for treatment of infection by various Gram-negative and Gram-positive bacteria colonizing their airways. Common reactions to TMP-SMX affect the skin and the gastrointestinal tract in children.…”

The importance of hapten–protein complex formation in the development of drug allergy

“…Importantly, individual T cell clones can be activated specifically by sulfamethoxazole or nitroso sulfamethoxazole. The parent drug interacts directly with HLA or T cell receptors or both, whereas the nitroso metabolite acts as a hapten and activates T cells via covalent modification of HLA bound peptides and non-HLA associated proteins [26][27][28][29]. Recently, we have shown in cystic fibrosis patients with allergy to sulfamethoxazole that the antigen-specific T cell response is directed exclusively towards nitroso sulfamethoxazole [29].…”