However, not all drugs seem to capable of interacting covalently with proteins, and some immune reactions to drugs occur without antigen processing. This has to led the pharmacological interaction or p-i hypothesis, whereby some chemically inert drugs are able to bind non-covalently to antigen-presenting structures such as the T cell receptors or HLA and cause stimulation directly of an immune response, as is the case with sulfamethoxazole. Most drugs have been designed to fit into protein pockets in receptors and enzymes. The drugs interaction with the receptors is highly specific such that small changes in drug structure can affect reactivity. T cell activation can occur rapidly, before metabolism and processing of the drug could occur. However, the reactions that occur are the same as those induced by a drug-modified peptide antigen, because the immune response once activated proceeds in a fixed way. The hypothesis could explain why reactions can sometimes occur without known previous sensitization.
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