Stimulation of the immune system by small chemicals can be independent of hapten-protein conjugate formation and is regulated by the TCR avidity for the HLA-drug complex (106.51)

Abstract

Abstract Rationale: The antiretroviral drug abacavir (abc) elicits a strong CD8-mediated immune response in HLA-B*5701+ subjects. We used this model to study the interaction of small chemicals with the immune system. Methods: We generated abc-specific T-cell clones (abc-TCC) from HLA-B*5701+ donors and analyzed their specific activation in Ca2+ influx assays and by annexin V staining. Results: Abc-metabolizing enzymes were absent in immune cells and inhibition of the proteasome in antigen presenting cells did not affect TCC reactivity. Five out of 50 abc-TCC reacted instantly (~120 sec) to soluble abc presented on HLA-B*5701, whereas many other TCC reacted after 20 min or later. Increasing the number of HLA-B*5701/abc immunogenic complexes by increasing the abc concentrations and/or using transfected cells with a high HLA-B*5701 expression accelerated the abc-TCC activation kinetic. Analysis of several abc-TCC revealed different TCR Vβ-segments, demonstrating their polyclonality. Conclusions: Since the observed abc-reactivity was metabolism- and processing- independent, an immune activation by small chemicals can occur without covalent drug binding to a carrier protein. Moreover, titration experiments revealed different TCC reactivity patterns. This finding suggests a crucial role of the TCR avidity for the drug in regulating T cell activation. These data have implications in drug regulation of the immune system as well as for understanding drug hypersensitivity.