A T-cell response to the anti-arthritic drug penicillamine in the mouse: requirements for generation of the drug-derived antigen

Abstract

Mice primed with the anit-arthritic drug D-penicillamine (DP) developed DP-specific T cells in the draining lymph nodes (DLN) which responded to drug-haptenated stimulator cells, but not to untreated control cells nor to free drug, in in vitro proliferation assays. The responder cells were CD4+ and the response was major histocompatibility complex (MHC) class II restricted. The conditions required to generate efficient stimulator cells for in vitro proliferation assays were investigated. Drug-haptenated syngeneic spleen cells, but not thymocytes, were able to stimulate T cells from DP-sensitized mice. However, prolonged incubations of spleen cells with DP were required to generate the drug-derived T-cell antigen. Further experiments revealed that the generation of a DP-derived antigenic determinant for T cells did not require intracellular processing, as stimulator cells pretreated with fixative or lysosomotropic agents before drug haptenation were as effective as untreated DP-haptenated cells in stimulating the responder cells to proliferative in vitro. These findings show that the protein-reactive drug DP can generate a cellular antigen that is capable of stimulating a T-cell response. Furthermore, the generation of this antigen appears to bypass conventional antigen processing, suggesting perhaps a direct chemical modification of cell surface molecules that are involved in immune recognition. This process may underlie adverse reactions to DP that are believed to be mediated by the cellular immune system.